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BACKGROUND: Rhesus (Rh) disease and extreme hyperbili-
rubinemia (EHB) result in neonatal mortality and long-term
neurodevelopmental impairment, yet there are no estimates
of their burden.
METHODS: Systematic reviews and meta-analyses were
undertaken of national prevalence, mortality, and kernicterus
due to Rh disease and EHB. We applied a compartmental
model to estimate neonatal survivors and impairment cases
for 2010.
RESULTS: Twenty-four million (18% of 134 million live births
≥32 wk gestational age from 184 countries; uncertainty range:
23–26 million) were at risk for neonatal hyperbilirubinemia-
related adverse outcomes. Of these, 480,700 (0.36%) had either
Rh disease (373,300; uncertainty range: 271,800–477,500) or
developed EHB from other causes (107,400; uncertainty range:
57,000–131,000), with a 24% risk for death (114,100; uncer-
tainty range: 59,700–172,000), 13% for kernicterus (75,400),
and 11% for stillbirths. Three-quarters of mortality occurred in
sub-Saharan Africa and South Asia. Kernicterus with Rh disease
ranged from 38, 28, 28, and 25/100,000 live births for Eastern
Europe/Central Asian, sub-Saharan African, South Asian, and
Latin American regions, respectively. More than 83% of survi-
vors with kernicterus had one or more impairments.
CONCLUSION: Failure to prevent Rh sensitization and man-
age neonatal hyperbilirubinemia results in 114,100 avoidable
neonatal deaths and many children grow up with disabilities.
Proven solutions remain underused, especially in low-income
countries.
Neonatal hyperbilirubinemia and jaundice occur in almost
all newborns (1–10) and may be benign if its progression
to extreme hyperbilirubinemia (EHB; total bilirubin (TB)
>428 μmol/l in full-term babies) is recognized, monitored,
and prevented or managed in a timely manner. Major risk fac-
tors include neonatal hemolysis (such as Rhesus (Rh) disease),
glucose-6-phosphate dehydrogenase (G6PD) deciency, infec-
tions, and an array of familial and genetic disorders. In addi-
tion to conditions such as preterm birth that make the neonate
more susceptible to bilirubin neurotoxicity, suboptimal breast
milk intake or dehydration may also contribute to EHB (1–10).
At present, once the early stages of hyperbilirubinemic brain
damage occur, therapeutic options are limited to the prompt
(<8 h) use of exchange transfusion, hence the imperative for
preventive approaches. Universal prenatal Rh screening for
specic risk of perinatal hemolysis and its prophylaxis with Rh
immunoglobulin have been highly eective practices for pre-
venting neonatal morbidities and mortality (11–14). Countries
with universal access to perinatal health services have virtually
eliminated severe hyperbilirubinemia (icterus gravis neona-
torum), which had been so common in the late 19th century
(15–28).
Now with emerging aordable technologies, the world-
wide prevention and management of newborn jaundice can
more feasibly reach those at risk even in low-income settings
(1,2,29–31). Yet, there remains a paucity of quality population
data on the prevalence of hyperbilirubinemia and related out-
comes to inform such a strategy for most countries (8).
In the absence of direct national or regional reporting, we
report systematic estimates for the prevalence, mortality, and
neurodevelopmental outcomes of Rh disease and EHB due
to other causes, e.g., G6PD deciency, prematurity, neonatal
hemolysis, and idiopathic causes. We based these estimates, as
doi:10.1038/pr.2013.208
1Programme for Global Paediatric Research (PGPR), Hospital for Sick Children, Toronto, Ontario, Canada; 2Division of Neonatal and Developmental Medicine, Department of
Pediatrics, Stanford University School of Medicine, Lucile Packard Children’s Hospital, Stanford, California; 3Faculty of Epidemiology and Population Health, London School of
Hygiene & Tropical Medicine, London, UK; 4Saving Newborn Lives/Save the Children, New Delhi, India; 5Keenan Research Centre, Li Ka Shing Knowledge Institute & Department
of Paediatrics, St. Michael’s Hospital, Toronto, Ontario, Canada; 6Department of Pediatrics, Aalborg University Hospital, Aalborg, Denmark; 7Department of Health Policy,
National Center for Child Health and Development, Tokyo, Japan; 8Center for Global Pediatrics, University of Minnesota, Minneapolis, Minnesota; 9Department of Pediatrics,
Kasr Al Aini University, El Mounira Children’s Hospital, Cairo, Egypt; 10WHO Collaborating Centre for Training & Research in Newborn Care, All India Institute of Medical Sciences,
New Delhi, India; 11The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, The People’s Republic of China; 12Nigerian Society of Neonatal Medicine, Lagos,
Nigeria; 13Federal University of São Paulo-UNIFESP, São Paulo, Brazil; 14Center for Healthy Start Initiative, Lagos, Nigeria; 15Post Graduate Institute of Medical Education and
Research, Chandigarh, India; 16Centre for Maternal Reproductive & Child Health, London School of Hygiene & Tropical Medicine, London, UK; 17Saving Newborn Lives/Save the
Children, Washington, DC. Correspondence: Vinod K. Bhutani (Bhutani@stanford.edu)
Neonatal hyperbilirubinemia and Rhesus disease of the
newborn: incidence and impairment estimates for 2010 at
regional and global levels
Vinod K. Bhutani1,2, Alvin Zipursky1, Hannah Blencowe3, Rajesh Khanna4, Michael Sgro5, Finn Ebbesen6, Jennifer Bell1,
Rintaro Mori7, Tina M. Slusher1,8, Nahed Fahmy9, Vinod K. Paul10, Lizhong Du11, Angela A. Okolo12, Maria-Fernanda de Almeida13,
Bolajoko O. Olusanya14, Praveen Kumar15, Simon Cousens4 and Joy E. Lawn16,17
Pediatr Res
00
00
2013
Pediatric Research
10.1038/pr.2013.208
00Month2013
74
s1
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00Month2013
Copyright © 2013 International Pediatric Research Foundation, Inc.
Beyond survival: burden of kernicterus
Bhutani et al.
Articles
Open
Beyond Newborn Survival Paper 6
86 Pediatric RESEARCH Volume 74 | Number s1 | December 2013 Copyright © 2013 International Pediatric Research Foundation, Inc.
Beyond survival: burden of kernicterus Articles
described below, on national risks of G6PD deciency, preterm
birth, neonatal hemolysis (not due to Rh disease), and other
idiopathic causes, along with measures of the implementation
gap for universal Rh prophylaxis.
METHODS
Denitions and Measurements
Inconsistent use of denitions and management approaches limit the
use of available data at both national and global levels. We used the
following denitions shown in Figure 1, starting from perinatal risk
factors, outcomes in terms of mortality, and then impairments (hear-
ing loss and neurodevelopmental impairment, including choreoath-
etoid cerebral palsy).
Rh disease or Rh hemolytic disease is dened by maternal–fetal Rh
(D) antigen incompatibility and the consequences associated with
maternal sensitization (see Web appendix I-iii for details and ref-
erences). is was the most common and severe cause of fetal and
neonatal hemolysis in Europe and the United States until about
60 y ago; it is now rare in countries where Rh prophylaxis is used.
Women whose erythrocytes are Rh (D)-antigen negative are sensi-
tized (develop anti-Rh (D) antibodies) during a previous pregnancy
in which the fetus is Rh (D)-positive or by exposure to Rh antigens
from blood products/transfusion. Severe hemolytic disease mani-
fests in utero as progressive anemia and hypoalbuminemia, leading
to anasarca (edema) and heart failure (hydrops fetalis), resulting in
stillbirths or early neonatal deaths. Surviving infants can present with
severe jaundice, anemia, and death from kernicterus or brain damage
resulting from EHB. ese complications can be treated with timely
exchange blood transfusions. In most high-income countries, Rh dis-
ease has been eradicated by coordinated obstetrical and neonatal care
(32). ese prenatal interventions require expert assessment, use of
Rh immunoprophylaxis, and diagnosis of fetal anemia, early signs of
cardiac failure, or hydrops, in addition to the timely use of intrauter-
ine transfusion to correct hemolytic anemia.
G6PD deciency is an X-linked inherited enzymopathy (33–40).
G6PD deciency is widespread (450 million people). ere are vari-
able data regarding the distribution of individuals at risk for neonatal
hemolytic crisis due to G6PD deciency, partly due to diverse assay
methods for enzyme activity or genetic identication and timing of
the assay in relation to postnatal and chronological ages. Recent popu-
lation migration, sample size, and validity of the surveys also limit the
accurate representation of a national prevalence (34). Existing pub-
lished data highlight important limitations due to the use of summa-
rized national levels that can mask subnational variations. Accurate
(phenotypic) quantitative identication of decient G6PD enzyme
activity by spectrophotometry is a measure of the condition soon
aer birth. However, variations due to both partial phenotypic mani-
festations of diverse genetic mutations and the high enzyme activity
of younger red blood cells are signicant confounding factors. DNA/
polymerase chain reaction screening for specic mutations is ideal
to identify female heterozygotes, but this approach is limited by the
diversity of known variants and the occasional mismatch with pheno-
typic expression of enzyme activity. More recently, Luzzatto et al. (37).
have suggested estimation of G6PD deciency allele frequency to pre-
dict and generate population-weighted estimates of aected popula-
tion. Howes et al. (33). have used this approach to propose a Bayesian
geostatistical model adapted to the gene’s X-linked inheritance that
circumvents the above-mentioned limitations to assess national prev-
alence. ere is paucity of data to estimate a neonate’s risk for G6PD
deciency following exposure to aggravating triggers that may cause
unpredictable adverse consequences (35).
Prematurity: Preterm birth is any birth before 37 completed wk of
gestation (<259 d since the rst day of the woman’s last menstrual
period) (41,42). Further subdivisions based on completed GA are
as follows: late preterm (34 to <37 wk); moderately preterm (32 to
<34 wk); and very preterm (<32 wk). e incidence of kernicterus in
1955, i.e., before the clinical use of phototherapy, was 10.1, 5.7, 3.2,
1.1, and 0.8% for infants at 30, 31–32, 33–34, 35–36, and >36 wk GA,
respectively (43). We limited our analysis to the group of preterm
births of >32 wk GA because preterm births <32 wk handle hyperbili-
rubinemia dierently, and according to International Classication of
Diseases rules, deaths and disability in this group should be allocated
to preterm birth as the primary condition to address, so we will not
include these here to avoid double counting the burden along with
those included in preterm birth direct complications.
Clinical State and Outcome Denitions
EHB is dened as total plasma/serum bilirubin >25 mg/dl (428
µmol/l) or those treated with exchange blood transfusion (44).
Kernicterus or CBE has been used as a clinical diagnosis that relies
on a history of excessive prolonged hyperbilirubinemia and classical
abnormalities of muscle tone, movement disorders, and aberrant pro-
cessing disorders (26,45,46). Acute signs of extrapyramidal dysfunc-
tion may precede CBE. Acute bilirubin encephalopathy (31) includes
progressive changes in an infant’s mental (behavioral) status, muscle
tone, and distinct cry patterns. Acute clinical signs, initially described
in 1955 by Crosse et al. (43), are as follows: “the rst 24 to 48 hours of
life are the most critical. Signs develop in a baby who is jaundiced…
and include head retraction, an expressionless facies, usually with
oculogyric movements, changes in muscle tone, cyanotic attacks,
refusal to suck, vomiting and hemorrhage prior to death. In severe
cases these signs are self-evident but in those less aected they are eas-
ily missed …. unless specically sought.” “Several babies who showed
minimal signs have proved to be denite cases of kernicterus.” us,
neonatal mortality is due to respiratory failure and progressive coma
or intractable seizures. An increased signal on magnetic resonance
imaging of the globus pallidus and other areas prone to bilirubin neu-
rotoxicity is oen evidenced in surviving infants. Posticteric clinical
sequelae include irreversible, but static, classic signs of athetoid cere-
bral palsy, generalized dystonia, paralysis of upward gaze, “kernicteric
facies,” and sensorineural hearing impairment. Neuromotor impair-
ment secondary to abnormal muscle tone includes dystonia that is
characterized by excessive or sustained contraction of opposing
muscles during voluntary movements, in addition to hypertonia or
hypotonia. Painful muscle cramps, incoordination of sucking, swal-
lowing, and visuomotor function may manifest during early infancy.
Cerebral palsy with choreoathetosis is another classic manifestation
of kernicterus, which is characterized by involuntary movements or
irregular muscle contractions that manifest as writhing or twisting.
Paroxysmal movement disorders are oen misdiagnosed and labeled
as seizures. Hearing impairment is dened by sensorineural abnor-
malities ascertained by objective tests. Auditory system abnormalities
with hyperbilirubinemia primarily involve brainstem nuclei, leading
to abnormalities in auditory brainstem responses and detected by
referred hearing screens during infancy. Auditory neuropathy, also
called ‘‘auditory dyssynchrony,’’ is oen subtler and associated with
childhood hearing impairment (47–52). Developmental delay or cog-
nitive impairment, ascertained by the Bayley Mental Developmental
Index, provides continuous variables to dene the extent of aberra-
tions for mental and psychomotor indexes. In addition, infants’ intel-
ligence can be estimated or tested for intelligence quotients of <70
using the Wechsler Intelligence Score for Children (47). Cognitive
impairment has been reported and possibly related to associated
hearing impairment, neuromotor impairment, or, possibly due to
social neglect. Other posticteric sequelae may result from subtle signs
either with exposure to TB levels that are lower than EHB or following
partial treatment of EHB. ese “so” perturbations of sensory pro-
cessing disorders have been described as the syndrome of bilirubin-
induced neurologic dysfunction or “BIND” (53) but are intentionally
not included in this study due to the limited data and consensus in
denitions found in the literature.
Data Searches for G6PD Deciency and Preterm Birth, With
Eects on Neonatal Mortality, EHB, and Kernicterus
Systematic reviews of the main electronic literature databases (Ovid
Medline, Ovid Medline In-Process and Non-Indexed Citations,
PubMed, Cinahl, Global Health, Scopus, and Popline) were under-
taken using a combination of medical subject heading and free text
words. Search terms used were exchange blood transfusion, kernic-
terus/bilirubin encephalopathy, death (from jaundice), phototherapy,
G6PD deciency, ABO incompatibility, Rh incompatibility, admission/
Copyright © 2013 International Pediatric Research Foundation, Inc. Volume 74 | Number s1 | December 2013 Pediatric RESEARCH 87
Articles Bhutani et al.
readmission (for jaundice), sequelae, impairment, and outcomes.
Reference lists of all the relevant studies were scanned to further iden-
tify studies of interest. We excluded case reports, nonhuman studies,
those that did not have the relevant population or age group, those
that did not focus on the relevant condition (jaundice, hyperbilirubi-
nemia, and encephalopathy), and those that did not provide relevant
primary data (e.g., for prevalence/risk). In addition, we conducted a
retrospective review of the historic Rh disease literature, commencing
from identication as a clinical disease to the period Rh disease was
considered “conquered.” Pivotal studies, cited in Appendix I, allowed
for estimation of mortality and disease among survivors. We also iden-
tied population-based studies before the use of phototherapy, which
reported on the outcome of systematic use of phototherapy. Due to
rapid improvement in the access to and quality of specialized/intensive
newborn care in countries with low-mortality settings, for mortality,
encephalopathy, and long-term impairment risk, we decided to focus
on recent literature only and extracted data from studies with birth
cohorts having median year of 2005 or later. Where sucient data
were available, standard meta-analysis techniques were used to obtain
pooled estimates of the relevant parameter’s risk, which included
EHB-related neonatal mortality and bilirubin encephalopathy (acute
and/or chronic). Heterogeneity across studies was evaluated using I2
and χ2 tests, and where evidence of heterogeneity was present (I2 > 70%
or P < 0.05), a random-eects model was used.
Data Searches for Rh Disease
A systematic review of the published literature using PubMed was
performed to establish the prevalence of Rh-negative blood groups by
country for all countries with NMR >5. Countries with NMR <5 were
presumed to have good Rh prophylaxis and strong health systems,
with very low number of cases of Rh disease in these countries. Search
terms included “rh, rh blood-group system” (medical subject head-
ing term), “Rhesus,” and “Blood group.” Reference lists of all the rel-
evant studies were scanned to further identify studies of interest and
Web-based resources were searched using Internet search engines.
For countries with no available data, the prevalence of Rh-negative
blood groups was estimated using the regional median prevalence
(Web appendix I-iii).
A further systematic review using PubMed (search terms included
combinations of “Rhesus,” “rhesus disease,” “erythroblastosis fetalis,”
“rhesus h(a)emolytic disease of the newborn,” “outcome,” “neonatal
death,” and “stillbirth”) was undertaken to estimate the outcome of Rh
disease in the absence of eective treatment and limited to primary
studies published before 1960 and to reviews without date limitations.
Pooling of Data by Country Context and Access to Neonatal
Services
Data were not available to estimate every parameter for every country.
Hence, we sought to use pooled data from countries that are simi-
lar in their access to and quality of care as these are closely linked
to outcomes. Outcomes of EHB depend on a systematic approach
to prevention and management of hyperbilirubinemia. We grouped
countries into three NMR bands (NMR/1,000 live births) as follows:
Group 1 (NMR <5), Group 2 (NMR 5 to <15), and Group 3 (NMR
≥15), which approximate to high-, middle-, and low-income coun-
tries, respectively. Where data were available, we sought to further
distinguish the outcomes between those with access to specialized
neonatal care if required (including phototherapy and exchange
blood transfusion) and those with basic/limited care only at home or
in a facility with no access to these specialized services because this
will aect the mortality and kernicterus outcomes.
Modeling Approach
A three-step compartmental model was constructed for each country
with at least 10,000 live births for the year 2010 (54,55) as follows: Step
1) estimation of the number of cases based on the prevalence of G6PD
deciency, late-preterm birth, and other causes of EHB, not due to Rh
disease, in addition to estimating the prevalence of Rh disease; Step 2)
estimation of the number of stillbirths, neonatal deaths, and cases of
kernicterus by applying the risk data to the estimated cases; and Step3)
estimation of the numbers of survivors with neurodevelopmental
impairment (Figure 2). All results are presented by regional grouping
according to the Global Burden of Disease Study Group superregions
Figure 1. Schematic representation of the prenatal and neonatal risk factors for Rhesus (Rh) disease and extreme hyperbilirubinemia and their impact on still-
births, neonatal death due to kernicterus, and long-term impairment of kernicterus during childhood. In view of the complex conuence of biological risk, inter-
action with other childhood disease, and social–cultural factors, we did not estimate childhood death due to kernicterus. ABE, acute bilirubin encephalophathy.
Pregnancy Neonatal period
Neonatal deathStillbirth
Childhood &
adulthood
Childhood death
Neurological (motor and
movement disorders) with
sensori-processing issues
Hearing impairment:
Sensori-neural hearing
loss, auditory neuropathy,
and auditory dys-
synchrony
Cognitive and
developmental
impairment
Rh disease
estimate: Rh
sensitization
of a pregnant
Rh-negative
female
Others
estimated:
Familial G6PD
deficiency and
risk of
preterm birth
Others
(combined):
Prenatal risk of
ABO incompatibility,
inherited red cell or
genetic disorders,
etc. “Idiopathic”
Increased risk for those born preterm,
with sepsis, perinatal asphyxia, birth
trauma (home delivery). Influenced by
gender and timely access to health
services
Hydrops fetalis,
severe hemolysis,
anemia, EHB, and/
or acute bilirubin
encephalopathy
Death due to
respiratory
failure, seizures,
or other signs of
ABE or
complications of
exchange
Chronic bilirubin
encephalopathy
Post-icteric signs
onset, often
during infancy
Normal
development
Impairment
Uncomplicated
88 Pediatric RESEARCH Volume 74 | Number s1 | December 2013 Copyright © 2013 International Pediatric Research Foundation, Inc.
Beyond survival: burden of kernicterus Articles
(56,57) (Appendix II). We quantied the uncertainty surrounding
these estimates by taking 1,000 random draws of the input parameters
at each step, assuming a normal distribution with mean equal to the
point estimate of the parameter and SD equal to the estimated SE of
the parameter (55). We summed the data at the worldwide or regional
level for each draw and present the 2.5th and 97.5th percentiles of the
resulting distributions as the uncertainty range.
RESULTS
We identied 23,145 relevant titles for the non-Rh disease causes
of EHB. Of these, 2,599 abstracts and 185 pertinent publications
were selected for full text review. Sixty-two studies (from 30
countries) were screened; 26 met the criteria to provide popula-
tion source for occurrence of kernicterus (acute and/or chronic)
and/or kernicterus-associated neonatal mortality (Web appendix
I-vii). We used the observational cohort of 41,324 infants born
without Rh disease who were recruited for a multicenter study in
the United States in 1959–1975 (58). Extrapolation of these data
to the 134 million live births yielded the result that 1.1 million
(0.8%) worldwide would develop TB >20 mg/dl (342 µmol/l),
214,400 would progress to TB >25 mg/dl (428 µmol/l), and a
total of 1,648,200 newborns would undergo exchange transfu-
sions. Studies excluded because of reported implementation of
routine bilirubin screening showed that prophylactic use of pho-
totherapy in 6.6 ± 1.3% (95% condence interval (CI): 4.4, 8.7)
of live births >34 wk gestational age (GA) (3,59–61) drastically
reduced the need for exchange transfusions.
Step 1: Estimation of Prevalence
Rh hemolytic disease prevalence. Postpartum Rh immuno-
globulin administration has been standard therapy for many
years in high-income countries and Rh hemolytic disease has
been virtually eradicated. Countries with a neonatal mortal-
ity rate (NMR) <5 were therefore presumed to have good Rh
prophylaxis and strong health systems, with very few cases of
Rh disease. It is likely that there are lapses in universal immu-
noprophylaxis in some of these countries. However, there are
inadequate data to estimate the number of protection failures
and the numbers would be small in the global perspective;
therefore, our focus was on countries with an NMR >5.
Process: e prevalence of Rh-negative blood group was esti-
mated by country (see Methods and Web appendix I-iii) and
the total births for 2010 were calculated as the sum of live births
(54) and stillbirths (estimated assuming no change in stillbirth
rates from 2009 to 2010) (62). ese were used to estimate the
total number of pregnancies in Rh-negative women in 2010.
e number of Rh-positive babies born to those women was
calculated knowing the Rh positivity prevalence in the fathers
(i.e., the prevalence of Rh positivity in the country). For an
Rh-positive baby to be born to an Rh-negative mother, it must
receive at least one Rh allele (positive) from an Rh-positive
father. e number of Rh-positive pregnancies represents the
number of women who should have received Rh immunoglob-
ulin prophylaxis postpartum. e number of women who did
Figure 2. Schematic representation of the three-compartmental model. This model delineates the serial steps toward input of country-specic param-
eters, processes, and outputs to estimate prevalence, burden of Rhesus (Rh) disease and extreme hyperbilirubinemia–related mortality, and the number
of postneonatal survivors with kernicterus and long-term impairment. A/CBE, acute/chronic bilirubin encephalophathy.
Prevalence of risk
factors Among
live births
Step 1 Step 2 Step 3
Country-specific
data
Rh+ve babies
born to Rh−ve
mothers
Rhesus
hemolytic
disease of
the newborn
Rhesus or EHB
related neonatal
death
Hearing
impairment
Neuro-motor
impairment
Cognitive
impairment
Impaired
survivors
Postneonatal
survivors with
kernicterus
Asymptomatic
survivor
Kernicterus
(A/CBE)
Non-Rhesus
EHB
Number
with EHB
and/or Rh
disease
G6PD
Preterm
(32–36
weeks)
None of these
3 risk factors
Live births
by risk
factor
group
Output Process
Coverage of
anti-D
prophylaxis
Risk of
mortality or
kernicterus
Risk of mortality or
kernicterus
Risk of impairment
Risk of EHB
(TB>425 µmol/l)
Parameters
Meta-analyses of data by level of care and NMR group Based on Canadian
population-based data
Neonatal case
fatality and
kernicterus risk
Risk of EHB and/or
Rhesus disease
Access to
care
Risk of long-term
adverse outcomes
Copyright © 2013 International Pediatric Research Foundation, Inc. Volume 74 | Number s1 | December 2013 Pediatric RESEARCH 89
Articles Bhutani et al.
receive prophylaxis is based on information on the worldwide
distribution of Rh immunoglobulin preparations, obtained
through the courtesy of e Marketing Research Bureau
(http://marketingresearchbureau.com/; Orange, CT), which
has tracked the plasma markets since 1974 through interviews
with public organizations and private rms, governmental and
nongovernmental organizations, trade associations, patient
groups, and opinion leaders. us, we determined the num-
ber of women who did not receive postpartum protection. Of
those unprotected women, it was previously calculated that
15% would develop Rh isoimmunization and their anti-Rh
antibodies would enter the circulation of their next baby (11).
We calculated the risk of a second baby being Rh positive from
the prevalence of the Rh positivity of the father. is risk fac-
tor was modied because the fathers in the second pregnancy
do not account for the Rh-negative men who could have been
fathers in the rst pregnancy.
ese serial calculations required several assumptions, lim-
iting their absolute accuracy. As will be noted, this results—for
the most part—in an underestimation of the severity of the bur-
den. First, all calculations are based on two Rh-positive preg-
nancies; however, in many countries, the fertility rate (average
number of babies per woman) is as high as 7.0; in Nigeria, e.g.,
in 2010, it was 4.9. With each successive Rh-positive pregnancy,
the prevalence of Rh immunization increases. Prevalence data
for Rh negativity were not available for all countries and within
countries too, they varied. Accordingly, regional median esti-
mates were applied. Second, it is likely that in many countries
where Rh immunoglobulin is available, there are many fail-
ures of protection. Our calculations are based on the assump-
tion that all the Rh immunoglobulin distributed in a country
was used postpartum. at means that none was used during
pregnancy or posttermination of pregnancy/miscarriage or
for other medical indications and that each vial was used as
a single dose and not divided for multiple recipients. Last, we
have not included in our calculations that blood type A, B, O
incompatibility reduces the likelihood of Rh isoimmunization
(Tabl e 1).
Outcome: In 2010, an estimated 373,300 babies were
aected with Rh hemolytic disease worldwide. Data inputs are
detailed descriptions by country in the Web appendix I-iv. e
global estimated prevalence for Rh disease was 276/100,000
live births. Prevalence for specic regions such as Southeast
Asia/Pacic countries, Latin America, North Africa/the
Middle East, South Asia, sub-Saharan Africa, and Eastern
Europe/Central Asia is estimated at 57, 252, 278, 385, 386, and
529/100,000 live births, respectively. ese data are in contrast
to Rh disease prevalence of 2.5/100,000 live births in coun-
tries that have well-established health-care infrastructure that
includes coordinated perinatal–neonatal care for virtually all
pregnancies.
Prevalence of Risk Factors for EHB
G6PD deciency prevalence. Process: Country-specic preva-
lence for overall G6PD deciency was obtained from (i) a geo-
statistical model reported for 97 endemic malaria countries (33);
(ii) pooled estimates of ≥3 studies for each of these six countries
(Croatia, Cyprus, Greece, Italy, Spain, and the United States)
and the studies had used diverse methodologies to assay G6PD
deciency; (iii) regional estimates from Nkhoma et al. for the
remaining 81 countries (33,34) (Table 2 , Web appendix I-ii).
Howes et al. (33) have provided the most recent report, a con-
tinuous evidence-based prevalence and estimate of the aected
population that represents a national risk for countries endemic
to malaria. Unlike the Nkhoma report (34), the G6PD deciency
phenotype was identied and then used to model the genotype
for these countries (35). Prevalence was generally lower across
Central and Southeast Asia compared with that in sub-Saharan
Africa (usually <20%) but accounted for >60% of the aected
general population.
Moderate- and late-preterm birth (32 to <37 wk gestational
age) prevalence. Process: Prevalence of preterm birth rates
by country was obtained from the data reported by Blencowe
et al. (41). e study estimated that 84% of all preterm births
occurred aer 32 completed wk of gestation.
Estimation of risk for nonpreterm neonates without G6PD
deciency or Rh disease. Process: e population at risk of
EHB but without any of the three quantied EHB risk factors
Table 1. Summary of input data on the prevalence of Rh disease,
Rh disease–associated mortality, and bilirubin encephalopathy
(kernicterus)
Summary of input data on the prevalence of Rhesus disease for countries
with NMR >5a (all calculations are based on two pregnancies per
Rh-positive woman; see Web appendix I-iii)
Step 1 Country prevalence of Rh negativity
Data from 55/138 countries
Estimate based on regional medians for countries with
no data
An estimated 6.24 million births to Rh-negative women in
these countries
Coverage of maternal anti-Rh (anti-D) immunoprophylaxis
Data available from 43 countries
For countries with no data available, it was assumed that
no Rh prophylaxis was available.
Risk of Rh isoimmunization in pregnant women without
prophylaxis (11)
15.0% (uncertainty range: 13.3–19.1%)
Outcome of pregnancies affected by Rh diseaseb
Step 2 Stillbirths (23): 13.9% (95% CI: 12.6–15.3%)
Neonatal deaths (16): 23.8% (95% CI: 14.5–36.6%)
Survivors with kernicterus (20,23): 7.2% (95% CI: 3.8–11.2%)
CI, confidence interval; NICU, neonatal intensive care unit; NMR, neonatal mortality rate;
Rh, Rhesus.
aAssuming universal availability of comprehensive pre- and postnatal treatment to
prevent adverse outcomes in those with failure of anti-D immunoprophylaxis in 46
countries with NMR <5, estimates were undertaken only for remaining countries.
bAssuming no availability of pre- or postnatal treatment such as intrauterine
monitoring, correction of anemia, exchange blood transfusion, or phototherapy for
progressive hyperbilirubinemia.
90 Pediatric RESEARCH Volume 74 | Number s1 | December 2013 Copyright © 2013 International Pediatric Research Foundation, Inc.
Beyond survival: burden of kernicterus Articles
Table 2. Summary of input data on the prevalence of risk factors, risk of EHB, neonatal mortality, and kernicterus in 2010 by NMR levels for non-
Rh-related EHB
Groupings
Countries according to NMR levels in 2010
NMR <5 NMR 5 to <15 NMR ≥15
184 countries 46 63 75
Live births 13 million 41 million 80 million
Step 1 Birth prevalence for specific risk factors
Input data: geostatistical model estimates (Howes et al. (33)) from 89 countries and regional pooled estimates
(Nkhoma etal. (34)) from 95 countries (see Web appendix I-ii).
Input data for preterm birth estimates from “Born Too Soon” (41)
30 countries 28 countries 41 countries
415 data sets 187 data sets 136 data sets
Preterm births Preterm births Preterm births
Sample = 11.0 million Sample = 5.2 million Sample = 1.9 million
Median: 6.8% Median: 5.9% Median: 8.5%
Range: 4.1–16.4% Range: 3.1–19.5% Range: 3.5–28.5%
Gestational age subdivisions: 345 data points
32–36 wk: 84.3% (95% CI: 84.1–84.5%)
Risk of EHB
In term babies without G6PD deficiency or Rh disease:
1 Country, 1 data set (Canada: phototherapy used to prevent EHB in widespread use)
n (babies with no risk factor) = 582,592
Risk = 0.038% (95% CI: 0.033–0.043%)
Increased risk in babies without access to phototherapy to prevent EHB (59)
Increased risk = 2.45 (95% CI: 1.44–4.16)
Overall risk = 2.45 × 0.038% = 0.093% (uncertainty range: 0.033–0.163%)
In babies with G6PD deficiency
1 Country ; 1 data set
n (G6PD-deficient babies) = 15,168
Risk = 0.132% (95% CI: 0.085–0.20%)
(Relative risk = 3.5)
Increased risk in babies without access to phototherapy to prevent EHB (59)
Increased risk = 2.45 (95% CI: 1.44–4.16)
Overall risk = 2.45 × 0.132% = 0.323% (uncertainty range: 0.082–0.669%)
In preterm births (32 to <37 wk)
1 Country ; 1data set
n (preterm births) = 42,240
Risk = 0.045% (95% CI: 0.029–0.070%)
(Relative risk = 1.20)
Increased risk in babies without access to phototherapy to prevent EHB (58)
Increased risk = 2.45 (95% CI: 1.44–4.16)
Overall risk = 2.45 × 0.045% = 0.110% (uncertainty range: 0.025–0.231%)
Step 2 Risk of mortality in infants with EHB with access to treatment
3 studies 2 studies 16 studies
n (deaths) = 8 n (deaths) = 10 n (deaths) = 144
Pooled mortality risk: 2.4%
(95% CI: 0–5.8%)
Pooled mortality risk: 8.2%
(95% CI: 3.3–13.1%)
Pooled mortality risk: 16%
(95% CI: 10.2–21.9%)
Risk of mortality in infants with EHB with no access to treatment
Not applicable 1 study, United Kingdom, 1952 (19)
n (deaths) = 18
Mortality risk: 31.6% (95% CI: 21.0–44.5%)
Risk of kernicterus in EHB survivors with access to treatment
6 studies 6 studies 15 studies
n (survivors with kernicterus) = 1,498 n (survivors with kernicterus) = 134 n (survivors with kernicterus) = 366
Pooled risk: 23.0% (95% CI: 9.9–36.1%) Pooled risk: 35.0% (95% CI: 12.0–58.0%) Pooled risk: 43.8% (95% CI: 25.5–62.1%)
Risk of kernicterus in EHB survivors with no access to treatment
Not applicable 1 study, United States, 1950s (20)
Risk: 50.0%
Uncertainty range: 36.1–63.9%
CI, confidence interval; EHB, extreme hyperbilirubinemia; NMR, neonatal mortality rate.
Copyright © 2013 International Pediatric Research Foundation, Inc. Volume 74 | Number s1 | December 2013 Pediatric RESEARCH 91
Articles Bhutani et al.
(G6PD deciency, Rh disease, or prematurity) was obtained
mathematically by subtracting the sum of the live births with
each risk factor from the total population of live births. is
subgroup includes infants with risk of undierentiated, but
major, causes of EHB: neonatal hemolysis (including ABO
incompatibility and other red blood cell disorders) and an
increasingly recognized array of idiopathic causes (Tabl e 2).
Risk of EHB. Process: Two sets of population studies from
Canada and Denmark (63–69) provided data on the num-
ber who develop EHB and listed causes for EHB (excluding
Rh disease because of eective national Rh prophylaxis pro-
grams). We requested Sgro and Ebbesen to provide additional
unpublished data to clarify the prevalence for G6PD deciency
and preterm births in a comparable EHB cohort. We relied on
the Canadian data (66–68) to inform prevalence data estimate
because the population and causes of jaundice were more
heterogeneous than that in the Danish data (63–65,69). e
combined Canadian and Danish data set includes unpublished
data on outcomes at age >2 y and EHB data for preterm neo-
nates. In the absence of data from other settings, the same risk
was applied to all countries. As these studies were undertaken
in populations with low rates of infection and intrauterine
growth restriction, with access to full prenatal screening and
comprehensive neonatal care including prophylactic interven-
tions with phototherapy and/or exchange blood transfusion,
the risk of EHB is likely to be lower than that in settings without
such access. In particular, for the “global” preterm baby, much
of the increased risk of EHB is due to its increased infection
vulnerability. In this supplement, to avoid double counting
the long-term impairment in these babies, this burden has
been included under infection (70). We sought to adjust for
the eect of access to phototherapy and the risk of EHB using
data for babies of >2 kg weight from a trial of phototherapy
to reduce hyperbilirubinemia, where babies without access to
phototherapy had 2.45 times the risk of developing EHB (58).
From the Canadian data, we estimated the global risk of EHB
without any of the three risk factors and assuming an average
2.37% G6PD prevalence reported in military recruits in the
United States (36) and extrapolated it to the Canadian data;
we calculated the risk of EHB in G6PD-decient babies to be
0.13%, as shown in Tab l e 3. To estimate the EHB prevalence
due to G6PD deciency, we assumed an equivalent biological
risk across the dierent countries and regions and applied this
risk to the prevalence of G6PD deciency in each country to
calculate the population of G6PD-decient babies who would
develop EHB.
e Canadian population–based study also reported 19cases
of EHB in preterm babies 34 to <37 wk gestation (66–68). is
gives a EHB risk of 0.045%, assuming that 6.6% of live births
are late preterm in Canada (Tabl e 3). is presents a likely
underestimation of the risk because of the following: (i) pre-
cise denitions for EHB are not available for preterm infants
and bilirubin-associated neurological damage is likely to occur
Table 3. Outcome of acute kernicterus (bilirubin encephalopathy) in two high-income countries
Canada Denmark Combined
Study period 2007–2008 2000–2007 —
Number of live births 740,000 502,766 (GA ≥35 wk) 1,242,766
Total cases of kernicterus (total prevalence per live birth) 20 3 23
(1.8/100,000)
Peak TB Mean: 568 μmol/l 651,734,986 μmol/l 429–986 μmol/l
Peak TB range 429–795 μmol/l
Presenting with acute kernicterus (prevalence/live births) 14 3 severea17 (74%)
(1.4/100,000)
Developmental follow-upb
Hearing impairment (abnormal ABR) 14/17 3/3 17/20 (85%)
(95% CI: 64.0–94.8%)
Abnormal MRI 16/18 1/3 17/21 (81%)
Follow-up at ≥2 y of age 14 3 17/23 (74%)
Developmental delay 11 3 14/17 (82.4%)
(95% CI: 59.0–93.8%)
Choreoathetosis or dystonia (cerebral palsy) 5 3 8/17 (47.1%)
(95% CI: 26.1–69.0% )
Normal development 3 0 3/17 (17.7%)
(95% CI: 6.2–41.0%)
Other neurodevelopmental issues 4 0 4/17 (23.5%)
(95% CI: 9.6–47.3%)
Data are provided, courtesy of Michael Sgro and Finn Ebbesen (63–68), who searched their databases that have previously been reported, and complemented with additional
information as shown above (see Web appendix I-vi for details).
ABR, auditory brainstem response; GA, gestational age; TB, total serum/plasma bilirubin.
aTwo other milder cases were reversible. bIncludes those with known outcome only.
92 Pediatric RESEARCH Volume 74 | Number s1 | December 2013 Copyright © 2013 International Pediatric Research Foundation, Inc.
Beyond survival: burden of kernicterus Articles
at lower levels than in term babies; and (ii) because there were
no surveillance data to quantify the risk of EHB in premature
babies GA 32 to <34 wk, we assumed the risk to be the same as
in those of GA 34 to <37 wk.
EHB outcome: Globally, we estimated that of the 11 mil-
lion (uncertainty range: 11–12 million) babies born at risk for
G6PD deciency, an estimated 27,000 cases of EHB occurred
in G6PD-decient babies. Latin America, South Asia, and
sub-Saharan Africa account for 2, 33, and 47% of the G6PD-
decient infants with EHB, respectively, for a combined
prevalence of 28/100,000 live births. is is in contrast with
high-income nations that account for 2.2% of global burden of
EHB due to G6PD deciency, with a prevalence of 5/100,000
live births.
We estimated that of the 13 million (uncertainty range: 12–
14 million) babies born at GA 32–37 wk, at least 10,000 devel-
oped EHB. Latin America, sub-Saharan Africa, and South Asia
account for 4, 32, and 39% of the EHB cases, respectively, for a
combined prevalence of 10/100,000 live births. is is in con-
trast with high-income nations where the 4% moderate and
late-preterm live births have an EHB prevalence of 3.5/100,000
live births.
We estimated that of the remaining 111 million babies born
at GA >36 wk, at least 70, 000 developed EHB that would be
attributed to undierentiated causes but we combined occur-
rence of EHB due to neonatal hemolytic and/or idiopathic
conditions, but unrelated to Rh disease.
Global prevalence of EHB and Rh disease. We estimated
that 373,300 live births (uncertainty range: 271,800–477,500)
in 2010 were aected by Rh disease (277/100,000 live births;
Tabl e 4) and 107,400 live births by EHB due to other causes:
10% moderate and late preterm (8/100,000 live births); 25%
G6PD (20/100,000 live births); and 66% due to other hemo-
lysis/idiopathic causes. e majority of the total EHB and Rh
disease (80%) occurred in those born in countries with NMR
>15 that account for 60% of the global live births.
Step 2: Estimation of Postneonatal Survivors From Rh Disease
and EHB
Rh disease–related mortality and kernicterus. Process: It was
assumed that infants born with Rh disease without the ben-
et of prenatal screening and coordinated Rh prophylaxis and
intensive treatment (such as serial middle cerebral velocity
measurements, recognition and correction of fetal anemia,
timing for safe birthing, and postnatal treatment with exchange
transfusion or phototherapy) would have an outcome similar
to that reported by investigators before the 1950s (before the
availability of exchange blood transfusion and phototherapy)
for neonatal mortality and before 1970 for stillbirth outcomes
(Web appendix I-v).
Walker described a large series of newborns with Rh
disease and reported the stillbirth rate at 14% (23). is is
consistent with a smaller study where 13% of noninduced
pregnancies aected with Rh disease were stillborn (19).
e reported neonatal mortality in live births aected by Rh
disease was 32% (24/75) in a series from the United States
during the period 1928–1945 (15), which is consistent with
the results in other retrieved studies (Web appendix I-v). As
noted by Vaughan in 1950 (16), these results are not com-
parable because the population denominator included only
clinical cases before the advent of serological testing in the
early 1940s and because the numerator frequently included
the composite measure of adverse outcome (kernicterus or
death) and not death only. In view of these limitations, we
used only the 1945–1946 data on live birth outcomes from
the Boston Hospital (16), where the population denominator
included all cases diagnosed serologically, including mild or
subclinical cases, and where it was possible to estimate the
mortality rate without including the kernicterus survivors.
Because our outcome of interest was the risk of neonatal
death out of all births in Rh-sensitized pregnancies (includ-
ing stillbirths), we adjusted the denominator (assuming the
stillbirth rate in the population to be 14%, as above) and
estimated that 24% of all Rh-immunized pregnancies would
result in neonatal deaths.
In Walker’s large series of pregnancies aected with Rh
disease, 33% of newborns required no treatment (23).
Wehave assumed that 14% of Rh disease pregnancies will
result in stillbirths and 24% in neonatal deaths and that the
remaining 29%, who require treatment, will have severe
hyperbilirubinemia. Hsia et al. (20) reported that 50% of
untreated infants whose peak TB reached >513 μmol/l
(30 mg/dl) developed kernicterus, consistent with observa-
tions made by Mollison and Walker (19). We assumed that
50% of babies with Rh disease and hyperbilirubinemia would
reach a level greater than 30 mg/dl (513 µmol/l) in keeping
with the clear indication for exchange transfusion for babies
with Rh disease (as described by Walker) to prevent kernic-
terus. Overall, we estimated 7.2% of all Rh disease–aected
Table 4. Estimated cases of Rh disease and EHB due to other causes grouped by country NMR levels
NMR group (per 1,000 live births)
Moderate and
late preterm
G6PD
deficiency
None of
three risk
factors
EHB (non-
Rh disease)
EHB uncertainty
range: low to high Rh disease
Rh disease
uncertainty
range: low to high
<5 500 700 4,400 5,600 4,800–6,600 0
5 to <15 1,600 3,000 16,200 20,800 16,500–23,400 69,600 50,700–89,000
≥15 8,100 23,100 49,800 81,000 34,800–102,700 303,600 221,000–388,000
Worldwide total 10,200 26,900 70,300 107, 400 57,000–131,000 373,300 271,800–477,500
EHB, extreme hyperbilirubinemia; G6PD, glucose-6-phosphate dehydrogenase; NMR, neonatal mortality rate; Rh, Rhesus.
Copyright © 2013 International Pediatric Research Foundation, Inc. Volume 74 | Number s1 | December 2013 Pediatric RESEARCH 93
Articles Bhutani et al.
infants who survived had developed subsequent kernicterus
(Tabl e 1).
Non-Rh disease EHB mortality and kernicterus adjusted for
access to neonatal care. Process: We estimated the number
of babies with EHB and/or Rh disease who develop acute
kernicterus or die in the neonatal period. e risk for acute
(ABE) and chronic bilirubin encephalopathy (CBE; ker-
nicterus) was calculated together to avoid overreporting of
cases because many articles had given gures for both with-
out specifying how many babies had both ABE and CBE. If
individual data were listed for ABE and CBE (kernicterus),
we chose the higher value for our analysis (Table 2 and We b
appendix I-v).
Outcome in countries with “good” access to neonatal care
(NMR <5): In these countries, almost all babies requiring care
would have access to specialized facilities. e risk of bilirubin
encephalopathy in this group was estimated from six relevant
articles from four countries (71–75), and it included a large
cohort study with 7-y follow-up from the United States (76).
e pooled risk of encephalopathy was 23.0% (95% CI: 9.9,
36.1). On the other hand, the pooled mortality data using two
data sets specically from the United States from among the
three pooled data sets showed a bilirubin encephalopathy rate
of 2.4% (95% CI: 1.0, 5.8).
Outcome in countries with “intermediate” access to neona-
tal care (NMR 5 to <15): In this group, the majority of the
population would have access to neonatal intensive care unit
(NICU) care, but the quality of care may be variable. A small
proportion would have no access to NICU care or treatment.
Pooling results from six studies conducted in NICU set-
tings yielded an encephalopathy risk of 35.0% (95% CI: 12.0,
58.0) for those with access to NICU care, whereas the aver-
age NMR derived from two studies was 8.2% (95% CI: 3.3,
13.1). For the small proportion of population with basic or
no access to health care, risks of encephalopathy and neona-
tal mortality derived from the “marginal access” countries
were applied.
Outcome countries with “limited” access to neonatal care:
is group of countries has the largest and most heteroge-
neous population, with around 50 million home births with
no care, facility births with some care, and a limited number
of urban or richer families with variable access to NICU care.
We used extensive work published elsewhere to estimate the
access to care within these countries (55) (Web appendix II-ii).
e neonatal kernicteric mortality for NICU care was esti-
mated by pooling results from 16 studies (eight countries) that
included ten countries from Africa. e pooled mortality risk
was 16.0% among infants with EHB (95% CI: 10.2, 21.9%). In
those without any access to care, we conservatively selected a
mortality of 35% based on a study conducted in the late 1940s,
when treatment options were limited to exchange blood trans-
fusion at specialized centers. For the risk of encephalopathy at
the NICU level, 15 facility-level data sets from seven countries
were available, and the pooled estimate was 43.8% (95% CI:
25.5, 62.1).
Global estimate of mortality associated with Rh disease and
EHB due to other causes. ere were 114,000 neonatal deaths
associated with these conditions in 2010 (85/100,000 live births
Figure 3. Number of stillbirths (due to Rhesus (Rh) disease; white bars) and neonatal deaths/100,000 live births due to kernicterus (black bars) for all live
births in 2010. These data are shown for regional geographic distribution. Regional categorization of countries is consistent with the global burden of
diseases (54,55).
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
Number of neonatal deaths with extreme hyperbilirubinemia
and Rh disease and stillbirths (due to Rh disease)
40,000
45,000
50,000
High-income
countries
East and
Southeast Asia/
Pacific
Eastern
Europe/
Central Asia
Latin
America/
Caribbean
North Africa
and Middle
East
South Asia Sub-Saharan
Africa
94 Pediatric RESEARCH Volume 74 | Number s1 | December 2013 Copyright © 2013 International Pediatric Research Foundation, Inc.
Beyond survival: burden of kernicterus Articles
(22% or 25,000 deaths with EHB, uncertainty range: 10,000–
36,000). ere were 89,000 deaths (78%) associated with Rh
disease (uncertainty range: 42,000–151,000). Eastern Europe/
Central Asia, Latin America, sub-Saharan Africa, and South
Asia account for 6, 7, 35, and 39% of the deaths, respectively,
for a combined prevalence of 119/100,000 live births compared
with 0.1% (n = 94; prevalence 1/100,000 live births) in high-
income countries (Figure 3).
Global estimated risk of stillbirths due to RH disease. We
estimated 52,000 stillbirths due to Rh disease (Figure 3). To
investigate the contribution of EHB and/or fetal Rh disease,
we relied on data reported from high-income countries from
an era before universal Rh immunoprophylaxis. It is unusual
for non-Rh disease EHB to present with fetal manifestations.
Stillbirths are less likely in pregnancies at risk for EHB without
Rh disease. However, we are underestimating both stillbirths
and neonatal deaths for remote communities or nations in
conict.
Global estimates of number of babies with kernicterus. ere
were 75,400 cases (uncertainty range: 43,200–95,800) that
represent 24% of the surviving 314,700 neonates with EHB
and Rh disease who developed kernicterus, for a prevalence
of 56/100,000 live births. Figure 4 illustrates the contributory
causes of newborn jaundice that led to kernicterus. ere were
48,500 (64%) and 26,900 (36%) cases of kernicterus associ-
ated with non-Rh EHB and Rh disease, respectively. Eastern
Europe/Central Asia, Latin America, sub-Saharan Africa, and
South Asia account for 3.8, 5.8, 35, and 37% of the kernicterus
cases, respectively, for a combined prevalence of 73/100,000 live
births, compared with 1.6% (n = 1,193; prevalence 10/100,000
live births) from high-income countries.
Step 3: Estimation of Impairment due to Kernicterus
Global estimate of survivors with NDI following kernicterus.
e estimated risk of long-term impairment among survivors,
globally, is shown in Figure 5. We based the risk on a recently
published systematic review and data provided by Sgro and
Ebbesen (63–68), which are more specic than those previ-
ously provided by Ip et al. (6). We assumed a constant biologic
risk and applied this risk of impairment to all the survivors of
kernicterus regardless of the level of care and mortality setting
because the eect of bilirubin encephalopathy is not reversible (a
global prevalence of 56/100,000 live births) and hence estimated
the number of impaired survivors with long-term impairment
according to specic global regions (Tab le 5 and Figure 6).
DISCUSSION
Our study is the rst to provide global estimates of Rh dis-
ease and EHB, in addition to the resulting burden, in terms
of deaths and impairment. Every year, ~24 million pregnan-
cies and their babies are at risk worldwide. e global burden
of EHB and Rh disease is disproportionately heavy for the
poorest countries: 11-fold higher for infants born in countries
with NMR >15 compared with those with NMR <5 (384,600
vs. 5,600 live births aected, with prevalence of 480 vs. 42 per
100,000 live births). e outcomes are aected by lack of both
preventive services and care (Figure 5).
Of the 480,700 live births at risk of Rh disease, 24% were at
risk of neonatal death (114,100; uncertainty range: 59,700–
172,000), 13% at risk for kernicterus (75,400; uncertainty range:
Figure 4. Estimated rates of kernicterus (per 100,000 live births). Data are presented and attributed to cause of hyperbilirubinemia due to prematurity
by yellow bars; G6PD deciency by green; hemolytic and idiopathic conditions by blue; and Rhesus (Rh) disease by red. These are shown for regional
geographic distribution worldwide using global burden of diseases (GBD) categorization (54,55).
High-income
countries
0.00
5.00
10.00
15.00
20.00
Estimated rate of kernicterus per 100,000 liverbirths
25.00
30.00
35.00
40.00
East and
Southeast Asia/
Pacific
Eastern
Europe/
Central Asia
Latin
America/
Caribbean
North Africa/
Middle
East
South Asia Sub-Saharan
Africa
Copyright © 2013 International Pediatric Research Foundation, Inc. Volume 74 | Number s1 | December 2013 Pediatric RESEARCH 95
Articles Bhutani et al.
43,200–95,800), and 11% for stillbirths. Yet, knowledge of Rh
disease has been iconic for more than 6 decades and means for
its prevention have been established for more than 40 y. ere
has been an egregious failure to prevent Rh sensitization and its
adverse consequences worldwide. e global “know–do” gap
can only be bridged if nations assume their responsibility to
address these disparities in maternal–child health care. Barriers
include low attention to this issue, poor dissemination of evi-
dence-based tools for eective Rh disease prevention, and high
cost for the currently available immunoprophylaxis. In addition,
prevention and management of EHB is even more neglected.
Our study exposes the variations in risk, and hence national
data are important for eective health service planning.
Currently, these newborns are born into the following three
very dierent worlds, reecting a transition from high neo-
natal mortality to preventable disability in otherwise-healthy
newborns:
1. Countries with higher NMR (≥15) are at the highest
risk for neonatal mortality due to Rh disease and EHB.
Here, reduction in Rh sensitization and better care of
every newborn, including management of EHB when
needed, is an urgent implementation priority. e
challenge is to provide unfettered and aordable access
to Rh immunoprophylaxis and reach those in remote
regions or those dispersed in areas of conict and post-
conict settings.
2. Emerging countries with lower NMR (5 to <15) that
exhibit variations in the quality of care, with vari-
able penetration of a systems approach for maternal
and newborn care, including for Rh disease and EHB
management. e management and prevention of
Rh sensitization appears to have penetrated clinical
practice, but it does not seem to be universal. On the
other hand, EHB burden is vastly underestimated for
preterm birth, G6PD deciency, and unrecognized
neonatal hemolysis. In addition, causes for underly-
ing neonatal mortality are erroneously labeled and
not attributed to kernicterus, which leads to further
underestimation of its disease burden. Here, there
is an urgent need to strengthen neonatal screening
and delivery services and to focus on the outcome of
impairment-free survival.
Figure 5. Outcomes for Rhesus (Rh) disease–aected pregnancies and
extreme hyperbilirubinemia (without Rh disease). aStillbirths due to non-
Rh disease have not been estimated or included.
Impaired outcome
at 2 years
13%
Neonatal death
with kernicterus
24%
No kernicterus or
requirement for
exchange
transfusion
(presumed normal
outcome)
50%
Stillbirth
(Rh disease)a
11%
Normal outcome
at 2 years
2%
Table 5. Global distribution of long-term impairment following kernicterus
GBD region (live births)
Hearing
loss (ABR) Low–high
Developmental
delay Low–high
Athetoid
cerebral
palsy Low–high
Other
neurological
disability Low–high
Normal
outcome Low–high
High-income countries
(11,693,000)
1,000 (9) 500–
1,600
1,000 (8) 500–
1,600
600 (5) 200–
1,000
300 (2) 0–600 200 (2) 0–500
East, Southeast Asia
and Pacific (29,021,000)
6,600 (23) 3,800–
8,700
6,400 (22) 3,600–
8,700
3,600 (12) 1,600–
5,600
1,800 (6) 0–3,600 1,400 (5) 0–3,100
Eastern Europe/
Central Asia (5,358,000)
2,500 (46) 1,400–
3,700
2,400 (45) 1,300–
3,700
1,400 (25) 600–
2,400
700 (13) 0–1,500 500 (10) 0–1,200
Latin America and
Caribbean (9,855,000)
3,700 (38) 2,100–
5,300
3,600 (36) 2,100–
5,100
2,100 (21) 900–
3,400
1,000 (10) 0–2,200 800 (8) 0–1,800
North Africa and
Middle East (9,665,000)
4,000 (42) 2,400–
5,200
3,900 (41) 2,300–
5,100
2,200 (23) 1,000–
3,500
1,100 (12) 0–2,200 800 (9) 0–1,900
South Asia
(37,103,000)
23,900 (64) 12,200–
31,100
23,100 (62) 12,200–
30,500
13,200 (36) 5,200–
20,500
6,600 (18) 0–13,000 5,000 (13) 0–11,000
Sub-Saharan Africa
(32,068,000)
22,500 (70) 11,700–
30,200
21,800 (68) 11,100–
29,400
12,400 (39) 5,100–
19,800
6,200 (19) 0–12,700 4,700 (15) 0–10,500
Worldwide total
(134,762,000)
64,100 (48) 36,000–
83,300
62,100 (70) 35,200–
81,800
35,500 (26) 15,000–
155,500
17,700 (13) 0–36,000 13,300 (10) 0–29,000
All numbers rounded to the nearest 100. Parenthetical data in columns 2–10 represent prevalence per 100,000 live births. Data in italics represent uncertainty. Bolded data represent
estimates of worldwide total.
ABR, auditory brainstem response; GBD, global burden of diseases.
96 Pediatric RESEARCH Volume 74 | Number s1 | December 2013 Copyright © 2013 International Pediatric Research Foundation, Inc.
Beyond survival: burden of kernicterus Articles
3. High-income countries, with NMR <5, have achieved
both a near elimination of neonatal mortality associ-
ated with kernicterus and reductions in impairment.
Here, a better identication of postnatal hemolysis and
improved management of idiopathic etiologies remain
as challenges.
Our estimates suggest that Rh disease accounts for the
majority of the total global EHB burden (uncertainty range:
271,800–477,500). Although it should be underlined that our
study vastly underestimates the burden of EHB because we
excluded cases of extreme preterm birth (<32 wk GA) and
those with infections to avoid double counting with the bur-
den estimates for those conditions because a neonatal death
in a very preterm neonate or in one with severe infection and
jaundice but no clear cause of hemolysis would be attributed to
preterm birth or infections as a cause of death by International
Classication of Diseases rules. In addition, given the lack of
population-based risk data, we relied on estimates of risk from
one low-mortality context in Canada for preterm birth, G6PD
deciency, and unrecognized neonatal hemolysis, including
ABO incompatibility, which will be much lower than the real-
ity in many other countries (Tabl e 2).
Estimates from high-income nations reveal benign out-
comes for most infants aected by Rh disease. For example,
kernicterus mortality trends in the United States from 1979
to 2006 used data from the US National Center for Health
Statistics of 108,888,600 live births; the crude kernicterus
death rate was estimated at 0.28 (95% CI: 0.25, 0.40) with a sig-
nicantly higher risk in males (28). In the same retrospective
review of kernicterus among children born from 1988 to 1997
in California, the time trend data estimated an incidence of
0.44 cases (95%CI: 0.28, 0.65) per 100,000 annual live births.
Incidence of EHB due to conditions other than Rh disease
following systematic prevention of Rh disease in the United
States, for 4 decades before 2004 was estimated at a preva-
lence of 169/100,000 live births (76) and has now declined to
40/100,000 live births through implementation of a systems
approach (71). Unlike in the United States, the Rh disease bur-
den remains extraordinarily high among countries with NMR
≥5 and overshadows EHB due to other causes.
Lack of Unfettered Access to Neonatal Services and Risk of
Impairment
e “screen and prevent approach,” which implements a sys-
tems approach, has started to transform the EHB burden, par-
ticularly in countries with NMR <10. e current prevalence
of EHB-related mortality in nations with good access to neo-
natal services (>90% access to NICU) compared with those
having marginal care (a combination of basic and NICU care)
shows extraordinary disparity. Data availability and inconsis-
tent denitions varied, with the least data coming from the
highest-burden settings. From a global perspective, we esti-
mate that among countries with NMR >15, infants with EHB
were least likely to be admitted to a facility where they can
receive the required specialized and coordinated perinatal-
NICU care. Overall, 46/100,000 live births (83% of survivors
with kernicterus) were estimated to have long-term neurode-
velopmental impairment (Tab l e 5). Our estimates of 36,000
cases of cerebral palsy (uncertainty range: 15,000–55,000)
globally is undoubtedly an underestimate because of our
reliance on the Canadian data for risk of impairment, apart
from the exclusion of those with extreme preterm birth and
infections. Indeed, a newborn who is preterm, with infection
Figure 6. Number of infants with major impairments due to kernicterus as presented for hearing loss (white bars) and athetoid cerebral palsy (black
bars). Data shown for all live births in 2010 are shown for regional geographic distribution. Regional categorization of countries is consistent with the
global burden of diseases (54,55).
High-income
countries
East and
Southeast Asia
Pacific
Eastern
Europe/
Central Asia
Latin America/
Caribbean
North Africa
and Middle
East
South Asia Sub-Saharan
Africa
0
5,000
10,000
15,000
20,000
25,000
30,000
Number of adverse neurologic experiences with
extreme hyperbilirubinemia and Rh disease
Copyright © 2013 International Pediatric Research Foundation, Inc. Volume 74 | Number s1 | December 2013 Pediatric RESEARCH 97
Articles Bhutani et al.
and jaundice, is at the highest risk of impairment (77). Here,
South Asia and sub-Saharan Africa were estimated at 26,000
(37/100,000) vs. 560 cases (5/100,000 live births) from high-
income countries (approximately an eightfold higher bur-
den). Low coverage and the quality of pre- and postnatal
coordination for “health services” is specically exemplied
by the ineective Rh immunoprophylaxis in low- and middle-
income countries. e transition of health services in certain
Eastern Europe/Central Asian countries illustrates the high
prevalence of Rh sensitization, but a much lower prevalence
of Rh disease adverse outcomes, compared with the situation
in South Asia and sub-Saharan Africa.
Data Limitations
Presently, no single replicable test exists to further measure
the risks for EHB. Hence, we sought to estimate burden as
conservatively as possible, including ABO incompatibility in
other causes of EHB because ABO hemolytic disease alone
has not been shown to cause neonatal death (1,6,8,27). A
recent retrospective review suggests a statistically signicant
interaction between a positive Coombs test, EHB, and lower
intelligence quotient during childhood (61), but more popu-
lation-based data are needed to dene the magnitude of this
risk. G6PD deciency prevalence data are limited, especially
regarding dened enzyme level activity adjusted for gender.
Adverse exacerbations by exposures to drugs, toxins, infec-
tions, and dietary agents add to the unpredictable risk of
EHB due to G6PD deciency (35) and are underestimated
in our study due to reliance on the risk data from Canada
alone. e EHB risk among late and moderate preterm birth
we applied was minimal (about 5% or less) because we used
a very high bilirubin threshold to dene EHB and the risk
from the Danish and Canadian data, which are in the con-
text of very high–capacity neonatal care. Adjustment for
risk for developing bilirubin neurotoxicity among preterm
infants is more complex (2). us, we believe that we have
signicantly underestimated the prevalence of neonatal
hemolysis, G6PD deciency, and prematurity-related EHB.
Similarly, race and ethnicity oen aect bilirubin elimina-
tion disorders due to an array of genetic conditions masking
as idiopathic factors (1,2). In developing nations, vulner-
ability to EHB continues to be confounded by comorbidi-
ties that include sepsis, intrauterine growth restriction, and
unscreened inborn errors. We also did not study infants who
received an exchange blood transfusion at lower TB values
in the absence of acute kernicterus, those who were too
moribund to receive an exchange blood transfusion, or for
whom there were no resources to perform the procedure.
We did not include children with the subtler form of biliru-
bin-induced neurologic dysfunction, and hence the results
presented are likely to be an underestimate of the total bur-
den of impairment following hyperbilirubinemia. In view of
insucient data and the likely preponderance of newborn
female discrimination at birth and gender-selective referrals
to tertiary care, we elected to forgo the highlighting of gen-
der dierences in our model.
Data Improvement and Programmatic Implications
Coupled with promotion of maternal and newborn care,
inclusion of essential newborn care—particularly breastfeed-
ing—and better care of preterm babies, including kangaroo
mother care and safer management of neonatal jaundice, are
key to public policies that engender better neonatal survival,
improved long-term development, and reduced disability (78).
Important “know–do” gaps that need attention include the
following:
1. Primary prevention, especially operationalizing sys-
tems strategies, including national identication of all
Rh-negative women before or during pregnancy and
ensuring that they receive Rh immunoprophylaxis
postpartum and ideally at the 28th wk of pregnancy
with coordinated obstetric and neonatal care. is will
necessitate building partnerships with families and
mobilizing community awareness.
2. Secondary prevention through care of aected pregnan-
cies and neonates, harnessing and implementing aord-
able and proven-eective technologies for identication
of and improved newborn care, as being promoted by
the Every Newborn Action Plan (79).
3. Tertiary prevention through early identication and
care of aected survivors to address long-term medical
and scholastic impairments among those exposed to
severe hyperbilirubinemia.
4. Improved data and use of data, including consistent
denitions of risk and outcomes to be measured during
routine data collection and in special cohort studies.
Conclusions
e failure to prevent Rh sensitization and manage EHB results
in the global burden of neonatal hyperbilirubinemia falling
most heavily on the world’s poorest countries, especially in
South Asia and sub-Saharan Africa. Knowledge gained to pre-
vent Rh disease 6 decades ago in high-income countries has
not been consistently implemented. e very fact that we are
forced to rely on data from Europe and the United States, now
70 y old, shows the low priority given to this condition. Global
and national leadership is needed to mobilize action and
embed proven systems approaches, policies, and programs to
substantially and sustainably reduce newborn deaths and dis-
ability, including jaundice-related mortality and disabilities.
ACKNOWLEDGMENTS
Global Prevent Kernicterus Network: Lois Johnson (USA); Martin Castillo
Cuadrado (Life Science Research Assistant, Stanford University); Ronald J.
Wong (Stanford University); Iman Seoud and Iman Iskander (Cairo, Egypt);
Hameed Numan Alhamdani (Baghdad, Iraq); Joshua Owa (Ife-Ife, Nigeria);
Priscilla Joe (Children’s Hospital of Oakland, CA); Margaret Manley (PGPR),
Adam Miller (PGPR), Sharmilaa Kandasamy (Research Coordinator, Inner
City Health Research, St. Michael’s Hospital, Toronto, Ontario, Canada), and
Judith Stanke, Tara Zamora, Kathleen Warner, Elizabeth Keating, and Shane
Richardson (University of Minnesota).
STATEMENT OF FINANCIAL SUPPORT
The study was funded in part by the March of Dimes Prematurity Research
Center at Stanford University School of Medicine. This article is published
98 Pediatric RESEARCH Volume 74 | Number s1 | December 2013 Copyright © 2013 International Pediatric Research Foundation, Inc.
Beyond survival: burden of kernicterus Articles
as part of a supplement sponsored by The Bill and Melinda Gates Founda-
tion to the Child Health Epidemiology Reference Group (CHERG) through
the US Fund for UNICEF and to Save the Children’s Saving Newborn Lives
program.
Disclosure: V.K.B. has received grant support from the National Institutes of
Health (NIH). H.B. and S.C. have received grant support from the Bill and Me-
linda Gates Foundation through the Child Health Epidemiology Reference
Group. T.S. has received grant support from the NIH and Thrasher Research
Fund. J.L. has received grant support from the Bill and Melinda Gates Foun-
dation through Save the Children’s Saving Newborn Lives program. The au-
thors declared no conict of interest.
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