Seminars in Fetal & Neonatal Medicine 20 (2015) 2e5

Contents lists available at ScienceDirect

Seminars in Fetal & Neonatal Medicine

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

Review

Impact of Rhesus disease on the global problem of bilirubin-induced

neurologic dysfunction
Alvin Zipursky a, Vinod K. Bhutani b, *
a
Centre for Global Child Health, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada
b
Department of Pediatrics, Division of NeonatalPerinatal Medicine, Stanford University School of Medicine, Stanford, CA, USA

s u m m a r y
Keywords: Clinical experience with Rhesus (Rh) disease and its post-icteric sequelae is limited among high-income
Rhesus disease countries because of nearly over four decades of effective prevention care. We hypothesized that Rh
Bilirubin-induced neurologic dysfunction
disease is prevalent in other regions of the world because it is likely that protection is limited or non-
(BIND)
Minor neurologic dysfunction
existent. Following a worldwide study, it has been concluded that Rh hemolytic disease is a signicant
Bilirubin public health problem resulting in stillbirths and neonatal deaths, and is a major cause of severe
Subtle bilirubin injury hyperbilirubinemia with its sequelae, kernicterus and bilirubin-induced neurologic dysfunction.
Knowing that effective Rh-disease prophylaxis depends on maternal blood-type screening, healthcare
afforded to the high-risk mothers needs to be free of bottlenecks and coupled with unfettered access to
effective Rh-immunoglobulin. Future studies that match the universal identication of Rh-negative
status of women and targeted use of immunoprophylaxis to prevent childhood bilirubin neurotoxicity
are within reach, based on vast prior experiences.
2014 Published by Elsevier Ltd.

1. Introduction high-income countries by the prophylactic use of Rh immuno-

The unacceptable occurrence of neonatal Rhesus (Rh) disease
and kernicterus are emblematic of a fractured or a fragile maternal
child healthcare system. Such disruptions in healthcare are most
likely in lowmiddle-income countries (LMICs) or in regions in
conict. A safer seamless transition from birthing facility to home,
including systems-based prevention of Rh disease, is crucial in
preventing stillbirths, perinatal adverse outcomes including brain
damage and death [15]. Earlier experiences and knowledge of the
knowdo gaps have illustrated the bottlenecks in public health-
care systems in emerging markets. The conclusion of these experts
is that innovative strategies and affordable technologies can over-
come existing social and access barriers in micro- and macro-health
environments in order to provide adequate screening for (and in
turn prevent) Rh disease [611].
Rh-hemolytic disease of newborn infants (referred to herein as
Rh disease) occurs in the Rh-positive newborn infants of Rh-
negative mothers. The disease has been virtually eliminated in
* Corresponding author. Address: Stanford Children's Health, Lucile Packard
Children's Hospital at Stanford, 750 Welch Ave, Palo Alto, CA 94305, USA. Tel.: 1
650 723 5711; fax: 1 650 497 7724.
E-mail address: bhutani@stanford.edu (V.K. Bhutani).
globulin given to the mother during the last trimester of pregnancy
and at postpartum. However, we have recently determined that Rh
disease is still a major public health problem in developing coun-
tries [6], a major cause of severe hyperbilirubinemia as well as a
cause of stillbirths and neonatal deaths. These estimates are also
corroborated by clinical reports from several nations (see Table 1).
However, there were no signicant epidemiological publica-
tions describing the incidence of this disease in LMICs. To this end,
we developed an indirect method of determining the incidence of
Rh disease. It was assumed that Rh disease would occur in countries
in which no Rh immunoglobulin prophylaxis was being used. We
were assisted in this regard by the Marketing Research Bureau of
Orange, CT (USA), which maintains a worldwide inventory of the
manufacturing and distribution of all plasma products including Rh
immunoglobulin. With the help of Mr Patrick Roberts of that
company, we obtained information on the amount of Rh immu-
noglobulin distributed annually to all countries worldwide. Using
those data together with information on the annual number of
births and the prevalence of Rh negativity, we determined the
number of Rh-negative women who did not receive Rh immuno-
globulin and delivered Rh-positive babies, and therefore who were
at risk of developing Rh isoimmunization. Their plasma would
contain anti-Rh antibodies and their next Rh-positive baby would
be at risk of developing Rh disease. An example of the calculations

http://dx.doi.org/10.1016/j.siny.2014.12.001
1744-165X/ 2014 Published by Elsevier Ltd.
 A. Zipursky, V.K. Bhutani / Seminars in Fetal & Neonatal Medicine 20 (2015) 2e5 3

Table 1 Table 3
Reports of Rh isoimmunization (presence of anti-D antibodies in Rh-negative Estimated burden of Rh disease as categorized by neonatal mortality per 1000
pregnancies). livebirths.a

Country Rh-negative pregnancies No. of women Neonatal mortality Rh disease estimated Uncertainty (low to high)
(n reported in the study) immunized (%) per 1000 livebirths burden

India [11] 2180 51 (2.4) <5 <1 e

India [10] 305 27 (8.9) 5 to <15 69,600 50,700 to 89,000
Czech Republic [8] 6815 181 (2.6) 15 303,600 221,000 to 388,000
Turkey [12] 743 65 (8.7) Worldwide Burden 373,300 271,800 to 477,500
Nigeria [13] 280 12 (4.3) a
Data exclude stillbirths [6].
Uganda [14] 72 4 (5.6)
India [15] 270 35 (13)
Thailand [16] 72 7 (10)
deciency, or ABO compatibility. Our data cannot specically esti-
Nigeria [17] 67 6 (9) mate the incidence of bilirubin-induced neurologic dysfunction
Zimbabwe [18] 629 25 (4) (BIND) due to co-morbidities of neonatal diseases, which are more
Zimbabwe [14] 85 4 (4.7) likely seen in countries with a neonatal mortality rate (NMR) >15
Mexico [20] 4857 631 (13)
per 1000 livebirths). These data would be confounded by lack of
Cameroon [21] 225 9 (4)
Iraq [22] 142 7 (4.9) access to care, suboptimal neonatal care, and other neurologic
manifestations. On the other hand, survivors with Rh disease
Percentage of pregnancies that were immunized: 2.4e13%.
Rh-negative pregnancies represent the number of Rh-negative women studied and
probably confound the unusually high incidence of childhood
reported. The number of women isoimmunized (%) represents those women whose neurologic burden reported in these nations.
blood contains anti-D (anti-Rh) antibodies. Rhesus disease is therefore a major problem in many countries
of the world. It should be pointed out, however, that the estimates
used is shown in Table 2 for Pakistan and India. It indicates that in noted above are likely to be underestimations for several reasons.
one year in India and Pakistan, 750,000 and 340,000 mothers, First, we have assumed that in countries in which Rh immuno-
respectively, did not receive protective prophylaxis. globulin is prescribed, compliance with prophylaxis is 100% (this
Fourteen percent of these Rh-negative women will develop anti- may be an unlikely assumption). Second, postpartum treatment
Rh antibodies evident within the rst six months postpartum or will only be 90% protective; additional protection is required using
during their next Rh-positive pregnancy. Prophylaxis with Rh antenatal injections during the last trimester of pregnancy [7].
immunoglobulin delivered within the rst 72 h postpartum will Furthermore, maternal Rh isoimmunization following abortions
reduce the number of women who develop Rh isoimmunization to and miscarriages are not calculated in the above estimate. They also
~1% (i.e. ~90% protection). In view of these calculations, it would represent a risk to the Rh-negative woman [9].
suggest that each year in India and Pakistan, 105,000 and 47,000 All of the above calculations are based on the assumption that
women, respectively, would develop anti-Rh (anti-D) antibodies no therapy had been given. Phototherapy may be of help for the
and, accordingly, their next Rh-positive baby would develop Rh lesser forms of hyperbilirubinemia. It is unlikely to be of benet to
disease. These calculations were extended to all countries and the the rapidly developing hyperbilirubinemia of Rh disease. Of course,
calculated estimate was that each year >350,000 cases of Rh dis- phototherapy would have little effect on babies born with hydrops
ease would occur worldwide. These calculations are also consistent fetalis or heart failure associated with severe Rh disease; exchange
with our reported estimate as listed in Table 3 (by neonatal mor- transfusion would be necessary for those cases. Therapy aimed at
tality rate) and in Table 4 for regions by global designation [6]. reducing stillbirths demands intrauterine diagnosis, early delivery,
As described in our publication [6], the outcome of pregnancies and, for some, intrauterine transfusions. It is unlikely that all these
in which the mother has anti-Rh antibodies is as follows: 33% of the resources will be available in LMICs for some time.
babies will not require treatment; 14% will be stillborn; 24% will The above calculations were also based on indirect evidence
result in death during the newborn period due to kernicterus, regarding the incidence of Rh hemolytic disease in LMICs. The
hydrops fetalis, or related problems. The remaining 29% will literature supplies numerous anecdotal reports of the prevalence of
develop severe hyperbilirubinemia. Drawing on information from Rh isoimmunization [women with anti-Rh (anti-D) antibodies in
the literature [6], it would appear that 50% babies with severe their blood]. These reports are summarized in Table 1 and provide
hyperbilirubinemia would develop kernicterus in the absence of direct evidence that Rh isoimmunization of pregnancy occurs in
sepsis, prematurity, or other perinatal complications that are
prevalent in resource-constrained nations. Using these calcula- Table 4
tions, we estimated that the annual burden of Rh disease world- Global burden of Rh disease among livebirths.a
wide is 41,000 stillbirths, 90,000 neonatal deaths, 97,000 cases of Global designation Live-births Rh disease: mean (IQR)
severe hyperbilirubinemia of which at least 48,000 will survive to
South East Asia/Pacic Islands 29,000,000 16,600 (370)
develop kernicterus. We estimated that annually there were South Asia 37,000,000 143,400 (43,577)
107,400 cases of severe hyperbilirubinemia due to other causes East Europe/Central Europe 5,400,000 28,350 (895)
such as prematurity, glucose-6-phosphate dehydrogenase Hi-income Countries 11,700,000 300
Latin America/Caribbean 9,900,000 34,200 (1697)
North Africa/Middle East 9,700,000 26,900 (2252)
Table 2 Sub-Saharan Africa 32,000,000 123,500 (2462)
Reports from India and Pakistan estimating women at risk and disparity on distri- Worldwide 134,700,000 373,300 (1479)
bution of Rh immunoglobulin (I).a
IQR, interquartile range.
Country Population Women at riskb Rh I unitsc Untreated (%) In infants born in high-income nations, estimates for impairment are based on the
following information. It is predicted that among infants with Rh disease alone, 29%
India 1,147,995,904 984,979 240,000 744,979 (75.6%)
will develop, if untreated, hyperbilirubinemia of which 50% will develop kernicte-
Pakistan 172,800,048 270,000 36,000 234,000 (87%)
rus. Risk estimates in Table 3 of our previous publication [6] provided the per-
a
Adapted from Bhutani et al. [6]. centage of cases with each of the neurologic handicaps. These were used to calculate
b
Rh-negative mothers with an Rh-positive newborn. the total number of cases with neurologic handicap. Impairment data in remainder
c
Amount of Rh immunoglobulin distributed annually in each country (one nations cannot be estimated with reasonable accuracy.
a
unit one prophylactic dose). Data exclude stillbirths [6].
4 A. Zipursky, V.K. Bhutani / Seminars in Fetal & Neonatal Medicine 20 (2015) 2e5
LMICs, indicating that Rh disease of the newborn has or will occur
in their offspring. The incidences shown in Table 1 are likely higher
because in all those studies many of the pregnant women were in
their rst pregnancy in which Rh immunization is quite rare. Also in
many of those countries, Rh immunoprophylaxis was available so
that the reported cases were those who had not received prophy-
laxis. Some of the reports described the severity of the disease in
aficted infants. Singhal et al. [23] described 37 cases of which 21
required exchange transfusion. In a series of six cases from Nigeria
[13], two died, three required exchange transfusions, and one was
stillborn. In Zimbabwe [19], of four cases, two were stillborn and
two required exchange transfusion. A larger series of inborn chil-
dren in one hospital in New Delhi [11] found Rh isoimmunization in
51/2180 of intramural livebirths. Of the 51 children with Rh iso-
immunization, 30 (57.7%) required exchange transfusions and
seven children (13.7%) died.
There is evidence that jaundice due to Rh disease is a more
signicant cause of brain damage than other forms of hyper-
bilirubinemia. For example, a report from Egypt described that in
children with hyperbilirubinemia [24] many had evidence of acute
or chronic neurotoxicity. It was found that the odds ratio (OR) for
the development of brain damage was 48.6 for Rh disease, 21 for
sepsis, and only 1.8 for ABO disease. Singhal et al. [23] also provided
additional evidence of the severity of Rh disease hyper-
bilirubinemia in a series of 454 newborn babies with severe
hyperbilirubinemia. In that series, Rh disease was found to be a
cause of hyperbilirubinemia in 8% of cases, yet 56.8% of the cases
requiring exchange transfusion were due to Rh disease. In that
series, ABO incompatibility was responsible for 14% of cases of
hyperbilirubinemia, but only 28% required exchange transfusions.
These data suggest that Rh disease is the most severe form of
hyperbilirubinemia requiring more frequent exchange transfusions
and at greatest risk of producing brain damage.
In developing countries, another factor affects interpretation of
the data. All of the above calculations have been made assuming
two pregnancies. Following an Rh-positive pregnancy, 14% of Rh-
negative women will develop Rh antibodies evidenced within six
months of delivery or during the next Rh-positive pregnancy. It is
clear that for many developing countries, those estimates may be
low because, in many of those countries, the average number of
pregnancies per woman (the fertility rate) was greater than two. In
Sub-Saharan Africa, the fertility rate varies from 4 to 7. The risk of
isoimmunization increases with each subsequent pregnancy as
shown in Table 5 taken from the article by al-Joudi et al. [22].
Clearly Rh disease is a major cause of hyperbilirubinemia and
kernicterus in LMICs. It is a disease that can and should be pre-
vented. Rh disease has been successfully eliminated in high-income
countries; this success has been a major achievement in medical
care. It is clear that the same benet given to Rh-negative women in
high-income countries should be applied to women in LMICs.
Accordingly, we have established a global program for the elimi-
nation of Rh disease e the Consortium for Universal Rh disease
Elimination (CURhE).
Table 5
Anti-D prevalence with successive pregnancies [22].
Order of pregnancies Rh-negative Pregnancies with anti-D
pregnancies antibodies (%)
First 172 3 (1.7)
Second 142 7 (4.9)
Third 96 21 (22)
Fourth 66 16 (24.2)
Fifth 11 5 (45.4)
2. Need for change
Recognition and treatment of Rh hemolytic disease, an estab-
lished preventable cause of kernicterus, is critical [25,26]. Urgent
need for other appropriate technologies includes tools that enhance,
visual assessment of jaundice, non-invasive bilirubin measurements,
readily available panel of bilirubin tests for hemolysis and blood
typing. In addition, dissemination and access to effective photo-
therapy is crucial with the use of light-emitting diode (LED) devices
[27,28], monitored for strict engineering for safety performance
[29,30]. We estimate that an effective Rh screening and disease
prevention will greatly reduce the need for exchange transfusions.
Some examples of practical solutions to overcome barriers and bot-
tlenecks [31] include: (i) technology barriers at primary/home facil-
ities; (ii) community barriers; and (iii) intervention barriers.
3. Future plans and challenges
These are not just limited to development of novel screening
and prevention technologies, improving access to healthcare or
monitoring global benchmarks of unacceptable neonatal morbid-
ities. Importantly, we need to embed systems maternal childcare
that is accountable to the mother and her family. Of the several
potential fatal or disabling neonatal conditions, newborn jaundice
and its spectrum of severe neonatal hyperbilirubinemia, acute
bilirubin encephalopathy, kernicterus and possibly BIND have
proven and tested evidence for near-ready implementation.
4. Conclusion
Bottlenecks exist in worldwide screening and prevention of Rh
disease that unduly and inappropriately add to neurodevelopmental
disabilities of children exposed to excessive bilirubin. In order to
scale-up optimal maternal and newborn care, effective solutions
exist which may be implemented readily through novel imple-
mentation. Currently, at a recently convened Stakeholders meeting at
the Pediatric Academic Societies, in 2014, there was large academic,
professional, and grass roots commitment to improve care before and
during birth to prevent perinatal deaths and stillbirths, and improve
healthy outcomes by reducing BIND. We have outlined and identied
the availability and quality of screening and prevention approaches
as an important area to achieve the aims of our plan. We now need to
build political, professional, and nancial support to develop and
scale-up solutions to these bottlenecks. As we build momentum, we
seek out and pre-empt local, regional, and national models that are
scalable in view of potential social and cultural barriers.
Practice points
 All pregnant women, worldwide, should ideally be
screened for Rh type and blood groups either prior to or
during pregnancy.
 All Rh-negative mothers should receive Rh immunopro-
phylaxis postpartum, ideally during the third trimester
and following abortion or placental trauma.
 All newborn infants born to an Rh-negative mother (who
is isoimmunized) should be intensively monitored for
onset and progression of jaundice and should have uni-
versal access to bilirubin testing, effective phototherapy,
and to at least a level II neonatal intensive care unit.
 An exchange transfusion as a tertiary neonatal intensive
care should be considered a therapeutic option only when
other forms of therapy fail.
 A. Zipursky, V.K. Bhutani / Seminars in Fetal & Neonatal Medicine 20 (2015) 2e5
Research directions
 Field performance of point-of-care blood typing and
group testing, done at primary health centers, birthing
units and home, should be validated for precision and
accuracy.
 Models that demonstrate the minimization of bottlenecks
to optimal referral to competency-specific neonatal units
should be considered for scale-up for national
implementation.
 Successful implementation should be validated for cost
effectiveness as well as for reduction of both disease and
disability burdens.
Conict of interest statement
None declared.
Funding sources
None.
References
[1] American Academy of Pediatrics. Management of hyperbilirubinemia in the
newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297e316.
[2] Bhutani VK, Maisels MJ, Stark AR, Buonocore G, Expert Committee for Severe
Neonatal Hyperbilirubinemia; European Society for Pediatric Research;
American Academy of Pediatrics. Management of jaundice and prevention of
severe neonatal hyperbilirubinemia in infants 35 weeks gestation. Neona-
tology 2008;94:63e7.
[3] National Institute for Health and Clinical Excellence. Neonatal jaundice. 2010.
uk/CG98, http://www.nice.org.
[4] Bratlid D, Nakstad B, Hansen TW. National guidelines for treatment of jaun-
dice in the newborn. Acta Paediatr 2011;100:499e505.
[5] Canadian Pediatric Society. Guidelines for detection, management and pre-
vention of hyperbilirubinemia in term and late preterm newborn infants (35
or more weeks' gestation) summary. Paediatr Child Health 2007;12:401e18.
[6] Bhutani VK, Zipursky A, Blencowe H, Khanna R, Sgro M, Ebbesen F, et al.
Neonatal hyperbilirubinemia and Rhesus disease of the newborn: incidence
and impairment estimates for 2010 at regional and global levels. Pediatr Res
2013;74(Suppl 1.):86e100.
[7] Bowman JM. Antenatal suppression of Rh alloimmunization. Clin Obstet
Gynecol 1991;34:296e303.
[8] Holuskova I, Lubusky M, Studnickova M, Prochazka M. [Incidence of eryth-
rocyte alloimmunization in pregnant women in Olomouc region.]. Ceska
Gynekol 2013;78:56e61.
[9] Karanth L, Jaafar SH, Kanagasabai S, Nair NS, Barua A. Anti-D administration
after spontaneous miscarriage for preventing Rhesus alloimmunisation.
Cochrane Database Syst Rev 2013;(3):CD009617.
5
[10] Varghese J, Chacko MP, Rajaiah M, Daniel D. Red cell alloimmunization among
antenatal women attending a tertiary care hospital in south India. Indian J
Med Res 2013;138:68e71.
[11] Venkatnarayan K, Sankar MJ, Agarwal R, Paul VK, Deorari AK. Phenobarbitone
in Rh hemolytic disease of the newborn: a randomized double-blinded pla-
cebo-controlled trial. J Trop Pediatr 2013;59:380e6.
[12] Altuntas N, Yenicesu I, Himmetoglu O, Kulali F, Kazanci E, Unal S, et al. The risk
assessment study for hemolytic disease of the fetus and newborn in a Uni-
versity Hospital in Turkey. Transfus Apher Sci 2013;48:377e80.
[13] Okeke TC, Ocheni S, Nwagha UI, Ibegbulam OG. The prevalence of Rhesus
negativity among pregnant women in Enugu, Southeast Nigeria. Niger J Clin
Pract 2012;15:400e2.
[14] Natukunda B, Mugyenyi G, Brand A, Schonewille H. Maternal red blood cell
alloimmunisation in south western Uganda. Transfus Med 2011;21:262e6.
[15] Basu S, Kaur R, Kaur G. Hemolytic disease of the fetus and newborn: current
trends and perspectives. Asian J Transfus Sci 2011;5:3e7.
[16] Puangsricharern A, Suksawat S. Prevalence of Rh negative pregnant women
who attended the antenatal clinic and delivered in Rajavithi Hospital: 2000
2005. J Med Assoc Thai 2007;90:1491e4.
[17] Kotila TR, Odukogbe AA, Okunlola MA, Olayemi O, Obisesan KA. The pregnant
Rhesus negative Nigerian woman. Niger Postgrad Med J 2005;12:305e7.
[18] Cakana AZ, Ngwenya L. Is antenatal antibody screening worthwhile in the
Zimbabwean population? Cent Afr J Med 2000;46:38e41.
[19] Mandisodza AR, Mangoyi G, Musekiwa Z, Mvere D, Abayomi A. Incidence of
haemolytic disease of the newborn in Harare, Zimbabwe. West Afr J Med
2008;27:29e31.
[20] Baptista-Gonzalez HA, Rosenfeld-Mann F, Leiss-Marquez T. [Prevention of
maternal RhD isoimmunization with anti-D gamma isoimmunization.]. Salud
Publica Mex 2001;43:52e8.
[21] Belinga S, Ngo Sack F, Bilong C, Manga J, Mengue MA, Tchendjou P. High
prevalence of anti-D antibodies among women of childbearing age at Centre
Pasteur of Cameroon. Afr J Reprod Health 2009;13:47e52.
[22] al-Joudi FS, Ahmed al-Salih SA. Incidence of Rhesus isoimmunization in
Rhesus-negative mothers in Ramadi, Iraq, in the mid-1990s. East Mediterr
Health J 2000;6:1122e5.
[23] Singhal PK, Singh M, Paul VK, Deorari AK, Ghorpade MG. Spectrum of neonatal
hyperbilirubinemia: an analysis of 454 cases. Indian Pediatr 1992;29:319e25.
[24] Gamaleldin R, Iskander I, Seoud I, Aboraya Hanan, Aravkin Aleksandr,
Sampson Paul D, et al. Risk factors for neurotoxicity in newborns with severe
neonatal hyperbilirubinemia. Pediatrics 2011;128:e925e931.
[25] Hameed NN, Na' Ma AM, Vilms R, Bhutani VK. Severe neonatal hyper-
bilirubinemia and adverse short-term consequences in Baghdad, Iraq.
Neonatology 2011;100:57e63.
[26] Slusher TM, Zipursky A, Bhutani VK. A global need for affordable neonatal
jaundice technologies. Semin Perinatol 2011;35:185e91.
[27] Bhutani VK, Cline BK, Donaldson KM, Vreman HJ. The need to implement
effective phototherapy in resource-constrained settings. Semin Perinatol
2011;35:192e7.
[28] Bhutani VK, Stark AR, Lazzeroni LC, Poland R, Gourley GR, Kazmierczak S, et al.
Predischarge screening for severe neonatal hyperbilirubinemia identies in-
fants who need phototherapy. J Pediatr 2013;162:477e82. e1.
[29] Bhutani VK, Committee on Fetus and Newborn, American Academy of Pedi-
atrics. Phototherapy to prevent severe neonatal hyperbilirubinemia in the
newborn infant 35 or more weeks of gestation. Pediatrics 2011;128:
e1046e1052.
[30] Kumar P, Chawla D, Deorari A. Light-emitting diode phototherapy for un-
conjugated hyperbilirubinaemia in neonates. Cochrane Database Syst Rev
2011;(12):CD007969.
[31] Dickson KE, Simen-Kapeu A, Kinney MV, Huicho L, Vesel L, Lackritz E, et al.
Every newborn: health-systems bottlenecks and strategies to accelerate scale-
up in countries. Lancet 2014;384:438e54.