RH Disease and Red Blood Cell Alloimmunization
When your body is exposed to germs or cells that are different from your own body's normal healthy tissues, your
body forms a substance called antibody (immunoglobulin) against areas on
the foreign cells that are different from your own cells called antigens (antibody
generator).Antibodies attach to the antigens and
destroy the invader directly , or label them for removal by
your white blood
The first response by your body to the unfamiliar foreign antigen is called
sensitization and your
body is now prepared to recognize and respond with greater
force on the next encounter with this same unwanted intruder.
The instructions for making the antigens on the
surface of your blood cells are stored in the form of molecules called
genes. Genes are found on structures in the cells of your body called
chromosomes that are inherited from each of your parents. Different versions of the same antigen may be produced by
differences in the
The different versions of the antigen form a blood group. There are thirty
major blood group systems currently recognized including the ABO , Rh
(Rhesus) , Kell ,Duffy (Fya), Kidd (Jka), MNS blood group systems .
that code for the different blood types (antigens) are inherited from your parents. One
set of genes from each parent. In general, a person
needs only one gene for a blood antigen
to produce that antigen on their red blood cells. The chances of a baby
inheriting a gene for a blood antigen depends on how many copies of the
gene each parent has available to pass on to the baby. In the example below a mother
who is RhD negative has children with a father who is RhD positive . The
father may have one or two copies of the RhD gene. If the father has only one copy (heterozygous) of the D antigen gene,
their children will have a 50% chance of being RhD positive. If the
father has two copies
(homozygous) of the gene for the D antigen, then all of their children will be
85% of the white European and north American population is
RhD positive and
just over half have of them have only one copy (heterozygous) of the RhD
gene. Approximately 9 percent of Caucasians and 2 percent of
African-Americans are Kell positive. Nearly all (>97%)
persons who are are Kell positive have only one copy of the Kell (K1) gene
If your baby inherits a blood
type from the father that is different from your own blood type
you may become sensitized to the baby's blood type and produce antibodies
against the baby's red blood cells.
Antibodies may be produced in five different forms. Immunoglobulin M (IgM) ,
and immunoglobulin G (IgG) are the forms found in the greatest amounts in
your blood . IgG is the only form of antibody that can cross the placenta
into the baby's blood .Women most often become sensitized
to a blood type different from their own during a pregnancy or after a
blood transfusion. The formation of antibodies against an antigen from
another human being (the same species) is called alloimmunization or isoimmunization.
More About Antibodies
There are 5 different forms (classes) of antibodies known as Immunoglobulin A (IgA), IgD, IgE, Immunoglobulin M (IgM) , and Immunoglobulin G (IgG) account for most of the antibodies found in your blood and are the two
types of antibody
of interest to us.
Immunoglobulin M (IgM)
first kind of antibody to be formed after you have come in contact with a germ
or other foreign antigen for the first time. IgM appears about
3 to 7 days after an infection . IgM may remain elevated from weeks to months
after exposure to antigen.
Some IgM antibodies occur
naturally and appear without previous exposure to antigen. Cold antibodies
are antibodies that
attach best to red blood cells at less than 37 degrees C (below body
temperature). Cold antibodies are mostly of
the IgM type . IgM antibodies
do not cross the placenta
G (IgG) usually appears about 7 to 10 days
after an infection and may remain elevated for life providing you with
resistance to infection or disease. . Transfer of your IgG
antibodies to your baby helps to protect your baby against infections
before birth and for the first months of life . IgG is the only kind of
antibody that can cross the placenta into the baby's blood
Hemolytic Disease of the Fetus and Newborn (HDFN)
If a mother has antibodies against the blood type of a baby she is
carrying , the mother's antibodies may cross into the baby's blood and
attach to the baby's red blood cells causing destruction of the red blood
cells (hemolysis) and lead to anemia (low red blood cells) in the baby.
The contents of the destroyed red blood cells are released and broken down
to form a yellow substance called bilirubin that causes yellowing of the
baby's skin and the amniotic fluid.
This condition is called hemolytic disease of the fetus and
newborn (HDFN) .
If the anemia becomes very severe, the baby
will try to keep up with the blood loss by producing new blood cells in the
liver. The liver may then become swollen and damaged causing fluid to
collect in the belly, chest, and under the skin of the baby . This condition
is called hydrops .
HDFN is most
commonly caused by a mother who does not have the D antigen on her red blood
cells (Rh negative) producing antibodies against the blood of her baby that
has the D antigen on its red blood cells (Rh positive)
Screening for Blood Antibodies
As the amount of antibody in your blood increases
the chances that your baby will have severe anemia also increases . The
antibody level that severe anemia and fetal hydrops is more likely to occur
is called the "critical" titer and in most centers this level is between 8
blood antibodies is part of usual prenatal care and is done using the
Coombs test (also known as indirect antiglobulin test or IAT) .The test is
commonly referred to as the "antibody screen" . Sometimes an antibody
will be found in too small of an amount to identify, and you will need to
have your blood retested.. Once identified , the level of
the antibody in your blood is measured and reported as a number called a
titer. A low titer number means there is a small amount of the antibody in
your blood. A higher titer number means you have a larger amount of the
antibody in your blood.
determine the level of antibody in your blood a sample of your blood
is diluted over and over again until the antibody is no longer
detected. The titer is
dilution at which the antibody is detected. In the example below a blood sample (tube 1) has
been diluted by 1/2 to produce tube 2, tube 2 was diluted by 1/2 to
produce tube 3 and so forth. A substance was added to each tube to detect
antibody. The 4th tube is the last dilution at which the antibody is
detected, and it is 1/8 th the strength of the original sample. The titer
of the antibody is 8
Anti-D (Rho) Immunoglobulin (RhD-Ig g, Rhogam) 
Rh immune globulin (RhIg)
anti-D (anti-Rh) is an antibody
given to women who are Rh negative (do
not have the D antigen on their blood cells ) to prevent sensitization of
the mother to the D antigen.
Rh-immune globulin must be given before
the mother begins to produce her own antibody to the Rh factor. RhiG does not prevent sensitization to any
other antigen of the Rhesus blood group or the antigens from any other blood
group. Rh immune globulin (RhIg) is marketed under several tradenames such
as HyperRHO , MICRhoGAM,RhoGAM, Rhophylac, WinRho . Because RhIg is an
anti-D antibody women who are Rh negative who have been given
may have the antibody detected for up to 12
weeks after receiving the shot (and in some cases even longer). An elevated anti-D
antibody level would be
expected to decrease over time if it is caused by treatment with anti-D (Rho)
Lewis (Anti-Lea, Anti-Leb ), anti-P1, anti-I,
anti-N, anti-M , and cold antibodies (antibodies that react below body
temperature , 37 degrees C) are
usually IgM antibodies that cannot cross the placenta
and would not be expected to cause HDFN. some naturally
occurring since they appear without previous exposure to antigen However some of these
antibodies such as anti-M may also be present in the IgG form than can cross the
placenta and potentially cause HDFN. If anti-M, IgG optimally
reactive at 37 degrees C, is identified in the mother's blood, the father's
blood must be checked for the presence of the M antigen.
The following antibodies do not usually cause HDFN [1-3, 10)
The following antibodies usually cause no or mild anemia .
Routine obstetric care is recommended by the
American College of Obstetricians and Gynecologists
anti-Jsb), Duffy (anti-Fyb,
anti-By3), Kidd (anti-Jkb,
anti-Jk3) , MNS (anti-N), Vw, Mur, Hil, Hut, Lutheran (anti-Lua,
(anti-Xga), Public antigens (anti-Ytb,
anti-Co1-b), Private antigens (
following antibodies may produce mild to severe HDFN. ACOG recommends fetal
anti-E, anti-c ), Kell (anti--K), Duffy (anti-Fya) Kidd (anti--Jka),
MNS (anti-M, anti-S, anti-s , anti--U, anti-Mia, anti-Mta) , Diego
(anti-D1a, anti-Dib) , P (anti-P1PK also known as anti-TJa)- may cause severe
HD Public antigen (anti-Yta, anti-Ena, anti-COa), Private antigens (anti-Biles,
anti-Radin, anti-Wrighta, anti-Zd)
(anti-D, anti-E, anti-c ), Kell (anti--K), Duffy (anti-Fya) antibodies are
the most likely to cause HDFN requiring intrauterine transfusion.
If you have an antibody that could cause severe anemia in your baby, then
the red blood cells of the father should be tested for the matching antigen
to the antibody. If the father does not have the antigen on his blood cells,
then the baby will not have the antigen either and repeat testing for
antibodies at 28 weeks is recommended. If the father
has the antigen or the father of the baby is unavailable for testing, then the baby
will need to be tested to see if it has
inherited the father's antigen.
the father's antigen status most laboratories will ask that you submit 5 mL
of the father’s blood drawn into a Lavender-top (EDTA) tube with a request to
perform Red Blood Cell Antigen Typing, and specify the bood group to be tested (Kell,
Duffy, etc.) group
on the father’s blood. If the father is negative for the antigen (and it is certain that he is the
father of the fetus) further evaluation is unnecessary. If the father has the antigen or the
status of the father is unknown, then amniocentesis to determine the fetal
antigen type maybe performed.
Monitoring a First Sensitized Pregnancy [1,4,5,8 ]
Except in cases of alloimmunization due to anti-Kell antibodies (and possibly
anti-M IgG antibodies) ,
red cell antibodies in pregnancy are managed in a similar fashion.
Antibody titers are not used for monitoring Kell-sensitized
patients because Kell antibodies levels do not predict the well being
of the baby. Kell sensitized pregnancies may be followed using ultrasound as
for a woman with a previously affected pregnancy.
Recommendations on the management of patients with anti-M IgG differ, some
authorities recommend in women with a first sensitized pregnancy have levels
of the antibody measured as for other blood antibodies if the first
titer is greater than 4.
Others suggest that serial antibody titers are not reliable, and the that
pregnancies with anti-M IgG should be monitoring as Kell-sensitized pregnancies are.
Antenatal testing is started at 32 weeks and
delivery at 37 to 38 weeks is recommended.
in a Woman with a Previously Affected Pregnancy [1, 3,6]
If you have had a previous pregnancy with stillbirth related
to HDFN , fetal hydrops, intrauterine fetal transfusion, preterm delivery
because of fetal anemia, or neonatal exchange transfusion ultrasound will be used to see if
your baby is developing anemia by measuring the speed of the
blood flowing through your baby's brain starting at about 18
weeks. The measurements are repeated every 1 to 2 weeks.
If the flow of the blood becomes
faster than the expected flow for your baby's age (1.5 MoM) , severe anemia is more
likely and you may be referred for blood transfusion of the baby while it is
still in the womb
Antenatal testing is started at 32 weeks and
delivery at 37 to 38 weeks is recommended.
Reviewed by Mark Curran, M.D. FACOG
1. Management of alloimmunization during pregnancy.
ACOG Practice Bulletin No. 75. American College of Obstetricians and
Gynecologists. Obstet Gynecol 2006;108:457–64.PMID: 16880320
2. Thompson DJ, et al., Anti-M antibody in pregnancy Obstet Gynecol Surv. 1989
Sep;44(9):637-41. PMID: 2771305
3. Moise KJ. Hemolytic Disease of the Fetus and Newborn. In: Creasy RK, Resnik
R, Iams JD, eds. Creasy and Resnik's Maternal-Fetal Medicine: Principles and
Practice. 6th ed. Philadelphia, Pa.: Saunders/Elsevier; 2009:477-503.4. De
4.Wikman A, et. al. Fetal hemolytic anemia and intrauterine death caused by
Transfusion. 2007 May;47(5):911-7. PMID: 17465958
5. Yasuda H, et. al., Hemolytic Disease of the Fetus and Newborn With Late-Onset
Anemia due to Anti-M: A Case Report and Review of the Japanese Literature.
Transfus Med Rev. 2013 Oct 19. pii: S0887-7963(13)00065-5. doi:
10.1016/j.tmrv.2013.10.002. PMID: 24262303
6. Moise KJ Jr, Argoti PS.Management and prevention of red cell alloimmunization
in pregnancy: a systematic review. Obstet Gynecol. 2012 Nov;120(5):1132-9. doi:
Ortho Clinical Diagnostics Revised November 2010
8. Moise KJ Jr. Management of rhesus alloimmunization in pregnancy. Obstet
Gynecol. 2008 Jul;112(1):164-76. PMID: 18591322
9.Gooch A, et al.,Guideline for Blood Grouping and Antibody Testing in Pregnancy. British Committee for
Standards in Haematology 2008 Available at:
10. Guidelines for
Blood Grouping and Antibody Screening in the Antenatal and Perinatal Setting. The Australian & New Zealand Society of Blood Transfusion Ltd. 2007
Standards in Haematology 2008 Available at:
11. Pregnant Women with Red Cell Antibodies: Scottish National Clinical Guidance. Version 2, July 2013
Available at: http://www.scotblood.co.uk/media/101700/pregnant_women_with_red_cell_antibodies_scottish_national_clinical_guidance_august13.pdf
12. Zimmerman R, et. al., Longitudinal measurement of peak systolic velocity in the fetal middle cerebral artery for monitoring pregnancies complicated by red cell alloimmunisation: a prospective multicentre trial with intention-to-treat.
BJOG. 2002 Jul;109(7):746-52.PMID: 12135209
McEwan A. Red cell alloimmunization. In Parvord S and Hunt B eds The
Obstetric Hematology Manual. 1st ed ,New York Cambridge University Press;
2010 p 771
Sikkel E, et al., On the origin of amniotic fluid bilirubin.
Placenta. 2004 May;25(5):463-8.PMID: 15081641