Rh disease (also known as rhesus isoimmunization, Rh (D) disease) is a type of hemolytic

disease of the fetus and newborn (HDFN). HDFN due to anti-D antibodies is the proper and currently
used name for this disease as the Rh blood group system actually has more than 50 antigens and
not only D-antigen. The term "Rh Disease" is not the current terminology but it is commonly used to
refer to HDFN due to anti-D antibodies, and prior to the discovery of anti-Rho(D) immune globulin, it
was the most common type of HDFN. The disease ranges from mild to severe, and occurs in the
second or subsequent pregnancies of Rh-D negative women when the biologic father is Rh-D
positive.
Due to several advances in modern medicine, HDFN due to anti-D is preventable by treating the
mother during pregnancy and soon after delivery with an injection of anti-Rho(D) (RhoGam) immune
globulin. With successful mitigation of this disease by prevention through the use of anti-Rho(D)
immune globulin, other antibodies are more commonly the cause of HDFN today.

Contents

 1Pathophysiology
 2Diagnosis
 3Prevention
 4Management
 5History
 6References
 7External links

Pathophysiology[edit]
During birth or throughout the pregnancy, the mother may be exposed to the infant's blood, and this
causes the immune system to respond to the red blood cells as foreign and mount a response by
creating antibodies. During the first pregnancy, the initial exposure to fetal RBCs results in the
formation of IgM antibodies, and these do not cross the placental barrier, which is why no effects are
seen in first pregnancies for Rh-D mediated disease. However, in subsequent pregnancies, the
immune system mounts a memory response when re-exposed, and these antibodies (IgG) do cross
the placenta into fetal circulation. These antibodies are directed against a protein found on the
surface of the fetal red blood cells (RBCs). The antibody coated fetal red blood cells are destroyed.
The resulting anemia has multiple sequelae:[1][2][3]
(1) The immature hematopoietic system of the fetus is taxed as the liver and spleen attempt to put
immature RBCs into circulation (erythroblasts, thus the previous name for this
disease erythroblastosis fetalis).
(2) As the liver and spleen enlarge under this unexpected demand for RBCs, a condition
called portal hypertension develops, and this taxes the immature heart and circulatory system.
(3) Liver enlargement and the prolonged need for RBC production results in decreased ability to
make other proteins, such as albumin, and this decreases the oncotic pressure leading to leakage of
fluid into tissues and body cavities, termed hydrops fetalis.
(4) The severe anemia taxes the heart to compensate by increasing output in an effort to deliver
oxygen to the tissues and results in a condition called high output cardiac failure.
(5) If left untreated, the end result may be fetal death.
The destruction of RBCs leads to elevated bilirubin levels (hyperbilirubinemia) as a byproduct. This
is not generally a problem during pregnancy, as the maternal circulation can compensate. However,
once the infant is delivered, the immature system is not able to handle this amount of bilirubin alone
and jaundice or kernicterus (bilirubin deposition in the brain) can develop which may lead to brain
damage or death.
Sensitizing events during pregnancy include c-section, miscarriage, therapeutic
abortion, amniocentesis, ectopic pregnancy, abdominal trauma and external cephalic version.
However, in many cases there was no apparent sensitizing event. Approximately 50% of Rh-D
positive infants with circulating anti-D are either unaffected or only mildly affected requiring no
treatment at all and only monitoring. An additional 20% are severely affected and require
transfusions while still in the uterus. This pattern is similar to other types of HDFN due to other
commonly encountered antibodies (anti-c, anti-K, and Fy(a)).

Diagnosis[edit]
Maternal blood
In the United States, it is a standard of care to test all expecting mothers for the presence or
absence of the RhD protein on their RBCs. However, when medical care is unavailable or prenatal
care not given for any other reason, the window to prevent the disease may be missed. In addition,
there is more widespread use of molecular techniques to avoid missing women who appear to be
Rh-D positive but are actually missing portions of the protein or have hybrid genes creating altered
expression of the protein and still at risk of HDFN due to Anti-D.[4][5]

 At the first prenatal visit, the mother is typed for ABO blood type and the presence or
absence of RhD using a method sensitive enough to detect weaker versions of this antigen
(known as weak-D) and a screen for antibodies is performed.
o If she is negative for RhD protein expression and has not formed anti-D already, she
is a candidate for RhoGam prophylaxis to prevent alloimmunization.
o If she is positive for anti-D antibodies, the pregnancy will be followed with monthly
titers (levels) of the antibody to determine if any further intervention is needed.
 A screening test to detect for the presence or absence of fetal cells can help determine if a
quantitative test (Kleihauer-Betke or flow cytometry) is needed. This is done when exposure is
suspected due to a potential sensitizing event (such as a car accident or miscarriage).
 If the screening test is positive or the appropriate dose of RhoGam needs to be determined,
a quantitative test is performed to determine a more precise amount of fetal blood to which the
mother has been exposed.
o The Kleihauer–Betke test or Flow Cytometry on a maternal blood sample are the
most common ways to determine this, and the appropriate dose of RhoGam is calculated
based on this information.
 There are also emerging tests using Cell-free DNA. Blood is taken from the mother, and
using PCR, can detect fetal DNA.[6] This blood test is non-invasive to the fetus and can help
determine the risk of HDFN. Testing has proven very accurate and is routinely done in the UK at
the International Blood Group Reference Laboratory in Bristol.[7]
Paternal Blood
Blood is generally drawn from the father to help determine fetal antigen status.[8] If he is homozygous
for the antigen, there is a 100% chance of all offspring in the pairing to be positive for the antigen
and at risk for HDFN. If he is heterozygous, there is a 50% chance of offspring to be positive for the
antigen.[9]

Prevention[edit]
All RhD negative pregnant women should receive RhoGam at 28 weeks gestation and within 72
hours after childbirth in addition to doses with any sensitizing event (miscarriage, trauma, bleeding).
Most RhD mediated disease can be prevented if this is done. There are theories as to why or how
this works, but none have been proven definitively to be the case. In addition, there has been
research into finding a non-human derived version of this antibody, but none have been as effective
as the currently available human derived formulations.