General Overview
To educate
individuals about the Rh factor and how this has changed over the years
involves a discussion regarding the external appearance of the red blood cell and
our immune system. Over 50 years ago, more than 10,000 fetuses/neonates were
lost every year due to a medical condition called “Rh disease”. Other names for
this disease are erythroblastosis fetalis or hemolytic disease of the newborn.
This was a condition in which an Rh-negative mother developed antibodies to the
Rh factor, and these antibodies then crossed the placenta and destroyed fetal
red blood cells, if the fetus happened to be Rh positive. These fetuses would
develop severe anemia leading to cardiac failure with hydrops (skin edema,
ascites, pleural effusions, etc.). They also could develop polyhydramnios with
an enlarged liver and spleen, as well as, a very thick placenta leading to
stillbirth and/or neonatal death. If the newborn survived, many developed cerebral
palsy.
Regarding
background history, in 1937 Weiner and Landsteiner discovered the “Rh factor”,
which was found to be a large protein on the surface of some red blood cells.
They did this by injecting rabbits with red blood cells from the Rhesus monkey
--- hence the term “Rh”. They identified
that some of these rabbits would develop antibodies to the red blood cells that
were injected. In 1944, Lavine discovered that the Rh factor was the primary
cause of erythroblastosis fetalis in humans and in 1946 described using an
exchange transfusion in these newborns to combat this disorder. The theory was
if you removed a large portion of the newborn’s blood that contained the maternal
antibodies and replaced it with different blood that did not have the
antibodies, the destruction of red blood cells in the newborn would decrease or
stop.
In 1960 Finn and
Clark in England
learned that ABO incompatible pregnancies often cleared red cells from the
maternal circulation, thereby decreasing the risk of Rh sensitization. Later
that same year they were able to isolate and extract these Rh antibodies from
individuals who were sensitized and concentrate them into something called “Rh
hyperimmunoglobulin”. In 1961 they gave Rh hyperimmunoglobulin to Rh-negative police
volunteers and then exposed these police volunteers to Rh positive blood. By
giving Rh hyperimmunoglobulin prior to the exposure they found a lower
sensitization rate.
In
1964 Dr. Vincent Freda, an obstetrician, Dr. John Gorman, a blood bank
pathologist, and Dr. William Pollack, PhD, an immunologist injected 9 prisoners
at Sing Sing prison in New York, 4 with Rh hyperimmunoglobulin and 5 with placebo
and then exposed them to Rh positive blood. Rh sensitization was prevented in
all 4 that received Rh hyperimmunoglobulin, but 4 of the 5 placebo cases became
sensitized.
In
1967 Hamilton
treated 500 Rh negative women postdelivery with unprocessed plasma obtained from
high Rh antibody titer patients (those that delivered a fetus with hydrops
fetalis). Of the 74 that had a 2nd pregnancy, all were unsensitized
(no anti-Rh factor antibody developed). In 1968 the group of Freda-Gorman-Pollack
conducted a multicenter randomized trial in pregnant women that demonstrated
the prevention of Rh sensitization using RhoGAM (the name given to the first
commercially made Rh hyperimmunoglobulin). RhoGAM was later approved for the
treatment process of Rh-negative women in pregnancy by the FDA in 1968.
For review,
antibodies (the injectable forms are called immunoglobulins) are made by the
human body as a form of protection against foreign substances that are not part
of a person’s biological makeup. Antibodies are made to attach themselves to
specific structures (usually proteins and other molecules) found on the surface
of foreign material, and these proteins and other molecules are called
“antigens”. Thus, the “antibody” is made to attach itself to a specific “antigen”,
and by doing so, this foreign substance can then be removed from the body. For
example, we get infected with a cold virus (the cold virus is not part of the
human body), and this virus makes us sick with “cold” symptoms. Our immune
system recognizes this virus as being a foreign substance and makes an antibody
against an antigen that is present on the surface of the virus, and by doing
so, allows the virus to be removed from the body so the “cold” symptoms go
away. Lastly, in the laboratory, if blood contains a specific “antigen” and an
antibody (immunoglobulin) specific to that antigen is added to the sample, the
blood will agglutinate (clump together).
Over time, more
and more antigens have been found on the surface of red blood cells that in
certain cases, can also lead to sensitization in those individuals exposed who
do not have those antigens on their own red blood cells. Some individuals have
classified this as the “Rh System” and it is very diverse consisting of more
than 50 different antigens. They have been given numbers, Rh1, Rh2, Rh17, etc.
They have also been designated by letters or names. The Rh factor, which is the
most antigenic and most important, has been labeled “D”. If someone has been
sensitized to “D” they have developed anti-D antibodies. Some of the other important
antigens are C, c, E, e, Kell, Duffy, Kidd, etc. Again, if someone has been
sensitized to one of these other antigens, they have developed anti-C, anti-c, anti-E,
anti-e, or anti-Kell antibodies, and so forth.
The production of
these antigens on the surface of red blood cells is also inherited genetically.
The gene that contains the Rh factor (or D) is found on chromosome
1-1p36.11. This gene also codes for
antigens C, c, E, and e, (there is no little d). Therefore, this gene can code
for D, Cc, and Ee. Having the Rh factor (or D) labels that person as being
Rh-positive and this is found in about 85% of Caucasians, 92% of African
Americans, and 99% of Asian and Native Americans and therefore, is very
prevalent. Those who do not have the Rh factor are labeled Rh-negative.
Variants of “D”
Because
the potential for producing the D, Cc, and Ee antigens are all found on the
same gene, does not mean that everyone has the genetic code to produce all of these
antigens. One person might have D, c, and E; whereas someone else might have D,
C, and e. Some individuals will lack the D (called Rh-negative) but can still
express C, c, E and e. If a person lacks an entire Rh gene, they are labeled Rh
null. Red blood cells that lack all of the Rh antigens do not agglutinate with
anti-D, anti-C, anti-E, anti-c, or anti-e and this is extremely rare in the
population.
There
are some people who have the full D-antigen, but in immunologic terms have a “weak
expression” of this antigen (less than the normal immunologic expression of the
D-antigen). In the past, these individuals were labeled Du positive patients. What
has been identified more recently is that the D-antigen may not be fully
exposed on the surface of the red blood cell membrane. It has been determined
that the D-antigen passes through the red blood cell surface membrane about 12
times, thereby only exposing portions of this protein externally. It has also been
discovered that this D-antigen protein has numerous locations along its length that
can produce an antibody response. These different locations are called “epitopes”
and up to 30 different epitopes have been identified for the D antigen. Because
the D antigen is not fully exposed on the cell surface, not all 30 epitopes may
be exposed depending on what portion of the protein is intracellular versus what
portion is extracellular. Only the portion that is extracellular can produce an
antibody response. This has led to the identification of 2 different types of
individuals; those who are Weak D individuals and those who are Partial D
individuals.
Weak D individuals
have the full complement of the “D epitopes” but due to transmembrane mutations
a smaller number of these antigenic loci are active on the extracellular
surface of the red blood cell. Therefore, they do not respond as strongly (from
an immunologic standpoint) as those that have the full complement of active epitopes
on the surface. However, these individuals cannot make an anti-D antibody if
they were exposed because essentially, they are Rh-positive or D positive
genetically.
A Partial D
individual has mutations that change how the D antigen protein passes through
the membrane reducing the number of visible epitopes. Therefore, these
individuals can make an anti-D antibody to epitopes that are not present on the
red blood surface if exposed to blood that has the full complement of antigenic
loci on the surface.
Therefore,
the identification of Weak D individuals and Partial D individuals has led to
situations where patients can be “labeled” Rh-negative in some circumstances
and Rh-positive in other circumstances; creating a large amount of confusion.
To review; because Weak D individuals have the full complement of the antigenic
loci, these people cannot produce an anti-D antibody if exposed to Rh-positive
blood because they are actually Rh-positive but just weak in their immune expression
of the D antigen (from a genetic standpoint). However, Partial D people, if
exposed to Rh positive blood, could make an antibody to an antigenic loci or
epitope that they themselves do not possess. This becomes important in
determining how to “label” someone based on medical problems that can occur in
the general population.
Pregnant patients
are tested for the presence of the D antigen by a direct anti-D
hemagglutination method. If the D antigen is present and is being fully
“expressed” from a antigenic loci standpoint, the blood will fully agglutinate
after adding anti-D immunoglobulin, and the person is labeled Rh-positive. Weak
D and Partial D patients would be labeled Rh-negative because they do not fully
agglutinate because the weak D individuals have a weak expression of the D
antigen and the Partial D individuals are missing some of the D antigen. Additionally,
individuals who are receiving a blood transfusion are also are tested in the
same manner and labeled the same way. A Partial D person would not want to
receive blood from someone who is fully D positive (or Rh-positive). Thus, a
potential blood recipient (a pregnant patient or someone that might need a
blood transfusion), who is Weak D or Partial D positive would be labeled
Rh-negative.
On
the other hand, blood donors and newborns are tested with direct
hemagglutination and indirect antibody testing which means that Weak D and Partial
D patients would be labeled Rh-positive because they contain some or all of the
D antigen loci. Thus, clinically, a person can be labeled Rh-positive if they
are a blood donor because Weak D and Partial D blood should not be administered
to someone who is truly Rh negative. These individuals, however, can be labeled
Rh-negative if they are a blood transfusion recipient or pregnant. If a Partial
D pregnant patient were to be exposed to a fetus’s red blood cells that contain
epitopes not found in the mother, she could become Rh sensitized to those
missing antigenic loci, which then could affect any future pregnancy. Once a person
is sensitized, they are sensitized for life.
Regarding the
administration of Rh hyperimmunoglobulin, an Rh-positive person and a Weak D
person cannot make anti-D antibodies if exposed to Rh-positive (D positive) blood,
and therefore, would not be candidates for Rh hyperimmunoglobulin. On the other
hand, Rh negative individuals and Partial D patients, can make an anti-D
antibody if exposed to Rh-positive blood and therefore are candidates for Rh hyperimmunoglobulin.
The only way to
differentiate a Weak D individual from a Partial D individual involves an RHD genotype
test, which currently costs somewhere between $300 and $500 and it is not
uniformly performed in most blood banks. This may change if the price of the
testing drops. Sandler and Queenan recently
argued that all pregnant women who are possibly Weak D individuals should have
genotyping performed because 90% of Weak D / Partial D individuals (15,000
pregnant women per year) are actually Weak D people. Thus 13,360 of these women
would be typed Weak D and would not receive over 24,000 unnecessary Rh
hyperimmunoglobulin injections. However, at the current pricing level, the annual
cost of 24,000 Rh hyperimmunoglobulin injections is roughly 2½ million dollars;
whereas the annual cost of 15,000 genotype tests is in the range of 7 million
dollars. To be cost effective, genotyping would need to drop to about 160
dollars per test.
Sensitization
It only takes 1/10
of a milliliter of fetal red blood cells that are Rh-positive to produce an
antibody sensitization in someone who is Rh-negative. The fetal red blood cells
appear at around 6-7 weeks gestation. If an Rh-negative woman carries and
delivers an Rh-positive newborn and is not treated, there is a 17% risk of
sensitization. Research showed that the administration of Rh
hyperimmunoglobulin postdelivery to an Rh-negative women who delivered an Rh-positive
newborn would decrease this sensitization rate by 90% (dropping it from 17% to
2%). This 2% failure rate is thought to be due to those individuals who were
exposed to their fetuses’ blood prior to delivery; hence the addition of the 28-week
gestation Rh hyperimmunoglobulin injection. By doing this, the sensitization
rate in Rh-negative women dropped to 0.1%.
How
are patients exposed in obstetrics?
Exposure to fetal blood can occur with spontaneous abortions, ectopic
pregnancies, therapeutic abortions, and elective abortions. It can also occur
with threatened abortions and various obstetrical procedures including chorionic
villus sampling, amniocentesis, umbilical cord blood sampling, and even with external
cephalic version (a procedure used to move a fetus from the breech position to
a cephalic presentation for attempt at vaginal delivery).
Therefore, it is
recommended that all Rh-negative pregnant women receive Rh hyperimmunoglobulin
at 28 weeks gestation antenatally and to those postdelivery (within 72 hours of
birth) if their newborn is found to be Rh-positive after delivery. It should also
be administered additionally to Rh-negative women who have any type of
abortion, ectopic pregnancy, threatened abortion, obstetrical procedures,
and/or version (if the patient who undergoes the version is not delivered on
the same admission). It should also be administered with abdominal trauma,
fetal demise, and second and third trimester bleeding.
Unfortunately,
despite the development of Rh hyperimmunoglobulin, there are Rh-negative women
who still become sensitized. One group of patients who can become sensitized
that are often missed are those who share needles if they are IV drug users. In
addition, it has been suggested that other fomites might transmit foreign blood
such as sharing of snorting straws. Other misses can occur if there are incidences
of unreported abdominal trauma in Rh-negative women, especially if it is
related to domestic violence. It can also occur in unreported and undetected
first trimester spontaneous abortions. However, it is estimated that about 50%
of the Rh-negative (D-negative) pregnant women who are found to be Rh
sensitized (have an anti-D antibody), are due to errors in clinical management
by not administrating the 28-week Rh hyperimmunoglobulin dosage or not giving the
postdelivery dose, especially if the mother needs more than one vial
postdelivery (this will be discussed further below).
Rh hyperimmunoglobulin
Overall Rh
hyperimmunoglobulin is a very safe agent and allergic reactions occur in less
than 1:1000 patients. Until recently, the production of Rh hyperimmunoglobulin
came from extracting the antibody from those individuals who have a high Rh
antibody titer or count. However, because the antibody is coming from the blood
of donors, there is always the concern of transmitting other blood-borne infections
including HIV, hepatitis B, or hepatitis C. Fortunately, all immunoglobulins
undergo a fractionation procedure in the manufacturing process and all
immunoglobulins over the past 20 years have been examined closely and have not
been found to transmit any types of infections. Many different types of
immunoglobulins exist including varicella zoster immunoglobulin, hepatitis B
immunoglobulin, etc. There were some transmissions of hepatitis C in patients
who received RhoGAM in the 1970’s but the manufacturing process was modified,
and this has not occurred since that time. Other studies have been published in
the 1990’s and 2000’s about individuals who became infected with blood-borne infections
following receipt of immunoglobulins that were administered in the 1970’s and 1980’s.
Again, no blood-borne infections have been reported following the
administration of any immunoglobulins in the past 25 years. Immunoglobulins in
general are made from pools of 10,000 to 20,000 plasma donations and the manufacturing
process uses cold ethanol fractionation that removes 1015 infectious
particles per cc. In the United
States a solvent detergent treatment is also
used.
What
does one vial or one dose of Rh hyperimmunoglobulin treat? The original product
(RhoGAM) contained 300 mcg of the antibody, which would cover 15 mL of fetal
red blood cells. Fetuses theoretically have a hematocrit of about 50% which
overall would suggest that it covers about 30 mL of fetal whole blood. In some locations
there is a product called MICHroGam or micro Rh hyperimmunoglobulin that only
covers about 2.5 mL of fetal red blood cells or 5 mL of fetal whole blood. This
smaller dose of Rh hyperimmunoglobulin is primarily used for first trimester
losses due to the blood volume of a fetus that small.
Currently, the protocol
that is instituted in most locations in the United States requires that all Rh-negative
pregnant women who deliver an Rh-positive fetus be tested for the presence of
fetal cells with either a Rosette, acid-elution assay, or column gel assay test.
The acid-elution assay test is tedious and costly, and the column gel assay test
is not standardized for routine use in the United States. Therefore, most hospitals
(99%) use the Rosette test. The Rosette test involves incubating a sample of
the Rh-negative maternal blood postdelivery with Rh immunoglobulin (antibody). If
Rh positive fetal red blood cells are present, the antibodies attach to these
fetal cells. The sample is then washed to remove any excess immunoglobulin. Enzyme
treated Rh D positive cells are then added and if Rh positive fetal cells are
present in the sample, these enzyme treated Rh D positive cells form Rosettes
around the antibody coated Rh D positive fetal cells that can be seen under a
microscope. If the Rosette test is positive a Kleihauer-Betke test is done to
quantify the amount of fetal blood that is present in the maternal circulation.
Flow cytometry is another option to evaluate the amount of fetal blood that is
present, but this test is not currently readily available in most locations in
the United States.
It is a slower test to perform and more expensive. The Kleihauer-Betke test is
much cheaper and faster to perform but may be less accurate in detecting smaller
amounts of fetal cells and can be affected by conditions that result in
elevated fetal hemoglobin levels such as hemoglobinopathies (i.e. sickle cell
disease, thalassemia, etc.).
The
Kleihauer-Betke test was named after Enno Kleihauer and Klaus Betke in 1957 who
developed the test. They showed that adult red blood cells were sensitive to
acid elution and fetal cells were not. Through a staining process, fetal cells
could be identified and counted to determine a percentage of fetal blood in the
specimen. The test is performed by a smear of blood where 2000 red blood cells
are counted and those that have stained positive for fetal blood are identified
and a percentage determined. If it is calculated that the amount of fetal blood
present is not adequately covered by one vial of Rh hyperimmunoglobulin, then
other vials would need to be administered in order to prevent sensitization in
that individual. Since the development of RhoGAM, other formulations of Rh hyperimmunoglobulin
are in existence including HyperRho S/D, Rhophylac, and WinRho SDF.
One
concern that occurred in the not too distant past was a potential for a
shortage in available Rh hyperimmunoglobulin. The treatment of Rh-negative
women with Rh hyperimmunoglobulin has markedly decreased the number of
sensitized women and therefore decreased the number of individuals with high
titers raising a concern for future shortage. This concern no longer exists in
that pharmaceutical companies have created sensitized donor pools that have
been thoroughly screened and tested. Therefore, it currently does not appear
that there will be a shortage of Rh hyperimmunoglobulin.
When Rh hyperimmunoglobulin
is administered, the date and time of the injection, the type of Rh
immunoglobulin given and the lot number, as well as, location of the injection
should be documented along with the signature of the person who administered the
Rh hyperimmunoglobulin.
Other Red Blood Cell Antibodies
There are other
antigens found on red blood cell that can cause erythroblastosis fetalis. A
common phrase that has been passed down over the past few decades is that K’s
kill and D’s die to help in remembering some of the ones that can be
problematic during pregnancy. These include red blood cell antibodies such as
Kell, Kidd, and Duffy. The other Rh antibodies of C, c, E, and e can also affect
a fetus along with M and Ss. Many other rare ones can also occur. In addition, there
are common antibodies that do not affect newborns such as Lewis A and Lewis B
and I. Most recently, a G antibody has been identified which occurs in someone
that is D antigen and C antigen negative. As previously discussed, the Rh gene
codes for DCcEe and there are 8 possible genetic haplotypes that a person can
have in the population, which are DCe / DCE / DcE / Dce / dCe / dCE / dcE / dce.
The first six listed will have the D and/or C antigen. The anti-G antibody can
only develop in an exposed person who is negative for both D and C (the last
two in the list). The purpose in mentioning this is that you may receive a
laboratory report from a blood bank that states a person has anti-G antibody.
Furthermore, there are even more rare antibodies including the P blood group, the
GLOB collection, as well as, public antigens, cold antibodies, and warm
antibodies that are too extensive for this current discussion. Therefore, the
best approach is to send any patient that has a positive antibody screen to a
specialist in obstetrics that can determine if the identified antibody is a potential
concern.
In a non-sensitized
Rh-negative pregnant patient (if paternity is not in question) then it is
plausible to test that father for his Rh status. If the father is Rh-negative,
then Rh hyperimmunoglobulin is not indicted at 28 weeks gestation and
postdelivery because the newborn should be Rh-negative. However, if there is
any question regarding paternity (and how can any healthcare provider be 100%
certain about paternity) then Rh hyperimmunoglobulin should be administered and
again the newborn tested postdelivery. If a mother enters prenatal care and is
found to be sensitized to D (her prenatal laboratory results show a positive antibody
screen for anti-D), then Rh hyperimmunoglobulin is not indicated. In these sensitized
patients, antibody titers should be obtained on a monthly basis with a critical
titer or level listed as 1:16. If you have a positive antibody titer to a red blood
cell antigen other than D, it is recommended that a consult be obtained to
determine whether antibody titers need to be followed and whether there is a
risk for hemolytic disease of the newborn (as stated above). It is recommended
that in all Rh-negative pregnant women, that they be retested for the Rh
antibody prior to the 28-week administration of Rh hyperimmunoglobulin. It is
not recommended that the antibody screen result be received prior to the
administration of Rh hyperimmunoglobulin but that it be obtained prior to
administration. Other questions that occur are whether or not an Rh-negative pregnant
woman undergoing a sterilization procedure postdelivery should receive Rh
hyperimmunoglobulin and expert consensus is yes. In addition, it is recommended
that Rh hyperimmunoglobulin be administrated even if it has been more than 72
hours from delivery or exposure. The 72 hours is an arbitrary number that came
from the original research from Sing Sing prison because they injected the
prisoners on a Friday and did not do anything over the weekend until the
following Monday. One study looking at time after exposure showed that there might
be protection even up to 13 days. Others theoretically have said that it might
still be useful up to 28 days postexposure.
Lastly, another new
testing possibility is identifying fetal Rh status through cell-free fetal DNA
testing. Up to 40% of Rh-negative women deliver a fetus that is also Rh-negative.
Many people who are Rh-positive are heterozygous meaning that they received the
D antigen from one parent but did not receive it from the other parent.
However, the D antigen is autosomal dominant and therefore these heterozygotes
are Rh-positive. In a pregnancy with an Rh-negative mother and an heterozygous
Rh-positive father, half of the newborns theoretically would be Rh-negative and
half would be Rh-positive. It is reported that cell-free fetal DNA (performed
in Rh-negative women looking for the presence of the fetal Rh status) is about
99% sensitive and 95% specific, but this test reports out an inconclusive
result about 6% of the time. Cost-effective studies have been performed
recently, one of which stated that it was cost effective to perform cell-free
fetal DNA for fetal Rh status and 4 suggested that it was not. Again, this
probably gets down to the cost of testing.
When following the
pregnancy of a woman who is Rh sensitized, the primary practice is to perform
ultrasounds looking for a thickened placenta, polyhydramnios, and the presence
of hydrops in the fetus including pericardial effusion, pleural effusions,
ascites, or skin edema. In addition, the peak systolic blood flow of the middle
cerebral artery (MCA) of the fetus can be evaluated. Multiples of the Median (MoMs)
of the peak systolic flow of the MCA have been developed that help determine if
a fetus may be anemic to a point where delivery and/or intrauterine transfusion
might be indicated. The optimal measuring angel is 0 but this is often
difficult to obtain in utero based on the position of the fetal head. Overall,
the test has about a 10% false-positive rate. An MoM of 1.0 is considered
normal; a value of 1.29 is borderline; and a value of 1.5 to 1.55 or greater
suggests fetal anemia leading to cordocentesis or percutaneous umbilical cord
blood sampling versus delivery (depending on the gestational age of the
pregnancy). After an intrauterine transfusion, the recommended MoM cut-off for a
2nd transfusion is greater than 1.70. It is important to remember
that other causes for fetal anemia can occur including infections with
parvovirus, cytomegalovirus, toxoplasmosis, and syphilis. Fetuses can also be
anemic from a fetal-to-maternal hemorrhage, aneuploidy, and it can occur in
twin-to-twin transfusion syndrome in monochorionic twin gestations. Other rare
genetic disorders have been found to produce fetal anemia including
thalassemia, Neiman Pick, Fanconi, G6PD deficiency, Gaucher, and lysosomal
disorders, etc.
To conclude, there are still many
unanswered questions regarding this subject matter.
1. Why
do only 17% of untreated Rh-negative pregnant patients develop isoimmunization postdelivery
when up to 40% experience a fetal-maternal bleed.
2. Are
all Rh hyperimmunoglobulin products equally effective?
3. How
long does Rh hyperimmunoglobulin really last? If Rh hyperimmunoglobulin is
given at 28 weeks gestation, should it be given again at 40 weeks if
undelivered?
In summary, the most important impact
that healthcare providers can do obstetrically is to identify Rh-negative women
and make sure that they receive their 28-week antenatal dosage of Rh
hyperimmunoglobulin followed by a thorough evaluation of the newborn
postdelivery with treatment after delivery if indicated including determining
whether one vial of Rh hyperimmunoglobulin is adequate. Likewise, being
vigilant in Rh-negative pregnant women with other potential exposures including
pregnancy losses, procedures, trauma, etc.
References and Suggested Reading:
1. American College of Obstetrics and Gynecology.
ACOG Practice Bulletin No. 181, August 2017. Prevention of Rh D
alloimmunization. Obstet Gynecol 2017;130:e57-70.
2. Mari
G, Norton ME, Stone J, Berghella V, et al. Society for Maternal-Fetal Medicine (SMFM)
Clinical Guidelines #8: The fetus at risk for anemia – diagnosis and
management. Am J Obstet Gynecol 2015;212:697-710.
3. Sandler
SG, Queenan JT. A guide to terminology for Rh immunoprophylaxis. Obstet Gynecol
2017;130:633-35.
4. Mioise
KJ, Gandhi M, Boring NH, et al. Circulating cell-free DNA to
determine the fetal RhD status in all tree trimesters of pregnancy. Obstet
Gynecol 2016;128:1340-46.
5. Queenana
JT. Rh immunoprophylaxis and fetal RHD genotyping. Where are we going? Obstet
Gynecol 2012;219-20.
6. Moise
KJ. William W. Pollack, PhD, A pioneer in perinatology. Obstet Gynecol
2014;123:493-94.
7. Sandler
SG, Gottschall JL. Postpartum Rh immunoprophylaxis. Obstet Gynecol
2012;120:1428-38.
8. Levine
RA, Sanderson SO, Ploutz-Snyder R, et al. Assessment of fibrosis progression in
untreated Irish women with chronic hepatitis C contracted from immunoglobulin
anti-D. Clin Gastroenterol Hepatol 2006;4:1271-77.
9. Bjoro
K, Froland SS, Yun Z, et al. Hepatitis C infection in patients with primary
hypogammaglobulinemia after treatment with contaminated immune globulin. N Engl
J Med 1994;331:1607-11.
10. Hawk
AF, Chang EY, Shields AM, Simpson KN. Costs and clinical outcomes of
noninvasive fetal RhD typing for target prophylaxis. Obstet Gynecol 2013;122:579-85.
11. Moise
KJ, Argoti PS. Management and prevention of red cell alloimmunization in
pregnancy. Obstet Gynecol 2012;120:1132-39.
12. Queenan
JT. The partial D antigen dilemma. Obstet Gynecol 2012;119:421-22.
13. Chaffin
DJ. The G antigen and Anti-G. Blood Bank Guy – Transfusion Medicine Education.
8/11/11.
14. Sandler
SG, Li W, Langeberg A, Landy HJ. New laboratory procedures and Rh blood type
changes in pregnant women. Obstet Gynecol 2012;119:426-28.
Dr. Visconti is currently the Director of Perinatal Services at Holston Valley Medical Center in Kingsport Tennessee. He is clinically active managing numerous high-risk pregnancies and is also involved in research with several publications in major medical journals. Though his research covers different areas in obstetrics, his primary interests involve opioid use disorder and fetal lung maturity. He has no conflicts of interest regarding this presentation.