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 2^nd 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 2^nd 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.