Isoimmunization An Introduction to Antibodies and Pregnancy by Monique Kinney Disclaimer DISCLAIMER: THIS BOOK DOES NOT PROVIDE MEDICAL ADVICE The information, including but not limited to, text, graphics, images and other material contained on this website are for informational purposes only. The purpose of this book is to promote broad consumer understanding and knowledge of various health topics. It is not intended to be a substitute for professional medical advice, diagnosis or treatment. The medical information in this book is provided as an information resource only, and is not to be used or relied on for any diagnostic or treatment purposes. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of something you have read on this website. The author does not recommend or endorse any specific tests, physicians, products, procedures, opinions or other information that may be mentioned on this website. Reliance on any information appearing on this website is solely at your own risk. Please consult your health care provider, before making any healthcare decisions or for guidance about a specific medical condition. The author of this book expressly disclaims responsibility, and shall have no liability, for any damages, loss, injury, or liability whatsoever suffered as a result of your reliance on the information contained in this site. By purchasing this book you agree to the foregoing terms and conditions, which may from time to time be changed. If you do not agree to the foregoing terms and conditions, you should not purchase this book. Copyright © 2016 Monique Kinney First Edition June 2016 Table of Contents Part 1: An Overview of Isoimmunization What is Isoimmunization (Iso)? Antibody? Antigen? What’s my body doing again? How it works How did I become sensitized? Why is Iso dangerous? Possible Outcomes How do I know if I have an antibody? What do I do? Where do I start? Part 2: Prenatal Testing Basic prenatal blood work – What it includes No antibody found Antibody found Antibodies that are NOT associated with Hemolytic Disease of the Newborn Antibodies that ARE associated with Hemolytic Disease of the Newborn Additional blood work Paternal blood work Testing baby More blood work for mom – maternal titers Ultrasound testing MCA Doppler assessment Biophysical Profile NST Amniocentesis Part 3: Prenatal Complications Hemolytic Disease of the Newborn Maternal Fetal Hemorrhage Fetal Anemia Ascites Fetal Hydrops Part 4: Prenatal Interventions Rhogam Intrauterine Transfusions (IUTs) Early delivery IVIG Erythropoetin Plasmaphoresis Phenobarbital Part 5: Delivery Induction Delayed Cord Clamping Vaginal birth Cesarean birth Special Care/NICU Part 6: Post-Delivery Blood Testing – All About Baby Direct Coombs test Hemoglobin Hematocrit Reticulocyte count Bilirubin test Neutrophil count Platelet Count Part 7: Post-Delivery Complications Anemia Jaundice Kernicterus Cerebral Palsy BIND Neutropenia Thrombocytopenia Part 8: Post-Delivery Interventions Blood Transfusions Partial transfusions Exchange transfusions Bililight Erythropoetin IVIG Part 9: Things to Think About Depression PTSD Having More Children Mourning the Lost Appendix Abbreviations Glossary Printable Forms Additional Resources References Part 1: An overview of Isoimmunization What is Isoimmunization (Iso)? Isoimmunization (also called alloimmunization), occurs when a woman’s immune system is sensitized to foreign blood cell antigens. This causes the woman to make antibodies that cross the placenta and destroy baby's blood cells1. During pregnancy, some of the mother's antibodies are transported across the placenta and enter the fetal circulation. This is necessary because newborns have only a primitive immune system, and the presence of maternal antibodies helps them survive while their immune system matures. A downside to this protection is that by targeting fetal blood cells, maternal antibodies can also cause HDN2. Blood production in the fetus begins at about 3 weeks, and the baby's blood cells can have antigens on the red cell membrane as early as 38 days after conception4. Antibody? Antigen? What’s my body doing again? Antigen – foreign protein on red blood cells of dad or baby Antibody – made by mom to defend her body from the antigen Antigens are foreign. Antibodies defend the body. How it works Dad makes the E antigen and passes it to baby. When baby’s blood and mom’s blood mix, mom’s blood finds the foreign antigen and makes antibodies to defend her body. This is called sensitization. The antibodies then find the foreign cells and destroy them in a process called hemolysis (hemo = cell, lysis = death). The next time mom’s sensitized body finds the E antigen, her antibodies are primed and ready to attack the foreign cells. So when mom has baby #2, who has dad’s E antigen, her antibodies cross the placenta and attack the baby’s blood. How did I become sensitized? The most common ways maternal sensitization occurs are1: Blood transfusion Birth Abortion Ectopic Pregnancy Fetomaternal hemorrhage Placental abruption Amniocentesis Chorionic villus sampling Percutaneous umbilical blood sampling External cephalic version (trying to turn a breech baby) Manual removal of the placenta (instead of spontaneous delivery of the placenta) Why is Iso dangerous? Isoimmunization is dangerous because the antibodies can cross the placenta during pregnancy and if the fetus is positive for the specific antigens, the fetal red blood cells are destroyed. This can result in anemia, hemolytic disease of the newborn (HDN), fetal hydrops (sometimes fatal), and more1. Possible Outcomes If you are sensitized, it is not a death sentence for your baby, and it does not mean you cannot have additional children. Advancements in fetal surveillance and treatment allow for successful outcomes for most of the affected fetuses. For the Rh D- woman, the drug Rhogam has reduced the risk of sensitization to less than 1% of susceptible pregnancies. Because of this other alloantibodies have increased in relative importance. These include antibodies to other antigens of the Rh blood group system (ie, c, C, e, E) and other atypical antibodies known to cause severe anemia, such as anti-Kell (ie, K, k), anti-Duffy (ie, Fya), and anti-Kidd (ie, Jka, Jkb)1. How do I know if I have an antibody? There is only one way to know if you have an antibody, you have to get tested. Routine antibody screening is done in the US on all pregnancies (unless refused) as part of the basic prenatal blood work. What do I do? Where do I start? Start by keeping a binder or folder. Use this to write down all your questions (and the doctor's answers). No question is silly. It is important that you are informed and able to actively participate in your care and advocate for your baby. Ask for copies of all your test results and keep them in your folder. Don't forget to get a copy of each ultrasound report and MCA scan (complete with all the PSV values, not just the highest or lowest). This way you can see how things are changing and how baby is doing. This is also helpful if you have to have multiple doctors. Sometimes things don't always get passed along between offices, so it is very important to have your own record. It is also a great place to put keepsakes such as ultrasound photos, bracelets, etc. Consider having someone come with you to tests and appointments for support or to drive you home after procedures. You also need to get a medical alert card for your wallet or a medical alert bracelet. Mine says “Transfusion Alert: Anti-E”. This is important even after you're not pregnant. If you are ever in an accident or unconscious and need blood, you do not want to have a life threatening transfusion reaction. Some blood banks, hospitals, or doctor's offices will provide them for you. There are also multiple places online where you can print a free card, or in the pharmacy section of our local Meijer, there is a USB medical alert card that you can put your entire medical record, not just your antibody status. Some cell phones have an In Case of Emergency or ICE section where you can write your antibody status and include emergency contact information for your MFM too. Part 2: Prenatal Testing Basic Prenatal Blood Work – What it Includes For me, my basic prenatal blood work (performed at Borgess Hospital in Michigan, USA) included:  Blood type ABO type and Rh type to find out what my blood type is (for me it is O+)  Antibody screen aka Indirect Coomb's test (not to be confused with the Direct Coomb's that is run on baby after birth). This came back positive so they ran an antibody ID panel.  The Antibody ID panel came back positive for Anti-E for me. They ran 2 more tests, a test looking for the antigen E, and another test called an antibody titer.  The antibody ID panel, antigen test, and the titer are all isoimmune specific tests. If you don’t test positive for an antibody, you won’t have these tests run.  Complete Blood Count (CBC). This checks for how many white and red blood cells you have in general. It also measures Hemoglobin (Hgb), Hematocrit (Hct), and a couple other things. This and the tests that follow are not iso related, but are done to check the general health of the person.  An automated differential checking how many of each specific white blood cells I had.  The last part of the blood test was for immunology. They wanted to make sure I was indeed immune to rubella. Rubella can cause serious problems if a pregnant woman is exposed to Rubella and is not immune to it.  They also tested my urine to see if I was pregnant, had blood cells, mucus, bacteria, protein, sugar, etc. being secreted in my urine. The most important parts of the blood test for the pregnant woman concerned about Isoimmunization are the blood type (ABO and Rh), Antibody screen, Antibody ID panel, Antigen ID panel, and the Titer. No antibody found A negative Indirect Coombs Test (also called an indirect agglutination test) means that your blood is compatible with the baby’s blood or that sensitization has not yet occurred (yay!). It checks to make sure that the pregnant woman has not developed antibodies against any potential antigen-positive blood of her baby. If sensitization has not occurred, in the case of Rh-D negative women, it can be prevented by a shot of Rhogam. See Interventions – Rhogam. This test should be repeated each pregnancy3. Antibody found A positive Indirect Coombs test result means that your blood is incompatible. If you have a positive indirect Coombs test, it means you have already been sensitized and there are antibodies floating around in your blood. In this case, an identification panel and the antibody titer test should be done. The mother can be tested early in pregnancy to check the blood type of her baby by amniocentesis or free floating fetal DNA. If the baby has antigen-positive blood, the mother will be watched closely throughout the pregnancy to prevent problems to the baby's red blood cells. If the mother declines in-utero antigen testing for the baby, she will still be monitored closely throughout the pregnancy just as if the baby was antigen positive3. There are many antigens. There is the Rhesus (Rh) group which includes D, c, C, e, E, and is the most clinically relevant (Note: no d antigen, pronounced “little d” exists so you will not find an Anti-d antibody.). However the non-Rh groups such as Kell, MNS, and Kidd have become increasingly more important as the incidence of Rh-D sensitization has decreased. Sensitization with Rh antibodies (c, C, e, E) is still responsible for the largest proportion of hemolytic disease in the newborn (HDN), followed by Anti-K, anti-D, anti-E, anti-Fya , anti- Jka4. Once you know which antibodies you have, you can find out if they are associated with hemolytic disease of the newborn (HDN). If an antibody is associated with HDN, additional blood testing occurs. While not all antibodies are included in the table below, these are some of the most common. Antibodies NOT Associated with HDN4 Duffy: Fyb Kidd: Jkb Lewis: Lea, Leb Lutheran: Lua, Lub Wright: Wrb Batty Becker Berrens Coa-b Evans G Gonzales Hil Hunt Hut Jobbins Jra Mur P Rm Ven Vw Xga Ytb Antibodies Associated with HDN4 Diego: Dia, Dib Duffy: Fya Kell: K , Kpa, k, Jsa, Jsb 1 Kidd: Jka MNS: M, S, s, N Rh: D, c, C, Cw, e, E Wright: Wra Far Good Lan LW Mta PP Pk (previously known as Tja) 1 U Zd In the case of Anti-E antibodies, it is advisable to retest at 28 weeks to be sure that Anti-c has not developed. Additional blood work Paternal blood work Once an antibody that has been associated with HDN has been found in Mom’s blood, Paternal testing takes place to see what chance the baby or future children from the couple have of being affected. At our lab this was called the Rh Phenotype test and they only checked to see how many of the genes he had for the specific antigen (E) matching my antibody (Anti-E).  If Dad is heterozygous (E/e), then there is a 50% chance that the baby or future babies will be affected by that specific antibody. In this case, the fetus can be tested in utero or after birth. They may also say that he has tested positive for both the E antigen and the e antigen.  If Dad is homozygous dominate (E/E) then there is a 100% chance of the baby and future children being affected by that specific antibody. They may also say he tested positive for the E antigen and negative for the e antigen.  If Dad is homozygous recessive (e/e) then there is a 100% chance of the baby and future children NOT being affected by that specific antibody. They may also say that he tested negative for the E antigen and positive for the e antigen. Testing Baby There are 3 ways that the baby can be tested to see if they have the specific antigens. 1. Amniocentesis is the test that is most commonly done while baby is still in the womb. See Prenatal Testing – Amniocentesis 2. Free floating fetal DNA. There are small pieces of fetal DNA floating around in Mom’s blood stream. In some places (not common practice everywhere), a simple blood test drawn from Mom can tell about some of baby’s antigens. Unfortunately, cell-free fetal DNA testing for determining the genotype for other red blood cell antigens such as E and Kell is not yet available in United States. 3. Direct Coombs test is the test that is done after birth. It is done for the babies of all sensitized mothers, and is especially important if amniocentesis or free floating fetal DNA testing was refused. See Post-Delivery Blood Testing – Direct Coombs. More blood work for mom – maternal titers What is it? Titers are a measure of expressing the concentration. Your titers will help tell you how much of the antibodies are in your blood. When is it done? Depending on doctor preference, titers are done monthly, biweekly, or weekly. Some doctors will only do titers at the beginning and at the end, and will treat baby as affected, especially in the case of an already affected pregnancy. When you have your prenatal blood work, if your indirect Coombs test comes back positive, the lab should automatically titer it for you. Where is it done? Titers are done in the lab. Why is it done? Titers are done to help tell the doctor about how many antibodies are in your system, however they are not an effective monitoring tool when you have already had an affected baby, or in the case of some antibodies. How is it done? A simple blood draw is all that is needed for titers. Usually only 1 vial of blood is taken. How often is it done? Titers are drawn anywhere from once or twice per pregnancy, to monthly, biweekly, or weekly. It depends on the doctor's preference. What do the numbers mean? Your titers will come as a ratio. Such as 1:lessthan1, 1:2, 1:4, 1:8, 1:16, 1:32, 1:1024, etc. This tells you how many times they need to dilute the blood to get rid of the antibodies. The higher the second number, the more likely baby is to be affected. Large differences in titer can be seen in the same patient between different laboratories, and a newer gel technique produces higher titer results than the older tube method. Therefore, standard tube methodology should be used to determine critical titer, and a change of more than 1 dilution represents a true increase in maternal antibody titer5. When to get additional monitoring You should have additional monitoring whenever you hit critical titer (1:16 for most antibodies, 1:8 for Kell), have a rise in titers, or have an antibody for which titers are not an accurate indicator of anemia. Ultrasound Testing What is it? Ultrasound is an imaging test that uses sound waves to create a picture of how a baby is developing in the womb. It is also used to check the female pelvic organs during pregnancy6. When is it done? Ultrasound can be done at any point in the pregnancy. Where is it done? Ultrasound can be done almost anywhere. It is frequently done in the doctor's office and doesn't require a special trip to the hospital. Why is it done? Ultrasound is used early on to establish correct gestational age. This is important for determining what the correct normal lab values are for the baby (amniotic fluid bilirubin levels, size of the baby, etc.). It is also used early to Confirm a normal pregnancy, determine the baby's age, look for problems, such as ectopic pregnancies or the chances for a miscarriage, determine heart rate, look for twins, and to identify problems with the organs (placenta, uterus, cervix, ovaries)6. Later on, ultrasounds are used to detect ascites and fetal hydrops. Ascites is the build-up of fluid in the space between the lining of the abdomen and abdominal organs. Fetal Hydrops is the end stage of hemolytic disease of the newborn where the baby has 1/3 normal hemoglobin or less. Both are severe complications from the antibodies and require immediate treatment. How often is it done?