Where does the Rho(D) immune globulin (anti-D) Come From?
by Kieran Froese
Earlier this year I was in the surreal position of watching myself on television being hailed a “hero” with “gold running through her veins”. I certainly don’t feel like a hero. The reason for the media attention was that I am an anti-D donor. Something which is made more significant because I am also a midwife involved in the administration of the end-product of that anti-D and I get to enjoy first-hand the benefits of this remarkable medication.
Why is rhesus factor important during pregnancy
Rhesus factor (Rh) is a protein found on some types of blood. It is inherited as a dominant gene and in Australia about 84% of the population are Rh positive, but globally it is thought to be 94% (1, 2). If a person with Rh negative blood is exposed to Rh positive blood it is possible that their immune system recognises the foreign protein and creates antibodies to attack it (2). Not everybody's immune system will be stimulated and there isn't a test to determine whose will be. Once the body has started producing antibodies it never stops (3).
If a person with Rh negative blood is pregnant with a baby who has Rh positive blood, there an increased risk of exposure to the positive blood; if the mother also makes antibodies, these freely cross the placenta and attack the foetal blood (3). Prior to the development of a preventative treatment, women with Rh negative blood would carry only one or two healthy pregnancies to term before having runs of successive stillbirths or babies born alive but only surviving long enough for their mothers to fall in love with them. For a long time, no one could explain why.
Linking rhesus factor to haemolytic disease
The discovery of the rhesus factor was borne of a research race during the late 1930s and early 1940s with several studies published almost simultaneously, identifying rhesus factor and soon after linking it to haemolytic disease of the foetus and newborn (4). Following this discovery, living babies could be treated with a blood transfusion immediately after birth. However, by then the effects of the disease had often already caused major complications in the child. It wasn’t until the mid-1960s that a preventative treatment was discovered.
Multiple people are attributed to the discovery of anti-D treatment, one of which was John Gorman, an Australian doctor working in New York, USA. Gorman and his team ran what would these days be considered entirely unethical experiments on inmates of the Sing Sing Correctional Facility in New York State. The anti-D antibody was harvested from the plasma of Rh-negative prisoners who had been sensitised with positive blood. These antibodies were then injected into unsensitised prisoners affording them complete protection from sensitisation when exposed to positive blood (5). This is known as a paradoxical treatment; introducing the very thing that you’re trying to avoid, in this case, the anti-D antibody. Keen to test his knowledge on the pregnant population but restricted by ethical limitations, Gorman recruited his own sister-in-law, Cath Gorman. Cath had a negative blood group and her husband, John’s brother, was positive. Cath consented and was injected with anti-D. She went on to have seven healthy children.
My journey to becoming an anti-D donor
I too have a negative blood group, and therefore I have had my own experience of being a consumer of anti-D. In my first pregnancy I was quite young, and I didn’t actively engage in decisions about my care. I trusted my care providers to tell me what to do and I followed. I received anti-D during pregnancy and again after my daughter’s birth, as she had a positive blood group. During my second pregnancy I discovered informed decision making and decided that I would do NOTHING that was routine without understanding why it was done. When it came to anti-D, I struggled to find balanced information. Almost 20 years ago, I was limited by the available technology. What information I did find, advised to just do it, but I couldn’t find anything that explained what anti-D was or how it worked. Ultimately, I chose to receive anti-D and I’m glad that I did, although that daughter turned out to be a negative blood group like me.
In my third pregnancy I participated in a trial of the Non-Invasive Prenatal Analysis (NIPA) test in Australia. The NIPA test is a maternal blood test in pregnancy which identifies fractionated foetal DNA and the foetal blood type with the aim of reducing anti-D usage in the context of a global shortage of donors. This test was already being successfully used in Europe (6).
I suffered from anaemia during my pregnancies as many women do. I coped well with the symptoms and used conventional treatments as needed. It was several years after my last pregnancy that I noticed symptoms of what turned out to be quite severe anaemia. I experienced heavy periods but didn’t have any points of comparison, so I assumed it was normal. By the time I sought treatment I had loud banging in my ears constantly and my haemoglobin had been in the 70s for well over a year. Sure, I was tired and washed out, I had three young children and I worked in continuity midwifery. It took a long time for me to recognize that something wasn’t right. I underwent multiple tests, treatments, and procedures, some of which made the bleeding worse. I received several blood transfusions, and I was so grateful for that blood. I wanted to be able to donate too but I had to look after myself first. Eventually, my treatment led to a hysterectomy. This was a scary time and I experienced grief at the loss of my uterus which had carried my babies and performed so well at its task. I was only 35 years old.
Following my recovery, I was motivated to donate blood as soon as I was able to. Blood and plasma donation is a wonderful gift. In Australia blood donation is altruistic but donors are well cared for and are given tasty snacks after each donation. During this period, I was learning about the source of anti-D. I knew that it was a blood-product, but I didn’t know how it was produced. When I learnt that people were intentionally sensitised for the sole purpose of anti-D donation, my interest was piqued. The whole process intrigued me and the idea that I could use my hysterectomy surgery to benefit maternity care was a huge motivation to make enquiries.
Voluntary sensitisation and anti-D donation
I made several requests to be voluntarily sensitised for the purpose of donation every time I went to donate blood. Voluntary sensitising is achieved by receiving repeated transfusions of closely matched positive blood. Not everyone creates antibodies, even when intentionally trying, and there is no test to predict who will (3). Most donors are men and I felt I had to assert myself to be taken seriously. Importantly, I had to provide evidence of my infertility via medical records of my hysterectomy. Once I was accepted into the program, I underwent a lengthy testing and consent process before I was ready to receive my first positive blood transfusion. My first transfusion was 40ml given by slow push and I felt… nothing. I had smaller top up transfusions every three months. It wasn’t until my third transfusion boost when I was told that I had, in fact become sensitised and was actively producing antibodies.
I am now several years on from that first transfusion. I try to donate plasma every two to three weeks, and I receive a boost transfusion of about 5-10ml every 6 months or so. I have a matched donor who remains anonymous and donates specifically for me. I feel sick for a day after having the boost as my body reacts to the foreign blood. I try to have the day off work and take it easy. I otherwise feel no different. I am at increased risk of a massive, potentially fatal, haemolytic response if I was ever to mistakenly receive a full blood transfusion of positive blood, but I’m privileged to live in a society where that risk is small. My current titre is 42 international units of anti-D per ml of donated plasma. At about 850mls per donation and about 20 donations a year, that equals 1142 doses of anti-D a year. Anti-D is made from pooled plasma which means that my plasma is pooled together with the plasma of other anti-D donors. It then goes through a process called “fractionisation” and the resultant IgG is polyclonal in nature (1).
Of all the life-altering medical discoveries made during the 20th century, the discovery of rhesus factor and subsequent anti-D treatment is one that has had immeasurable impact on perinatal outcomes. Western nations are so fortunate to be living in an age where we have the privilege of being naïve to the heartbreak of haemolytic disease of the foetus and newborn, but this privilege is limited to access to both testing and treatment and that privilege is not (yet) afforded to all (7). I’m so grateful to those who have come before me to allow me to be a mother, a midwife and especially, an anti-D donor. I encourage all those who are able, to consider blood donation as a priceless gift that your remarkable body can give another.
1: Zipursky, A., Bhutani, V.K. and Odame, I., 2018. Rhesus disease: a global prevention strategy. The Lancet Child & Adolescent Health, 2(7), pp.536-542.
2: Australian Red Cross Lifeblood, 2023. Rh. https://www.lifeblood.com.au/health-professionals/testing/blood-groups/rh
3: Whickam, S. 2021. Anti D Explained. Birthmoon Creations. 9781999806453 (ISBN10: 199980645X)
4: Fisher, R.A., 1947. The Rhesus Factor a Study in Scientific Method. American Scientist, 35(1), pp.95-113.
5: Freda, V.J., Gorman, J.G. and Pollack, W., 1964. Successful prevention of experimental Rh sensitization in man with an anti‐Rh gamma2‐globulin antibody preparation: a preliminary report. Transfusion, 4(1), pp.26-32.
6: Yang, H., Llewellyn, A., Walker, R., Harden, M., Saramago, P., Griffin, S. and Simmonds, M., 2019. High-throughput, non-invasive prenatal testing for fetal rhesus D status in RhD-negative women: a systematic review and meta-analysis. BMC medicine, 17, pp.1-10.
7: Routray, SS, Behera, R, Mallick, B, et al. 2021. The Spectrum od Hemolytic Disease of the Newborn: Evaluating the Etiology of Unconjugated Hyperbilirubinemia among Neonates Pertinent to Immunohematological Workup. Cureus 13:e16940