Rhesus Disease: The Mother-Baby Blood Clash

By Akeesha Subasinghe

Edited by Ananyaa Vishwanath

Rh sensitisation and rhesus disease present a unique and rare immunological conflict that can arise during pregnancy or labour when an Rh‑negative mother carries an Rh‑positive foetus. In a shocking twist of nature, a mother’s immune system will turn on her child, recognising the foreign antigen as a threat. Whilst this usually has no effect on the foetus at present, it presents a great danger to future pregnancies, possibly leading to jaundice, anaemia and even stillbirth in the worst cases. Due to developed understandings of blood groups and medicine, Rh sensitisation is now rare in high‑income countries. However, due to global healthcare inequality, it remains a preventable cause of large scale infant mortality worldwide. Ensuring universal access to anti‑D prophylaxis (the programme of prevention of rhesus disease) is extremely important as a medical necessity and an ethical responsibility.

When can RH sensitisation occur?:

To explore this question it is first important to understand the rhesus (Rh) factor. Have you ever wondered what the ‘positive’ or ‘negative’ part of your blood group referred to? Well, it refers to the presence or absence of a type of protein (the rhesus factor) on the surface of your red blood cells. Around 85% of people are Rh positive and do have the protein, including the immunogenic RhD antigen. If you are part of the minority without the Rhesus factor protein, you do not have this antigen. Being Rh positive or Rh negative has no effect on your health and only becomes significant when there is a situation where blood from different individuals comes into contact[1]. This includes blood transfusions as well as pregnancy and childbirth. The reason why it is important to be aware of your blood type in these situations is that the two types are incompatible. When Rh negative and Rh positive blood comes into contact, the immune system of the Rh negative person will detect the Rhesus antigens on the Rh positive blood cells, marking them out as foreign. The immune system will then coordinate a response, producing anti-D antibodies to attack the Rh positive blood cells. 

In pregnancy or childbirth, this plays out when an Rh negative mother carries an Rh positive foetus. The Rh positive allele is dominant, meaning that even if the mother is Rh negative, if the father is Rh positive, the baby may also be Rh positive. This mismatch between the mother and baby’s blood is known as Rh incompatibility. Even this is not problematic in most cases, as in pregnancy the blood of the mother and the foetus are not shared and normally do not mix, separated by the placental barrier. However, there are certain instances in which the two may come into contact:

This is the moment of Rh sensitisation- upon coming into contact with the foreign antigens, the mother’s immune system will begin to develop antibodies against the Rh factor antigens detected on the baby’s red blood cells. However, complications do not often arise instantly- this pregnancy and this baby will normally be unaffected. This is because the mother’s blood is unlikely to come into contact with the baby’s until delivery, where a few of the baby’s blood cells may leak into the mother’s bloodstream. The mother’s anti-D antibodies (which start being produced at sensitisation) take a long time (often weeks)  to form as part of the primary response, and so will not be ready until after the baby has been born, by which point the baby is out of the womb and so out of risk of being attacked by the mother’s immune system [2]. The real risk is when the mother becomes pregnant with another child- a second Rh positive child to be exact. 

The second pregnancy: 

Now that the mother’s white blood cells have produced anti-Rh antibodies for the first time the second time will be much easier- the immune response will be much faster. There is no need for sensitisation this time- the anti-D antibodies (and corresponding memory-B cells) are already circulating in the mother’s bloodstream. The next time her blood is exposed to the RhD antigen (on red blood cells of a second Rh positive foetus during the pregnancy)* The white blood cells will mass produce antibodies immediately and very rapidly as part of the secondary response- much quicker than the slow and delayed primary response with the first pregnancy.  Whilst blood is not directly shared between the two, the transfer of antibodies from the mother to the baby’s bloodstream across the placenta is a completely normal process, and so these anti-D antibodies are actually able to cross through into the foetus's bloodstream. There, they can wreak havoc, attacking the baby’s red blood cells, which are identified using the RhD antigens found on their surface as a foreign threat. The baby's red blood may be made to swell up and burst (haemolysis), and this relentless attack can even continue a few months after birth. This phenomenon is known as rhesus disease or haemolytic disease of the newborn (premature breakdown of red blood cells). 

What is rhesus disease?:

Symptoms

It is important to note that this disease will only physically affect the baby and not the mother [3]. Furthermore, the symptoms depend on severity, with around 50% of babies diagnosed with rhesus disease being easily treatable with only mild symptoms, according to the NHS. 

If rhesus disease is developed in a foetus they may become anaemic (haemolytic anaemia) as their red blood cells are being destroyed faster than their body can produce them. This will lead to their blood flowing at a faster rate as their blood is thinner. When a foetus is deemed to be at risk of developing the disease, a doctor would monitor this by measuring the flow of blood in their brain. This can be detected with the Doppler ultrasound scan, although there may not be any other noticeable symptoms. If anaemia inside the womb becomes severe, it can lead to fluid retention and swelling (detected in scans), and in the worst cases foetal heart failure and stillbirth. [4]

In a newborn the symptoms arise in two main ways- haemolytic anaemia and newborn jaundice. Haemolytic anaemia is when red blood cells are destroyed prematurely, at a faster rate than they can be replenished. This may lead to pale skin, poor feeding, unusual tiredness, an increased breathing rate (as there are less red blood cells to transport oxygen around the body for respiration), or jaundice, which are all important signs indicative of rhesus disease. Newborn jaundice turns the skin (most noticeably on their palms and soles) and whites of the baby’s eyes yellow. This is caused by increased levels of bilirubin, a yellow substance that is naturally formed from the breakdown of red blood cells. The rate at which blood cells are being destroyed creates bilirubin levels that are too high for the liver of a newborn to process at a sufficient pace, so it builds up in the bloodstream, leading to the development of jaundice. 

Treatment and risks

As mentioned above, around half of the cases of rhesus disease are mild: whilst the baby is still monitored regularly for signs of change (e.g. with blood tests), much treatment is not usually needed. Newborn jaundice (whether it is caused by rhesus disease or not) is usually harmless. It will typically clear itself up when the newborn is around 2 weeks old, as their liver develops and becomes more effective at processing bilirubin.  

In severe cases however, this disease can be incredibly frightening. Without immediate treatment, severe anaemia can develop into a critical illness when insufficient levels of oxygen are being transported around the body [5]. Severe cases of jaundice and the build up of bilirubin in the brain (if left untreated) can lead to kernicterus, a neurological condition. This may cause hearing loss, vision loss, brain damage, learning difficulties, or even death in some cases. To prevent this, a newborn may be treated with phototherapy (light treatment) to get bilirubin levels down to normal levels. They may also be prescribed folic acid, to help increase production of red blood cells. [6]

In other severe cases, treatment may need to start before the baby is born, inside the womb. Blood transfusions may be performed - (IUT) intrauterine transfusions-  to treat anaemia, although this could result in complications with the pregnancy. The baby also may need to be delivered early using medicine to induce labour or a caesarean section, to allow for immediate treatment. This is usually only done in/after the 34th week of pregnancy. 

Diagnosis and reducing the risk: 

A sure fire way of knowing whether a foetus is at risk of rhesus disease are blood tests, which are done early on in most pregnancies. This can determine whether or not the mother is RhD negative. If she is, further steps are taken- the blood of the father and/or the foetus may also be taken in some cases to determine the risk of Rh incompatibility. If there is a risk, her blood will be tested for anti-D antibodies. If these are already present during pregnancy the mother and foetus will be under regular monitoring to assess the situation [7]. If the antibodies are not present the mother would be offered an injection of anti-D immunoglobulin, one shot at the 28th week of pregnancy, and the second within the first 72 hours postpartum, to prevent the formation of antibodies, which can reduce the risk posed for future pregnancies. 

Rhesus prophylaxis and prevention: 

Thanks to anti-D immunoglobulin (RhoGAM), or more specifically anti-D prophylaxis** (also known as anti-D immunoprophylaxis), rhesus disease is incredibly uncommon these days. I’m sure many of you, (like me up until recently) had never heard of it. Anti-D prophylaxis (the prevention strategy) and anti-D immunoglobulin (the drug) were developed in the 1960s and introduced in the 70s. The administration of this medication at the correct time reduces the chance of sensitisation to 0.35%.[8], showing how effective it is. Despite this, the number of global deaths from rhesus disease has only decreased by 50% within the 50 years [9]. This suggests a problem with availability and access, rather than a lack of the technology/knowledge.

Lack of access

The difference in the frequency of rhesus disease in different parts of the world is glaring evidence for healthcare disparities and inequalities. In high income countries it is easy to think of the disease as having been virtually eradicated, but rhesus disease remains a pressing public health issue in low to middle income countries (LMICs). Annually, it affects more than 150,000 children causing 1000s of preventable stillbirths, neonatal deaths and cases of other complications [10]. The reason for this is an estimated half of the women in the world who need anti-D prophylaxis have no access to it [11]. Many of these women are found in South Asia, Sub-Saharan Africa, South America and even in China, where the drug has yet to be domestically approved through clinical trials, despite global acceptance [12]. Here in the UK, the drug would be free through the NHS, but the same cannot be said for other parts of the world, where a woman might find herself having to pay unaffordable sums of money to get it. Even the detection of possible Rh incompatibility (which ensures a quick and low risk response in developed countries) faces challenges due to limited resources, inadequate access to antenatal care, and a lack of universal screening programs. This means that mothers (and babies) at risk are left unprotected and unaware of the risks of their pregnancy. In countries where health infrastructure and resources are overwhelmed by other, more prevalent issues like malaria or HIV, it can be difficult to tackle the lack of access to anti-D prophylaxis.   

It is not, however, impossible. The calculations of Dr. Steven Spitalnik, the executive director of the World Initiative for Rh disease Eradication, and his team, estimated that the necessary investment (needed to sponsor doses and fund technology which would make blood typing cheaper), would simply be a dime’s worth for many governments/global organisations: 

“We did a back-of-the-envelope calculation. It would be around $150 million a year to solve this problem,” - Dr Spitalnik. 

In the article [12] ‘Hostile Blood: The Forgotten History of Rh Disease and its Miraculous Cure’, Hope Hodge Seck remarks that this would amount to a simple rounding error in the context of global health or even just the cost Jeff Bezos’ pair of Gulfstream private planes. For the price of two private planes a year (or just a single personalised ‘Kim Air’ plane), global investment and attention could massively change the picture and save the lives of millions. 

Ignorance and Complacency 

Lack of access and availability in LMICs is not the only obstacle to reducing infant mortality. Even in higher-income countries, where access and affordability is assured, complacency and inaccurate knowledge presents a threat to the global eradication of Rh disease. The rising trend of vaccine hesitancy and ‘anti-vaxxers’ since COVID-19, has left a small number of women (in countries such as the USA) declining the treatment, at the risk of her unborn baby. 

The problem is only worsened by ignorance, scepticism and a lack of advocacy from health professionals/administrators in both developed and developing areas. Furthermore, the rarity of the disease in high income countries has led to the decline in awareness of the disease amongst health professionals. This is an obstacle to effective prevention, as doctors may not know to administer the medicine at the correct times and may be unable to recognise the signs of rhesus disease in newborns. [12]. 

Supply issues

Another issue: falling rates of blood donations. Anti-D immunoglobulin is made using the plasma of Rh-negative donors, who have already been sensitised and are producing anti-D antibodies. Prior to the drug becoming prevalent, there were plenty of these naturally sensitised women who were able to donate. Due to anti-D prophylaxis successfully reducing the incidence of sensitisation, there is now a very small number of naturally sensitised women. Blood donors are now put through a lengthy, time consuming process so they can be intentionally sensitised to produce these antibodies. Combined with the already falling numbers of blood donors since COVID-19, this has significantly lowered the amount of vital plasma being donated to make anti-D immunoglobulin. This has created supply issues and shortages around the world, making it even harder for people in low income countries/rural areas to access it. 

Conclusion: 

Rhesus disease is an incredibly serious disease, which could theoretically affect any family. Rh incompatibility is a danger with no consideration for lifestyle, wealth or country. It cannot be avoided with hygiene, exercise or education. The only thing that matters; genes. 

This is why it is important for all women to be aware of these risks during pregnancy, and why it is crucial for them to know their blood type. The continuing education of health professionals around the world on this matter is essential to avoid the risks of complacency, so women and their babies are given the best chance of early detection and treatment. It is important that governments, charities and global health organisations invest in programs to improve antenatal care in deprived/rural areas of the world, to improve detection of Rh incompatibility. 

Despite the high risks of the disease, it is also extremely preventable. With the highly effective anti-D prophylaxis, the global eradication of rhesus disease has been possible for decades. Even so, infant mortality due to rhesus disease remains an issue in many parts of the world due to global healthcare inequalities. With dedicated and continuous investment to simplify technology, reduce the cost of anti‑D immunoglobulin, strengthen healthcare infrastructure, and improve distribution networks, access to prophylaxis can be expanded. Advocacy should be used to encourage more people to donate blood, so the supply of anti-D immunoglobulin can be improved and stabilised. It is a crucial, life saving drug, so everything must be done to protect and increase its availability. Investment could also help to expand antenatal care and to introduce universal screening. With combined efforts from governments, charities and NGOs, vulnerable communities can be protected and global health disparities can start to be narrowed. With this, an easily preventable cause of infant mortality could be eliminated in all parts of the world. 

‌Footnotes:

*You may be confused about how the mother’s white blood cells are exposed to the fetus's red blood cells during the second pregnancy, as I have already stated that mother and foetus have separate bloodstreams which do not mix. Whilst this is true, in the majority of pregnancies a very small number of foetal red blood cells will cross into the mother’s circulation. This is known as fetomaternal hemorrhage (FMH) or transplacental microtransfusion.  The amount is so insignificant that it is usually not enough for Rhesus disease or even sensitisation to occur with the first pregnancy. The amount of blood mixed in delivery is much more significant, which is why this is usually the point of sensitisation. However, during the second pregnancy, when anti-D antibodies and memory B cells are already present in the mother’s circulation, the small number of foetal blood cells is enough for her immune system to instantly recognise the foreign antigen and trigger the rapid mass production of anti-Rh antibodies- the secondary response. 

**Anti-D immunoglobulin refers specifically to the substance (medication) given to pregnant women, whilst anti-D prophylaxis (and anti-D immunoprophylaxis) refers to the preventative practice/strategy of administering anti-D immunoglobulin at specific times during and after the pregnancy- it describes the overall program of prevention of rhesus disease, not just the drug. 

References: 

1. Cleveland Clinic. 2022. “Rhesus (Rh) Factor.” Cleveland Clinic. November 10, 2022. https://my.clevelandclinic.org/health/diseases/21053-rh-factor.

2. ‌“Rh Sensitization during Pregnancy.” 2023. Columbiadoctors.org. 2023. https://www.columbiadoctors.org/health-library/condition/rh-sensitization-during-pregnancy/.

3. Nguyen, Thinh. 2018. “Rh Incompatibility during Pregnancy (for Parents) - KidsHealth.” Kidshealth.org. 2018. https://kidshealth.org/en/parents/rh.html.

4. NHS. 2017. “Rhesus Disease - Complications.” Nhs.uk. October 23, 2017. https://www.nhs.uk/conditions/rhesus-disease/complications/.

5. “Hemolytic Disease of the Fetus and Newborn (HDFN).” n.d. Www.nationwidechildrens.org. https://www.nationwidechildrens.org/conditions/hemolytic-disease-of-the-fetus-and-newborn-hdfn.

6. NHS. 2021. “Rhesus Disease.” NHS. November 16, 2021. https://www.nhs.uk/conditions/rhesus-disease/.

7. NHS. 2017. “Rhesus Disease - Diagnosis.” Nhs.uk. October 23, 2017. https://www.nhs.uk/conditions/rhesus-disease/diagnosis/.

8. “Rhesus D (RhD) Negative Blood Type: Care in Pregnancy and after Birth.” n.d. Cambridge University Hospitals. https://www.cuh.nhs.uk/patient-information/-guidance-on-the-use-of-routine-antenatal-anti-d-prophylaxis-raadp-and-postnatal-care-for-rhd-negative-women/.

9. Visser, Gerard H.A., Gian Carlo Di Renzo, Steven L. Spitalnik, Gerard H.A. Visser, Gian Carlo Di Renzo, Diogo Ayres-de-Campos, Maria Fernanda Escobar, et al. 2019. “The Continuing Burden of Rh Disease 50 Years after the Introduction of Anti-Rh(D) Immunoglobulin Prophylaxis: Call to Action.” American Journal of Obstetrics and Gynecology 221 (3): 227.e1–4. https://doi.org/10.1016/j.ajog.2019.05.019.

10. Zipursky, Alvin, Vinod K Bhutani, and Isaac Odame. 2018. “Rhesus Disease: A Global Prevention Strategy.” The Lancet Child & Adolescent Health 2 (7): 536–42. https://doi.org/10.1016/s2352-4642(18)30071-3.

11. Pegoraro, Valeria, Ducciocompet Urbinati, Gerard H. A. Visser, Gian Carlo Di Renzo, Alvin Zipursky, Brie A. Stotler, and Steven L. Spitalnik. 2020. “Hemolytic Disease of the Fetus and Newborn due to Rh(D) Incompatibility: A Preventable Disease That Still Produces Significant Morbidity and Mortality in Children.” Edited by Ju Lee Oei. PLOS ONE 15 (7): e0235807. https://doi.org/10.1371/journal.pone.0235807.

12. Hope Hodge Seck. 2023. “Hostile Blood: The Forgotten History of Rh Disease and Its Miraculous Cure • the Blood Project.” The Blood Project. November 27, 2023. https://www.thebloodproject.com/hostile-blood-the-forgotten-history-of-rh-disease-and-its-miraculous-cure/.

Image 1: “Mauritius Images.” 2025. Mauritius-Images.com. 2025. https://www.mauritius-images.com/en/asset/ME-PI-10180719_mauritius_images_image_number_10460183_overhead-view-of-mother-holding-newborn-boy-s-fingers-in-hospital-bed.

‌Image 2: “Rhesus Disease: Over 171 Royalty-Free Licensable Stock Illustrations & Drawings | Shutterstock.” 2025. Shutterstock. 2025. https://www.shutterstock.com/search/rhesus-disease?image_type=illustration&dd_referrer=https%3A%2F%2Fwww.google.com%2F.

Bibliography:

“Rhesus D (RhD) Negative Blood Type: Care in Pregnancy and after Birth.” n.d. Cambridge University Hospitals. https://www.cuh.nhs.uk/patient-information/-guidance-on-the-use-of-routine-antenatal-anti-d-prophylaxis-raadp-and-postnatal-care-for-rhd-negative-women/.

‌“Strengthening Supply Chain of Anti-D Immunoglobulins | European Medicines Agency (EMA).” 2025. European Medicines Agency (EMA). July 4, 2025. https://www.ema.europa.eu/en/news/strengthening-supply-chain-anti-d-immunoglobulins.

‌“Haemolytic Disease of the Newborn (HDN).” n.d. Milton Keynes University Hospital. https://www.mkuh.nhs.uk/patient-information-leaflet/haemolytic-disease-of-the-newborn-hdn.