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Alloimmunization is a global problem.

Alloimmunization is a condition where a woman’s body makes antibodies to foreign red blood cells. These antibodies are capable of crossing the placenta and attacking her unborn child. When this happens, it is called Hemolytic Disease of the Fetus and Newborn (HDFN). Approximately 15-17% of the US population is Rh- and at risk for developing alloimmunization.29 Despite the life-changing invention and routine use of RhD prophylaxis, HDFN due to anti-D continues to affect 6.7 out of every 1,000 live births in the United States. With 123,040,800 global births YTD (November 2019)30, and knowing that HDFN affects 276 out of every 100,000 births globally29, we can estimate that about 339,593 infants around the globe will be affected by HDFN in 2019 alone. Over 300,000 infants per year is a big deal. Alloimmunization and the resulting HDFN doesn’t just affect the woman, but the child and the family for years to come. 


Alloimmunization increases the stress level of many women during pregnancy. Many women spend hours or days in fear for their child. This can lead to crying, difficulty sleeping, anxiety, and depression. It can lead to increased difficulty bonding after birth; some women are afraid to become too attached to their baby in the hope that it will hurt less if they lose the child. Women with high risk pregnancies are more at risk for postpartum depression and this risk goes higher if there is not a strong attachment to the child in the womb.27 There are multiple women who claim to experience symptoms of post traumatic stress disorder after they have gone through an alloimmunized pregnancy. For those who make it through without mental and emotional stressors, there is the possibility of Mirror Syndrome. This is a rare disorder where the symptoms of anemia are mimicked in the mother. She will develop edema and may develop high blood pressure, anemia, and heart failure unless the child is delivered. If mirror syndrome develops, there is a much larger risk of fetal mortality and maternal morbidity.28 Unfortunately, the risks are not over once pregnancy is finished. Women with red blood cell antibodies are at an increased risk of hemolytic transfusion reactions, and must declare their antibodies for life before any transfusions, medical, and surgical procedures. A woman’s antibodies follow her for life, but they also affect her child. 


An alloimmunized pregnancy leads to the birth of a live child 99 out of 100 times. In one study, 0.61% of antibody births in Sweden were stilborn.31 Infants of alloimmunized mothers are considered to have Hemolytic Disease of the Fetus and Newborn; this is just a fancy way of saying a newborn whose blood is being destroyed. HDFN babies may be born prematurely. If premature then there are additional preemie issues on top of the HDFN to deal with. When a child is born, testing is immediately carried out on the cord blood. Depending on the results, the child may be placed in an incubator with phototherapy lights, or may be allowed to stay with the mother. Some infants are given an umbilical line, while others have an IV inserted. This is helpful if medications like IVIG will be given or if transfusions are expected. If there is a line into the baby, then blood draws may be available through the line. For infants with no line, heel sticks are frequently performed. It is not uncommon for an infant to have 20-40 cuts on his or her heels from all of the required blood testing in the first weeks of life. Many infants end up experiencing hyperbilirubinemia where there is a vicious struggle involving waking and feeding. The high levels of bilirubin will make the infant sleepy, which can cause low blood sugar, making it harder for the infant to wake up. If the infant is not awake and feeding, it is difficult to get rid of the bilirubin which means increased sleepiness. Untreated bilirubin can lead to cerebral palsy, intellectual difficulties, brain damage and even death. In addition to hyperbilirubinemia, anemia is a very large concern since untreated anemia can be fatal. Often when the body is working so hard to produce red blood cells, it will forget about producing the other blood cells so neutropenia and thrombocytopenia are both common struggles for an infant with HDFN. It is not uncommon for an infant to end up requiring additional supplementation or to be woken for feeds. The reality is that these infants tend to spend longer in the hospitals, require more testing than usual, and struggle with various issues for approximately 3 months until the mother’s antibodies die and leave the child’s system. Once the antibodies are gone and the child released from hematology, the effects may continue to haunt the rest of the family as well.


An alloimmunized pregnancy affects the entire family. Often parents must find a way to provide childcare for other children when additional doctor’s appointments are needed. Fathers may feel an additional financial burden as the cost of pregnancy increases. It may be difficult to watch the emotions the mother is going through, and the number of children a couple plans to have are frequently cut short to avoid the stress of another alloimmunized pregnancy. Parental involvement in the community may decline as the family deals with the additional stress. Siblings are affected too, but how and to what degree varies. Some children are more anxious and fearful, while others are more caring and concerned about the welfare of their sibling. Grandparents or other adults in the support network may be asked to take on additional activities like caring for the other children, help with housework, and meal preparation; all of which are an invaluable help to the family. It would be very difficult for a woman to go through an alloimmunized pregnancy without a good support network around her. Families going through a difficult pregnancy need to be supported in order to be healthy families that can stay together and heal.


Alloimmunization and Hemolytic Disease of the Fetus and Newborn are devastating diseases that are still happening around the world today. Over 300,000 infants are affected each year, and while over 99% of them are born alive, the effects of HDFN are felt for years to come. Women with red blood cell antibodies must make certain all of their health care providers are aware of their antibodies. Infants may become harmed or have lasting effects from the HDFN. The entire family feels the burden of dealing with an alloimmunized pregnancy as financial and time stressors abound. Alloimmunization and HDFN affects the woman, her child, and her family for years to come. 


Global Statistics

Let’s take a moment to look at the risk of developing alloimmunization around the world. It would be impossible to provide data for all of the antigens, so we will focus on D and Kell, two of the most dangerous antibodies to form, and c and E. Together these antigens are four of the most immunogenic antigens with the potential to cause severe HDFN 1, 22. The countries chosen for statistical representation are those that had a study done in their country providing statistics on the prevalence of the antigens. 


Antigens are present on all human blood cells. The type of antigen determines what type of blood cell it will be. For instance, blood cells with the B antigen are labeled B blood type. Blood cells with the Rhesus D antigen (referred to here as D) are labeled +. So a B+ blood type belongs to a blood cell that has the B antigen and the D antigen on it. If a person lacks a specific antigen, they are at risk for developing the corresponding antibody. In the charts below, there are four columns. The first column names the antigen. D, Kell, c, and E are four of the most immunogenic antigens and are four antibodies that can cause some of the most severe cases of HDFN. The next two columns are both percentage numbers. The first number is the frequency of the specific antigen; this tells how many people in a given population have the antigen. The next number is the percentage without the antigen; this is the percentage of people who are at risk for developing an antibody to that specific antigen. The percentage without the antigen is found by subtracting the frequency from 100. It is important to note that not all women exposed to the antigen one time will become alloimmunized. The exact immunogenic frequency varies and has not been studied for all population groups. So instead of using a number claiming “this percentage will develop alloimmunization”, the term, “at risk of developing an antibody” was chosen.The last column translates these percentages into the number of women at risk for developing that specific antibody. This is done by taking the total female population of a country, and multiplying it by the percentage of people at risk for developing the specific antibody.



Basque 2, 3, 4

Total Female Population: 1,123,940

[[PASTING TABLES IS NOT SUPPORTED]]

The Basque people have the highest frequency of RhD- in the world. Numbers vary, but many studies report it around 40% or higher. With anti-D forming in 70% of patients exposed to the D antigen10, it is absolutely vital that people in this region have unfettered access to RhD prophylaxis in order to prevent alloimmunization and HDFN.



Chile5, 6
Total Female Population: 9,690,540

[[PASTING TABLES IS NOT SUPPORTED]]


China 7, 8, 9

Total Female Population: 701,076,434

[[PASTING TABLES IS NOT SUPPORTED]]

It is important to note that the vast majority of Chinese are kk, and do not possess the K antigen. The exact number varies by study, but all data points to a 0 or <1% chance of a Chinease person having the K antigen. That means nearly all Chinese are at risk for developing anti-Kell. It also means that a Kell+ man is nearly guaranteed to have his partner develop anti-Kell. This is very important when you consider immigration and interacial relationships. It is also important in transfusion medicine. It would stand to reason that with such a high Kell- population, all Chinese should only be given Kell- blood to prevent alloimmunization and hemolytic transfusion reactions. 



Cote d’Ivoire 11, 12

Total Female Population: 13,077,895

[[PASTING TABLES IS NOT SUPPORTED]]

The frequencies of D, K, c, and E in countries in Subsaharan Africa are similar13. 



India 14, 15

Total Female Population: 662,903,415

[[PASTING TABLES IS NOT SUPPORTED]]


Nigeria 16, 17

Total Female Population: 101,669,950

[[PASTING TABLES IS NOT SUPPORTED]]


Pakistan 18, 19, 20, 21

Total Female Population: 107,220,324

[[PASTING TABLES IS NOT SUPPORTED]]

In Pakistan, the RhD- is more common in females (12.22%) vs males (9.01%). 19



Frequency by Ethnicity 23, 24, 25, 26

[[PASTING TABLES IS NOT SUPPORTED]]

References
  1. https://www.sciencedirect.com/science/article/abs/pii/S2352302616300199

  2. https://countryeconomy.com/demography/population/spain-autonomous-communities/basque-country

  3. http://www.biologiaevolutiva.org/memoriaIBE2018/files/VASCOS_s41431-018-0232-1.pdf

  4. https://www.karger.com/Article/Abstract/152616 

  5. https://www.worldometers.info/demographics/chile-demographics/

  6. https://www.researchgate.net/publication/282709944_Frequency_of_antigens_in_Rh_and_Kell_blood_system_in_blood_donors

  7. https://www.worldometers.info/demographics/china-demographics/

  8. https://www.ncbi.nlm.nih.gov/pubmed/27320061

  9. https://www.ncbi.nlm.nih.gov/pubmed/26638180 

  10. https://www.dovepress.com/prevention-and-management-of-transfusion-induced-alloimmunization-curr-peer-reviewed-fulltext-article-IJCTM

  11. https://www.worldometers.info/demographics/cote-d-ivoire-demographics/ 

  12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4189989/

  13. https://www.ncbi.nlm.nih.gov/pubmed/18296094

  14. https://www.worldometers.info/demographics/india-demographics

  15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705660/

  16. https://www.worldometers.info/demographics/nigeria-demographics/ 

  17. https://www.researchgate.net/publication/326328609_Rh_and_Kell_blood_group_antigen_prevalence_in_a_multi-ethnic_cohort_in_Nigeria_implications_for_local_transfusion_service 

  18. https://www.worldometers.info/demographics/pakistan-demographics

  19. http://ayubmed.edu.pk/JAMC/PAST/20-4/Khattak.pdf

  20. http://www.gjtmonline.com/article.asp?issn=2468-8398;year=2018;volume=3;issue=1;spage=26;epage=29;aulast=Jabin;type=0

  21. https://www.ncbi.nlm.nih.gov/pubmed/26454398

  22. https://www.researchgate.net/publication/6398567_Update_on_HDFN_New_information_on_long-standing_controversies

  23. https://www.ncbi.nlm.nih.gov/books/NBK2270/

  24. https://www.ncbi.nlm.nih.gov/books/NBK2269/

  25. https://ashpublications.org/blood/article/114/22/4188/76549/Frequency-of-Minor-Blood-Group-Antigens-Among

  26. https://www.redcrossblood.org/content/dam/redcrossblood/forms-and-certificates/immuno_33_3_linked.pdf

  27. https://womensmentalhealth.org/posts/depression-is-more-common-in-women-with-high-risk-pregnancies/

  28. https://www.ncbi.nlm.nih.gov/pubmed/20357423

  29. https://www.ncbi.nlm.nih.gov/books/NBK459353/

  30. https://www.worldometers.info/world-population/

  31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258779/