Hemolytic disease of the newborn (HDN) as we call it now had different names over the years. Hippocrates may have described it, but a French midwife was the first to record the symptoms after the birth of twins. She reported the first baby was swollen and died promptly, the second, in good condition after birth became yellow, and died a few days later. By the time the Rh reaction was recorded in a lab test, doctors and midwives had seen the results for centuries. Here’s what we know for sure no matter what name it went by: HDN was the major cause of infant death in utero and after birth, during the neonatal period. The infants that survived were severely brain damaged.
In the 1930s, there wasn’t one disease of newborns called HDN, but four. Doctors did not see the symptoms as being related, and none understood the cause. That information came later after the discovery of Rh factor and Levine’s 1939 report on the woman at Bellevue Hospital. I should mention that desperate doctors did try blood transfusions, but in their ignorance, they often transfused more Rh + blood making the problems worse. Once the Rh antigen was discovered, better treatments occurred. (See treatments below).
The Rh Newborn Diseases by Symptoms:
Hydrops, which means waterlogged, was used to describe swollen babies with universal edema. Babies with hydrops died quickly or were born dead.
Icterus gravis neonatorum, means severe yellowing of the newborn, also called yellow jaundice. Born healthy at first the babies quickly deteriorated. Their organs were enlarged, and they died from heart failure because their blood wasn’t carrying oxygen as it should. This type of death is painful. On autopsy the babies were found to have yellow brains, stained by bilirubin a substance made in the liver (also called kernicterus).
Congenital anemia, a severe deficiency of red blood cells was felt to be caused by something happening in utero. Doctors observed unexplained hemorrhaging into the gut, lungs, and spinal fluid. Congenital anemia didn’t become critical until the second or third week after birth. Some babies died, others recovered.
Erythroblastosis fetalis, means the presence of too many red blood cells or immature blood cells called erythroblasts. When red blood cells are disrupted, oxygen isn’t carried normally throughout the body. The immature cells spread and cause swelling in spleen, liver, kidneys and brain. Again, a very painful death for a baby.
Here is what Doctor Levine wrote in his 1941 paper published in the Journal of the American Medical Association after he was called in to consult on a fetal death of erythroblastosis fetalis. “It is probable that there is a connection between the occurrence of these complications and the presence of immune antibodies in the mother. This relationship lends itself readily to form a theoretical basis for the etiology of a least some cases of erythroblastosis fetalis…The hypothesis of immunization can readily explain the familial incidence of this condition.
The blood picture characteristics of erythroblastosis fetalis, ie., destruction of red cells and compensatory reaction of the bone marrow, can also be explained in terms of the immunization theory. One may assume that the antibodies in the mother’s circulation under certain conditions are capable of penetrating the placental barrier…and, by their continual action on the blood cells and perhaps tissue cells of the fetus, induce erythroblastolis fetalis, and its several manifestations…The fetus may die in utero…There is sufficient evidence to indicate that most of these women’s serums contain an antibody which parallels the anti-Rh antibody of Landsteiner and Weiner.” (1)
Note: *Levine mentions Landsteiner and Wiener’s blood test because the main science body believed his test found the same antigen that he did. Levine wrote it, but he didn’t believe it. We know now that isn’t true and Levine was correct. Today we understand (I hope) that animal and human anti-Rh are not the same thing. Also, Levine’s point of the mother’s antibodies crossing the placenta was a big stumbling block back in his time. Doctors felt the baby and mother were shut off from each other. Plus, Levine said it was inherited, which few believed.*
After the discovery of the blood test for Rh factor, and the problem described between mother and baby, the medical people now saw all four diseases as one condition. They lumped the disease into two terms: Rh Hemolytic Disease and now HDN or Hemolytic Disease of the Newborn. Due to the blood tests and documented abnormal immature erythroblasts, some still use the older terminology of Erythroblastosis Fetalis.
According to Zimmerman, doctors set out to determine the scope of the problem. His book lists 12% of all American marriages paired an Rh negative woman with an Rh positive man. This made their offspring at risk for Rh incompatible births, but the first incompatible child usually escaped dire symptoms. A precise newborn death count was never made. Educated death counts in America ranged between 5,000 to 10,000 deaths per year. The additional burden: once Rh hemolytic disease killed the first baby, it took all the others that came afterward. (2)
Obstetricians tested every mother for Rhd, if one was identified, they tested the father. In that way, the doctors began to closely monitor women at risk. For a short while, they took babies early through Cesarean, hoping to avoid complications, but that practice soon produced new problems. (3) Women were monitored and identified babies were given exchange transfusions as quickly as possible. In this manner, fetal deaths dropped dramatically, globally. But doctors noticed unless the Rhd woman had had a previous transfusion reaction, her first RhD baby escaped symptoms of hemolytic disease. (4)
Weiner offered the first explanation, but he never pursued the idea: “There is some indirect evidence that the maximal amount of fetal blood escapes into the maternal circulation at the time of labor and delivery, possibly due to disturbances at the placental site.” (5)
Levine had calculated that one drop of fetus RhD blood was enough to immunize the mother, and she’d start making antibodies. He had no idea why first babies escaped disease. All the doctors knew for certain was that once the mother did become immune, she was immune for life, and each baby was sicker than the previous if they were born with RhD (Rh positive blood). (6)
Then Weiner and also Race in Britain discovered there were 2 forms of the Rh antibody. This discovery more than any other really threw fuel on the Blood Feud mentioned earlier. Once they realized there were 2 forms of Rh antibody the theories piled on, and that’s why so many people can’t make sense of the situation today. I will try to keep this discovery as simple as possible. (7)
The two anti-Rh antibodies in the gamma globulin were called 7S and 19S in the sixties. The question of how each one destroys RBCs was difficult to determine. One key feature they discovered is that the 19S antibody, made by the mother, wouldn’t cross the placenta into the fetus. 7S did cross the placenta. In 1969, Diamond discovered that 19S appeared in the blood first when the mother became sensitized to Rh Factor (the Rh antigen). Then 19S dropped its level in the blood, allowing the deadlier 7S to penetrate the placenta.
In 1942, Levine had observed that in parents of children with Rh hemolytic disease the husband was unlikely to be compatible with the wife. But the answers didn’t really jell for doctors until 1960.
Examples of HDN Risk:
The highest level of risk for HDN (16%) came from a Rh + homozygous, ABO compatible father. Rh+ homozygous means the father isn’t carrying a recessive Rh – allele, he’s 100% Rh+ pure blood, and ABO compatible means he’s got the same blood type as mother and baby. It would work out like this. Mother is B-, Father is B+, Baby is B+ = 16% risk for HDN.
If the father is Rh positive heterozygous, and ABO compatible there is an 8% risk. Mother is B-, baby is B+, and father is B+ but carries the recessive allele for Rh. Notice how the risk was reduced by half because the father carries a recessive Rh – allele.
If a father is Rh + heterozygous, ABO incompatible, the risk drops to 3%. Mother is B-, Father is A+ but carries the recessive Rh – allele, and baby is B+.
Of course no risk for HDN would be Mother B-, Father B- and infant – with any ABO group. (8)
In 2014 all women have blood work drawn when they go for their first antenatal visit. Doctors used to draw blood from the father’s to get ABO compatibility and Rh designation, but stopped. Plus, doctors quit taking the mother’s word about her blood type because people have faulty memories. Now only the mother is tested. Occasionally you see women complaining about this on forums. They say “I know my husband’s blood type and Rh factor because it’s on his military dog tags.” After a few major problems, doctors realized some married men weren’t the fathers of the baby. Babies got sick and died because of this practice. To avoid lawsuits and high drama, doctors now proceed on the mother’s blood work alone and rely on infant testing after birth.
During the twenty years after the blood test for Rh Factor was discovered, and before the vaccine known as RhoGAM came on the market, doctors used blood transfusions of Rh negative blood to save babies stricken with hemolytic disease. Alexander Weiner was one of the first doctors to try a transfusion on a baby, and on his first attempt the baby died. His second was successful, and he coined the term “exchange transfusion.” Weiner took blood from a baby’s wrist, replacing it with Rh negative blood in the ankle. The goal was a total body transfusion before the major organs were affected. Another doctor, Wallerstein, advocated skull transfusions but that one fell out of favor after Weiner called it dangerous. ( Zimmerman)
Doctor Diamond in Boston came up with a better method for exchange transfusions. He suggested untying the umbilical cord, transfusing through the umbilical vein, and removing the old blood a few teaspoons at a time. Exchange transfusions through the umbilical were successful and estimated at saving over 200,000 lives in the twenty years they were used before vaccine.(3) Zimmerman. Obviously, exchange transfusions didn’t help the sickest or the ones that died in the womb, but they were an effective bridge until the vaccine became available. (10)
In 1956 Amniocentesis was introduced by Dr. D.C. Bevis. He proved that measuring the bilirubin in the amniotic fluid was a guide for prognosis and treatment. In 1963 the first intra-uterine blood transfusion was done on a fetus with a high bilirubin in amniotic fluid indicating hydrops. The child was delivered by C-section and survived but did require a second transfusion. Today doctors can diagnosis hydrops by amniocentesis, doppler ultrasound, or low fetal hemoglobin. (11)
Another treatment Phototherapy is very effective for jaundice. After birth, baby’s that have high bilirubin levels or if they look yellow (jaundiced) are put under a blue light at 460mm until their blood work drops to normal. The light breaks down the bilirubin in the skin and makes it water soluble for the kidneys or bile to excrete out the body.
According to Reid and Shine, this is the treatment’s affects on Death Rates: (12)
Date Clinical Management Death Rate
Pre 1942 None 50%
1942-1952 Exchange transfusion 25%
1954-1961 Selective induction 16%
1963-1964 Intrauterine fetal transfusion 8%
1969-1975 IgG (vaccine) at delivery 3%
1975-1983 IgG at 28 weeks & delivery 0.5%
OCURRENT UNDERSTANDING OF HOW HDN DEVELOPS
Here are the hallmark elements of HDN: This is the exact clinical process that the French midwife observed, but doctors didn’t understand the process then and do now. Taken from Reid and Shine (13) I’ve tried to make it more laymen friendly.
Baseline Requirement: An Rh- woman gets pregnant by an Rh+ man.
1. The Rh negative mother lacks the Rh antigen that the baby inherited from the father.
2. The baby’s RhD (Rh positive red blood cells) pass through the placenta into the mother’s circulation throughout the pregnancy in tiny amounts, but during the delivery a major exchange of the baby’s blood is passed to the mother.
3. The mother’s immune system springs into action. Her B lymphocytes produce the antibody called (IgG) immunoglobulin G, in response to the baby’s Rh antigen, inherited from its father.
4. Antibody production is primed at first contact (the first Rh + child). If the next pregnancy is another Rh + child (RhD), the mother produces massive amounts of antibodies.
5. Mother’s Rh IgG antibodies during this second pregnancy ramp up and cross the placenta to the baby. *Note: Breast feeding could be lethal because the deadly antibodies are passed in breast milk as well as blood.
6. Once the mother’s antibodies enter the baby’s circulation they attach to the baby’s red blood cells, leading to their destruction.
7. This red blood cell destruction causes anemia in the baby. The baby’s body tries to help the baby by producing more red blood cells, but this leads to erythroblasts in the baby’s circulation. Erythroblasts are immature blood cells. They don’t carry oxygen effectively and they die quickly.
8. Lysis (the dying of the red blood cells) releases hemoglobin into the circulation and it’s converted to bilirubin. Bilirubin is taken to the liver and it binds to ligandin. This causes a complicated process best described as—The bilirubin and ligandin mix with glucuronic acid and it changes to a water soluble form in the endoplasmic reticulum(a network of tubes and sacs in cells that perform varied functions).
9. The liver is responsible for making red blood cells until the 24th week of a baby’s development. Liver production of RBCs ceases after birth, except in cases of HDN. The liver can’t stop making RBCs, and now it can’t conjugate bilirubin or make albumin. Anemia and heart failure then impair the baby’s liver function.
10. When the baby’s blood has a concentration of unconjugated bilirubin that exceeds 18/mg/dl, it binds to the neurons (brain cells) in the base of the brain causing kernicterus.
11. Hydrops occurs, but not in every baby. Hydrops happens because there is low albumin (protein) in the baby’s plasma, creating a series of catastrophic events leading to shutdown of the baby’s major organs.
1. Levine, P., Katzin, E., and Burnham, L., 1941. Isoimmunization in pregnancy; its possible bearing on the etiology of erythroblastosis foetalis. JAMA 116:825-827.
2. Zimmerman, D. 1973. Rh: The Intimate History of a Disease and Its Conquest. New York, Macmillan Publishing Co., Inc.
3. Reid, M., Shine, I. 2012. The Discovery and Significance of the Blood Groups. Cambridge, Massachusetts, SBB Books.
4. Clifford, S.H., Hertig, A.T. 1932. Erythroblastosis of the Newborn. NEJOM 207:105-110.
5. Ibid Zimmerman page 56.
6. Ibid Zimmerman page 56.
7. Race, R., Sanger, R. 1950 Blood Groups in Man.Oxford: Blackwell.
8. Bowman, J.M. Alloimmune Hemolytic Diseases of the Fetus and Newborn. Volume 3: Chapter 66-on line.
9. Ibid. Zimmerman
10. Diamond, Louis, K. 1948. Replacement Transfusion as a Treatment of Erythroblastosis Fetalis. Pediatrics 2:520-524
11. Ibid Reid and Shine page 42
12, Ibid Reid and Shine page 43
13. Ibid Reid and Shine page 40