This is super long and goes from simpler questions to more complex questions. It is intentionally pretty dry and I try to stick to the facts. I am Rhesus negative myself, so have done the weighing of these options with all three of my pregnancies, two of which were first trimester losses, one full term baby.
I highly suggest you get a copy of Sara Wickham’s book “Anti-D in Midwifery: Panacea or Paradox” and also check out her work online on the topic here – https://www.sarawickham.com/tag/anti-d/
1. What different blood types are there?
There are the 4 main “blood types” we typically talk about in the context of blood transfusions – A, B, AB and O. There is also the rhesus factor and other factors that make blood types unique, which really means that there are many different antigens that can be expressed on the red blood cells (that is what ABO is as well). A full “blood type” of any individual person would include information about 30 substances (or systems) that are found (or not) on their red blood cells. Having the antigen means you are positive for that designation (could be Rh, Kell, M, etc) and not having it makes you negative.
“Information for women who are Rhesus negative”
2. What is the Rhesus factor?
Rhesus factor is the second most important blood group/system, with 50 antigens, though D is the most relevant in pregnancy. You can be Rh negative (or positive) with any of the main blood types. We will be talking about Rhesus D factor/antigen.
3. How can someone determine their blood type?
You can get blood work done through a lab, or use an Eldon card. Your blood is mixed with antibodies against A and B type blood (separately) to see if your blood “agglutinates” or clumps together. Same goes for Rhesus factor. The lab also does another test where they mix your serum (no blood cells) with blood of different types to see how they react. Blood cells clump together when exposed to antibodies against their own proteins. The Eldon card just does the first part of the test, and based on that you can deduce which type of blood you have. Type A blood has B antibodies, type B blood has A antibodies, type O blood has both A and B antibodies, and AB blood doesn’t have antibodies against A, B or O types.
4. What is the distribution of blood types among the population in the US?
Type O is the most common, and type B is the least common. O = 44%; A = 42% B = 10%; AB= 4%. Rh negative versions of each type are less common. For example, only 15% of Caucasian people are Rh negative and only 3% of Asian people are.
Anti-D, page 3
5. How does Rh negativity impact pregnancy and birth?
Usually Rhesus negativity isn’t a big deal beyond the typical blood transfusion issues. But in pregnancy there is a potential for fetal and maternal blood to mix, which can cause issues if the mother is Rh – and the baby is Rh +. If the mother’s body senses the positive blood it sets off a chain reaction called “isoimmunization” in which her body makes antibodies to attack the baby’s positive red blood cells. This most commonly occurs at the time of birth when the placenta separates from the uterus, so it isn’t usually a problem for the CURRENT baby, only future babies, but it can be very serious for those future babies (more on the risks as well as management of sensitized moms later)
“Information for women who are Rhesus negative”
6. What blood type incompatibilities are there?
Rhesus incompatibility is the most clinically important but there are others. There are also the major blood group incompatibilities (ABO) based on the way they interact with each other. A has B antibodies, B has A antibodies, O has both and AB has none. There are also other less common incompatibilities that do contribute to issues. Below is a link to a chart of the incompatibilities that ARE associated with hemolytic disease of the newborn.
7. How does sensitization occur?
Almost 90% of sensitizing events happen at the time of birth. About another 10% happen in pregnancy, typically in the 3rd trimester. Trauma and events that affect the placental site can cause blood mixing – CVS, amniocentesis, external versions, etc. Sensitization CAN happen earlier in pregnancy, with abortions, miscarriages, ectopic pregnancies, and even threatened abortions. The Rh D factor has to be present on the fetal blood cells though, and the earliest this has been noted (so far) is 38 days of gestation, or about 7 ½ weeks of pregnancy. Fetal blood leaks into the maternal bloodstream in about 1 in 3-4 pregnancies and during 1 in 3 births. When Rh+ fetal red blood cells come into contact with the mother’s body, her immune system starts manufacturing antibodies to clear the Rh+ cells from her system. Future blood mixing will result in a faster immune system response. Most sensitization occurs from very small amounts of blood mixing, less than .1 ml.
ACOG Practice Bulletin: Prevention of Rh D Alloimmunization
Studies in Rh Sensitization
8. What is Rhogam?
Rhogam (the brand name) or “anti-d” is an immunoglobulin derived from pooled human blood that is given via intramuscular injection, and can help prevent isoimmunization from occurring with a blood mixing event. When it works correctly, the anti-D antibodies fight off the rhesus positive cells from the baby before the mom’s body notices them, which prevents the process of isoimunization. The “active ingredients” so to speak are antibodies to Rhesus D. According the the makers of Rhogam, it “is a sterile solution that contains antibodies to the Rh factor. The antibodies are derived from human plasma.”
“Information for women who are Rhesus negative”
9. How is Rhogam created?
Rhogam is made from the plasma of individuals who have been sensitized to Rhesus D factor and therefore have antibodies in their own bloodstream. Usually they are sensitized on purpose so that their blood can then be used to make Rhogam. The final product is created through a “Cohn cold ethanol fractionation method”, a method of extracting albumin (a blood protein) from plasma. The blood is pooled, or mixed, to create the product – each injection is not from a single donor, but is from many donors combined. In the US, people who give blood to create Rhogam are paid, which has raised concerns.
10. How does Rhogam work?
According to the Rhogam manufacturer, “[w]hen RhoGAM® Brand is injected into the muscle of an Rh-negative mother, these antibodies circulate in her bloodstream and protect her against any Rh-positive red blood cells from the fetus. Her immune system then sees no need to take further action.” The anti-D antibodies are injected, and fight off the baby’s rhesus positive cells before the mom’s body notices and triggers the isoimmunization process.”
11. What is the current recommendation for Rhogam administration?
It is recommended that every rhesus negative mom with a rhesus positive baby (or uncertain of type) receive Rhogam within 72 hours of the birth. A Kleihauer test is sometimes done to see if a larger fetomaternal hemorrhage happened, necessitating a larger dose. It is also routinely offered after any other sensitizing event (amniocentesis, abdominal trauma). Some areas offer it prenatally as well, like in the US.
12. How effective is Rhogam in preventing isoimmunization when given at the time of birth?
The result of the original studies in the late 60’s was that .2% of women who received Rhogam were sensitized at 6 months, whereas 7.5% of women in control groups were. But in subsequent pregnancies, they found that 2.34% of treated women versus 10.24% of women in the control group were sensitized, so more than originally thought. These studies may not be methodologically sound though (particularly those that looked at subsequent pregnancies). It may also be an indication of “sensibilization” where a woman doesn’t show antibodies until a subsequent rhesus positive pregnancy. The studies have been clear that Rhogam is effective on a population level, but have ALSO shown that the large majority of women don’t need it at all. Further, the studies that have been done were on women who had actively managed labors and births, including the third stage.
Anti-D, 15-16, 21, 22
13. How soon after birth does Rhogam need to be given to be effective?
Studies were done on prisoners in Sing Sing, and they were given Anti-d within 72 hours, which was found to be effective. The recommendations to administer Rhogam in the first 72 hours is based on this, not on any research that showed a longer wait would be ineffective!!! There needs to be more research done.
14. How effective is prenatal Rhogam?
ACOG recommended routine Rhogam at 28 weeks starting in 1983. The Derbyshire study showed the routine 28 and 34 week Rhogam offering for first time moms decreased the overall sensitization rate from 1.12% to .28% though they hypothesized that this was due to the women requesting Rhogam more for potentially sensitizing events as they became more educated. For example, if a woman came in after getting into a car accident, she was perhaps more likely to ask for Rhogam if she knew this was recommended. Two high quality studies looked at randomizing women to get Rhogam or not at 28 and 34 weeks, one study with 50mg and the other with 100mg – the first showed no difference in outcomes, with the second (with 100 mg ) showed a definite decrease in sensitization.
Anti-D 39, 40
15. What are the known side effects?
Known side effects include local inflammation, malaise, chills, fever, and rarely, anaphylaxis. Some women have reported getting an irritating, itchy, full body rash.
16. What are the theoretical risks of Rhogam for the mother?
There is concern about immune system compromise, use of mercury as a preservative in the injection, and the possibility that Rhogam itself carries blood borne infections. (“Mercury-free rhogam is available in this country from Bayer Pharmaceuticals under their product name of BayRoh-D. This mercury free product has been available since 1996” – http://www.vaccinetruth.org/rhogam.html) Their number is 800-468-0894.) 3000 women in Ireland were infected with Hepatitis C from infected Rhogam (mostly in the 1970’s), and HIV has also been transmitted this way. While those pathogens are screened for and neutralized in the processing now, the concern is that there may be other as of yet unknown infectious agents that we aren’t screening or neutralizing. The original studies only included 3476 women! About 10,000 women have been a part of trials since then, but that is still a relatively small sample, and none of those studies have looked at long term health data. The UK buys blood for their Rhogam/Anti-D from the US due to concerns about New Variant Creutzfeldt Jakob disease. Ina May brought up concerns about how prenatal Rhogam may relate to the finding that gamma globulins impair the immune system for up to 5 months in children aged 4-10 – so how might that affect a newborn? With prenatal rhogam, there is the risk of enhanced sensitization as well, the OPPOSITE of what rhogam is supposed to do. This could happen if the passive exposure through the prenatal anti-D primes the mom’s immune system so that blood mixing at the time of birth (or before) leads to her immune system launching a primary immune response. This has been shown to happen in experimental models.
Anti-D, 7, 20, 30-31, 46
17. What are the real and theoretical risks of Rhogam for the unborn baby?
No long term research has been done on the effects of Rhogam on babies in utero, or subsequent babies. The other large concern is the effect of anti-D on subsequent babies who are exposed to the mother’s blood post anti-D injection, since we don’t know how the injection may change the mother’s blood, immune response, etc, and how those changes would affect the babies exposed to them, particularly baby girls, and those girls reproductive futures. We are only just beginning to see women who were exposed to anti-D (or gestated in a post anti-D environment) having babies of their own. About 10% of Rhogam crosses the placenta, so prenatal rhogam can lead to anemia in the baby, though the research has shown that is doesn’t require immediate treatment (probably a good reason to delay cord clamping a LONG time for these babies though). There is the theoretical risk that the baby could have an anaphylactic reaction to Rhogam in utero as well.
Anti-D, 7, 21, 46
18. How many women will be sensitized without the use of Rhogam?
It is hard to say since the studies available are old, and don’t include information that could help us determine if other factors have lowered the sensitization rate. Most rhesus disease didn’t manifest until the 3rd or 4th baby, so smaller families may be largely responsible for the drop, along with changes in maternity care. The studies showed a rather large range of 1.96 – 13.39% of Rh negative women were sensitized at 6 months after the birth of a Rhesus positive baby and without Rhogam. The average was 7.5% which implies that about 90% of women don’t “need” Rhogam. There is no way from the studies that were done to determine why some women were sensitized and others weren’t. ALSO, not all women who have a transplacental hemorrhage will be sensitized, although larger volumes are more likely to cause sensitization. The biggest question that remains is, what would the sensitization rates be for women who have an undisturbed birth? The studies were all conducted post-medicalization of birth.
Anti-D 16-17, 22, 68
19. Is there evidence that supports using Rhogam prenatally?
Recommendation was added in 1976 to give Rhogam to all RH – women following a miscarriage or abortion. Then in 1981 the recommendation to give Rhogam to Rh – women experiencing a “sensitizing event” was added – these included car accidents, abdominal trauma, vaginal bleeding, medical interventions like amniocentesis, and external cephalic version. It is estimated that 2500-3000 or 4000 (depending on who you ask) women need to be given prenatal Rhogam to prevent one baby death from hemolytic disease (not morbidity, just death).
Anti-D, 17, 44, 48
20. Are there different doses of Rhogam? How much does someone need?
The US and many parts of Europe administer 300mg shots, but the UK uses 100mg shots. An early study showed no difference in outcomes when women were given 20, 50, 100 and 200mg injections.
21. What does the evidence say about using Rhogam after miscarriages and abortions?
There is not a lot of good information about this. The general consensus seems to be that the Rh factor is found on the baby’s blood cells starting at about 8 weeks, or as early as 52 days post-conception, and therefore women having a miscarriage should have a dose of “micRhogam” which is a smaller dose of 50iu before 13 weeks and a full dose of Rhogam, 300iu, after 13 weeks.
The evidence however, is not there for this practice. “The evidence to support the use of Rh immune globulin for a diagnosis of first trimester spontaneous abortion is minimal. There is a paucity of well-designed research that examines maternal sensitization or hemolytic disease of the newborn as an outcome in patients receiving, versus not receiving, Rh immune globulin in first trimester bleeding. There is significant evidence to demonstrate fetomaternal hemorrhage in first trimester spontaneous abortions; yet, no studies demonstrate subsequent maternal sensitization or development of hemolytic disease in the fetus as a result of this hemorrhage.”
22. How long do the antibodies in Rhogam last in the bloodstream?
It depends. One source said that when Rhogam was given at 28 weeks, there was between undetectable amounts and 25iu at 40 weeks. The body breaks down all of the anti-D within 6 months, and it can take up to that long. The half life is 21-30 days
23. Does an Rh – woman need Rhogam if the baby’s father is Rh -?
Anti-D 44 (all throughout the book though)
24. What lab tests can be done to detect if blood mixing and sensitization has occurred? Are they accurate?
The Kleihauer test determines if fetal cells have crossed into the maternal bloodstream but is not 100% accurate. The fetal blood cells are dyed/stained a darker color than maternal cells. Then the operator looks at a smear of the sample under a microscope and counts the number of fetal cells visible which then gives an estimate of the amount that entered the maternal bloodstream. Issues are that not all the fetal cells pick up the dye; the test relies on the assumption that a random sample is representative of the total maternal blood volume; human error can occur in counting the cells and procedure to carry out the test.
An indirect Coombs test looks for free flowing antibodies, and can be done (and should be done) to see if a woman has been sensitized, ideally prior to conceiving again. If she is positive for these antibodies, a titer is given, 1:1 being the least. Anything more than 1:4 is considered sensitized. A direct Coombs test can be done on a baby to see if their blood cells have been being attacked by maternal antibodies.
25. How often does blood mixing occur?
About 15% of the time, a transplacental hemorrhage will occur when an Rh – mom births an Rh + baby.
An alternative perspective is that blood mixing occurs at varying amounts depending on the type of birth. This study had a volume small sample size, but they did Kleihauer testing and found “FMH was nil in normal spontaneous delivery without syntocinon drip but the incidence of FMH in normal delivery preceded by syntocinon drip was 19.05%, in forceps delivery 40%, in lower uterine caesarean section 50% and in normal delivery followed by manual removal of placenta 100%. The incidence of FMH was more in postpartum period (16%) than that in antenatal period (8%).”
26. What can be done to prevent sensitization, besides getting the Rhogam shot?
It has been shown that trauma to the uterus increases the risk (study done on curettage following abortion, unclear if this meant spontaneous or elective) of sensitization. Not known whether the liklihood can be related to birth or maternal factors. Another study showed rates of fetomaternal hemorrhage were 7.5% for spontaneous births, 11.1% for vacuum extractions, and 17.7% for cesareans. The type of birth didn’t affect the likelihood of larger fetomaternal hemorrhages though.
ABO incompatibility also confers some amount of protection since the mother’s body destroys the fetal blood on the basis of ABO group before reacting to the rhesus status, and may avoid sensitization altogether. The perinatology.com piece states that the risk of sensitization after a first pregnancy when the mom doesn’t get Rhogam is 4-5%.
There are lots of suggestions for strengthening the placental bed and reducing the chances of fetomaternal hemorrhage that midwives give for preventing fetomaternal hemorrhage and sensitization: optimum nutrition, whole foods, organic foods, raw veggies, pulses and seafood, magnesium, iodine, vitamin C and bioflavinoids, herbs like red raspberry leaf, elderflower and echinacea, garlic, daily activated charcoal, breastfeeding (possible immunosuppression theory), emotional and spiritual clearing, avoiding caffeine, avoiding alcohol and sugar (anti-nutrients), avoiding flouride, no directed pushing, only physiological pushing, only a physiological third stage!!!!! There is little to no evidence for most of these interventions (or lack of interventions) since that hasn’t been the focus of the research done on rhesus isoimmunization unfortunately. Wickham states that there has been research that showed citrus bioflavinoids improving the outcomes of pregnancies where the mom is already isoimmunized.
Anti-D, 19, 75,102
27. If a woman does have Rhesus antibodies, how likely is her next baby to have problems?
Babies you are gestated by a sensitized mom have a 90%+ chance of surviving and having normal neurological function. Of the babies who have a positive direct Coombs test, 50% have mild hemolytic disease (may need some phototherapy, and serial blood work to watch for anemia), 25% have moderate hemolytic disease (jaundice within the first 24 hours of life, transfusions, serial blood work), and 25% have severe hemolytic disease and either have hydrops and/or are stillborn.
28. Why would a woman’s body launch a NEW antibody attack with a next pregnancy in the absence of anther blood mixing event?
I couldn’t find a concrete answer for this other than the obvious, or really anyone else asking this question, but based on my reading, it seems that it would be due to “silent” fetomaternal hemorrhages or not so silent fetomaternal hemorrhages, including during procedures that may be part of monitoring an already sensitized pregnancy, like amniocentesis.
29. What is hemolytic disease?
“Hemolytic disease of the newborn: Abnormal breakup of red blood cells in the fetus or newborn. This is usually due to antibodies made by the mother directed against the baby’s red cells. It is typically caused by Rh incompatibility, that is differences between the Rh blood group of the mother and baby. Severe hemolytic disease can cause anemia and heart failure. Less-severe cases include jaundice, and can lead to brain damage is left untreated. Also known as erythroblastosis.” – http://www.medicinenet.com/script/main/art.asp?articlekey=369
31. What are the risks of hemolytic disease to the baby?
Mild jaundice is the most mild risk, but the more serious risks are anemia, enlargement of the liver and spleen, organ damage from the anemia, hydrops fetalis which includes severe tissue edema and heart failure, stillbirth, and post birth there is the risk of kernicterus and the resulting brain damage, deafness, seizures, and death.
32. Are there ways to prevent hemolytic disease when the mother is sensitized?
I am trying to get ahold of the actual studies, but Rebecca Lessard says in her paper that bioflavinoid supplementation reduces the risk of fetomaternal hemorrhage for sensitized and non-sensitized moms, reducing the risk of becoming sensitized and reducing the severity of hemolyic disease respectively. She recommends 1000 mg of time released vitamin C 3 times a day, and 400 mg of time released citrus vitamin P with rutin and hesperidin also 3 times a day.
33. How is hemolytic disease monitored and managed in a pregnant woman?
No monitoring needed if the father of the baby is Rhesus negative too (as in the case of a new partner for example). It can be helpful to determine if the father is hetero or homozygous for the D allele. If homozygous, it is certain that the baby is positive. If heterozygous, the baby could be negative, and it could be worthwhile to determine the baby’s blood type and group with a sample of maternal blood while still in utero if that testing is available to minimize additional and more invasive testing if the baby is negative. For all other women who are suspected of having a Rhesus positive baby, and are having their first sensitized pregnancy, antibody titers should be done every two-four weeks if the titers continue to be under 1:32. A four fold increase in titers also requires fetal evaluation. If titers reach this critical level, amniocentesis used to done every 10-14 days to assess the amount of bilirubin in the amniotic fluid, and therefore the severity of the hemolytic disease of the fetus. Now, peak systolic MCA Doppler velocity has largely replaced amniocentesis for monitoring these pregnancies thankfully since it has much less risk and is very accurate (100% sensitivity for moderate and severe fetal anemia but not accurate after 35 weeks). Serial ultrasounds can also evaluate for signs of anemia and early signs of hydrops. If the MCA or amniocentesis indicates likely anemia, cord blood is sampled, and If the baby’s hemoglobin drops below 11gm or the hematocrit drops below 30, intravascular transfusion is initiated, where the baby is given a transfusion in utero. There are differing approaches as term approaches, but at 35 weeks an amnio may be done to determine lung maturity, and then induction may be considered depending on maturity, severity of disease, etc.
Intravenous immunoglobulin therapy is sometimes moderately effective before a fetus is able to more likely withstand IVT after 17-20 weeks.
When it isn’t the mother’s first affected pregnancy, titres don’t accurately reflect the severity of hemolytic disease, so MVA doppler studies are relied on more heavily.
34. What treatments exist for pregnancies complicated by hemolytic disease?
IGIV or intravenous immunoglobulin administered weekly to the mom is moderately effective in postponing more invasive cord blood sampling and intrauterine transfusions until 20-22 weeks when it is less risky.
IVT or intrauterine transfusion is when an in utero baby is directly given packed red blood cells straight into the umbilical vein.
IPT or intraperitoneal transfusion, or injecting packed red blood cells into the in utero baby’s peritoneum, is what they used to do prior to IVT.
35. What can be done for a baby who has suffered from hemolytic disease after they are born?
The baby needs to be assessed for anemia throughout the first 6 weeks, and needs to be monitored and treated for jaundice. Mild cases need minimal phototherapy. Moderate cases usually become jaundiced in the first 24 hours, and may benefit from IGIV to reduce the need for phototherapy and/or a blood transfusion, though transfusions are commonly needed for these babies. Severe cases need intense monitoring and management including phototherapy, transfusions, management of metabolic derangements, etc. Mild hydrops reverse in 88% of cases with IVT with improved survival, but severe hydrops only reverse in 39% of cases and has poor survival rates.
36. What is the relationship between hemolytic disease of the newborn and subsequent jaundice?
As the mother’s antibodies break down the baby’s red blood cells, bilirubin is produced, and since the rate of breakdown is so fast (and there is a spectrum, depending on the severity of the disease) that the baby can’t clear the bilirubin as fast as it is produced, leading to jaundice earlier and more severe than in the case of physiological jaundice.
37. Do babies born with hemolytic disease have more issues later in life?
90-95% of babies who survive IVT have no long term developmental problems. 5-10% have evidence of cerebral palsy, but this is possibly due to prematurity. “Studies have not shown a relationship between how sick the baby is in the womb and the chance for long-term developmental problems.” These babies have a slightly higher rate of hearing loss, inguinal hernias in boys, and umbilical hernias in girls.
38. What is the history of hemolytic disease?
It was first discovered by Plato and has been referenced here and there since the 17th century. In 1938 it was first hypothesized that it was due to an immune reaction in the mother. Isoimmunization was understood starting in 1941. 1963 by Clarke et al hypothesized that using anti-D would clear the fetal cells and prevent isoimmunization.