They call him the man with the golden arm

When asked about his track record of 1000+ blood donations, James Harrison simply says “An hour of your time is a lifetime for someone else.”

It’s true, especially for him. You see, Mr. Harrison is Rhesus negative, and his blood has been used for decades to combat a potentially deadly condition affecting babies born to Rhesus negative mothers. It comes in the form of a shot given during pregnancy or just after birth, typically referred to as RhoGAM in the United States and Anti-D in other parts of the world.

So what exactly is RhoGAM, and when should it be used?

When I picked up a copy of Anti-D in Midwifery, written by Dr Sara Wickham PhD, RM, MA, PGCert, BA(Hons), I hoped to discover black and white answers to those questions. What I walked away with instead is a deep respect for the choices that Rhesus negative women must make, and the desire to see more (and better) research in this area. In this post I’m going to share what I’ve learned so far – I hope you find it helpful!

Please keep in mind that – as I wrote in my posts on the Vitamin K shot, Glucola and being GBS positive – “Best Boo-Boo Kisser South Of Puckett’s Gas Station” is about as official as things get for me professionally. I am not a doctor, this is not medical advice, and your decision is completely up to you. If you need some convincing on this, read my full disclaimer where I say it over and over again.

Special Note: Normally posts like this draw from many different sources. This one is unique because it relies mostly on Anti-D in Midwifery, with just a few updates based on research that became available after it went to print. If you are a midwife or birth worker, I highly recommend investing in her book. There is so much valuable information covered on best care practices that will not be covered in this article.

Also, both British and American spellings are used in this article depending on whether I am quoting Dr. Wickham or sharing my thoughts. Feel free to read quotes from Dr. Wickham with a lovely accent – I do!

What does it mean to be Rhesus negative?

You already know about the four blood types, right? Well, in addition to being A, B, AB or O, we’re all also either rhesus positive or rhesus negative. What this means is that some of us have rhesus proteins in our blood (which makes us positive) and some don’t (making us negative). Of the rhesus proteins, the D factor is the most common. That’s what we’ll be discussing in this post.

Caucasians are the most likely to be rhesus factor D negative (RhD-). About 15% of the population lacks the protein.

Some people believe that the lack of rhesus D factor is an indication of alien heritage. I’m personally going with the genetic mutation theory. 🙂

What is Rhesus D incompatibility?

Though normally the blood of a mother and baby do not mix during pregnancy – the placenta acts as a mediator that transports nutrients and waste without intermingling – problems can occur if blood does mix when a woman is Rh-negative.

If the baby is RhD-positive, the mother’s immune system will react to the presence of the rhesus D protein by creating antibodies against it – a process called sensitization.

What if my baby is also Rhesus negative?

If your baby is Rh negative there is no risk of sensitization.

Can I find out if my baby is Rhesus negative before he/she is born?

If your husband is also Rh-negative your baby will also be Rh-negative. You can request a blood test to find out his Rh status.

Also, Sequenom Laboratories recently released a fetal Rh D genotyping test that is 99% accurate when performed in the first trimester. The test is performed using just the mother’s blood, and the only downside is that additional analysis is sometimes needed if you’re having a girl, which means that you’ll know the sex of your baby if you require additional testing. I’m a fan of surprises, but I personally would ask for this test if I was Rh-negative.

One test said I was rh-positive and another said I am rh-negative. What happened?

Here’s the deal: The D antigen is composed of many parts which have been historically referred to as a mosaic. Some people have parts of the mosaic but not all – these individuals are said to have “partial D” expression. If an individual with partial D status encounters the blood of a Rh D-positive individual, their immune system will react to the parts of the mosiac they don’t carry in their blood.

On the other hand, some people who are classified as rhesus negative actually have the full mosiac, only in smaller quantities than typical Rh D-positive individuals. Theoretically, these individuals should not make anti-D since they possess all parts of the mosiac. (source) In the past individuals with weak D were considered functionally Rh-positive, but recent changes in guidelines have re-classified them as negative as a precaution. This is because there is a very small chance they could have a reaction. However, the only published report I could find of a weak D individual having a reaction to the rhesus D protein was in the case of autoimmunity. In other words, they were reacting to their own proteins, not someone else’s. (source)

I am rh-negative. What happens if I become sensitized?

If sensitization happens during the birth process, any future rhesus-positive babies the mother becomes pregnant with will be affected. This is because “the antibodies are able to cross the membrane at the placenta (even though the actual blood cannot) and may attack the rhesus proteins in the baby’s blood. This can cause a wide range of problems, from mild jaundice to severe rhesus haemolytic disease, which in the worst cases can result in the death of the baby. Although a far greater proportion of babies suffering from rhesus disease survive nowadays as a result of advances in care, they may require blood transfusions, early delivery or intensive care.” (Wickham p.4)

Firstborn children are not usually affected unless the mother was sensitized prior to the pregnancy through a blood transfusion or pregnancy loss. However, if sensitization occurred early in the pregnancy for some reason and was not treated, rhesus disease can occur.

What are some potentially sensitizing events?

The birth process (Birth interventions may significantly increase the rate of sensitization. More on this later.)

Abdominal trauma, such as from a car accident or serious fall

Abdominal surgery, such as a cesarean section

Placenta abruptio or placenta previa, both of which can cause placental bleeding

External version (breech repositioning)

Obstetric procedures such as amniocentesis, fetal blood sampling, or chorionic villus sampling (CVS)

Miscarriage, ectopic pregnancy, or in utero death after 8 weeks of fetal age (when fetal blood cell production begins)

Partial molar pregnancy involving fetal growth beyond 8 weeks

Blood transfusion (if blood is mismatched)

(source)

How can I know if a sensitizing event has occurred?

A flow cytometry test can be done to determine whether feto-maternal hemorrhaging has occurred.

Can I request a RhoGAM shot if I suspect I have experienced a potentially sensitizing event?

Yes, you can.

How does Rhogam work?

Rhogam is made from the blood of Rh-negative individuals who have intentionally “infected” themselves with Rh D factor in order to produce antibodies. The antibodies are then injected into the mother with the goal of neutralizing any Rh D factor that has leaked into the mother’s bloodstream. If caught in time, the Rh D will be neutralized before her immune system reacts.

Does rhogam really work?

Yes, but not in 100% of cases. Experimental models also suggest the possibility that in rare instances it may intensify a woman’s immune reaction instead of suppress it. (source)

What are the risks of RhoGAM?

RhoGAM is a Class C pregnancy drug, which means that “Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.” (source)

“The known and documented side effects listed by the manufacturers and pharmaceutical guidelines include local inflammation, malaise, chills, fever and, rarely, anaphylaxis. Some women have reported suffering an intensely irritating rash covering all or a large part of their body following administration of anti-D. Further concerns include those of immune system compromise and the issue of some pharmaceutical companies using a mercury-based preservative, which some women are actively choosing to avoid because of potential toxicity.” (Wickham p.7)

A note on mercury: In the U.S. all RhoGAM shots are labeled as mercury-free. However, as the FDA states here, vaccines labeled as mercury-free may still contain trace amounts. This is because companies use it in the manufacturing process and then filter out as much as they can. Though RhoGAM is not a vaccine, it is my understanding that it may contain trace amounts as well due to similar manufacturing processes.

“The second issue is that of blood-borne infections. Anti-D is a blood product, and as such as the potential to carry such infections. The risks of anti-D in this area are compounded by the fact that the blood used to make the product is pooled, so blood from one infected donor may end up in several hundred doses of the product. Several years ago, over 3000 women in Ireland contracted hepatitis C from infected anti-D (Miesel et al., 1995), and HIV has also been transmitted through anti-D (Dumasia et al., 1989). While both of these viruses are now screened for and would be rendered harmless by the purification processes involved, the most pressing concern relates to the presence of as yet unknown viruses, which may not be killed by current treatments. We can clearly only screen for and treat anti-D for those viruses that we know about and have the effective means to treat.” (Wickham p. 7, emphasis mine)

Are there any additional risks related to receiving RhoGAM while pregnant?

Possibly. This study suggests that in some experimental models, passive antibody treatments like RhoGAM have actually done the opposite of what they’re intended to do. In other words, they intensified the immune response upon exposure rather than canceling it out.

She also points out that “about 10 percent of the anti-D given to the mother will cross the placenta to the baby (Hughes-ones et al., 1971; Urbaniak, 1998). Studies have shown that this causes a portion of babies to test positive for antiglobulins (via a direct Coombs test) after they are born (Bowman and Pollock, 1978; Tovey et al., 1983; Herman et al., 1984). The few studies that have looked at this have suggested that, while babies may suffer some anaemia, this does not require treatment in the immediate postnatal period. Although Romm (1999) points out that the manufacturers of anti-D clearly state that this should not be given to babies, nobody has considered whether there are long-term consequences of this. It should be remembered that unborn babies will also be exposed to the risks that women face, such as that of virus transmission. Is it also possible that a baby could suffer the equivalent of an anaphylactic reaction? If this is a possibility, how would this manifest, and is there any way we would be able to treat it before it was too late?” (Wickham p. 45-46)

What are the risks of not using RhoGAM?

Sensitization “can cause a range of problems, from mild jaundice to severe rhesus haemolytic disease, which in the worst cases can result in the death of the baby. Although a far greater proportion of babies suffering from rhesus disease survive nowadays as a result of advances in care, they may require blood transfusions, early delivery or intensive care.” (Wickham p.4)

Is there anything I need to know about studies on RhoGAM?

Yes. First, all of the clinical trials on rhogam were conducted during the late 60’s and early 70’s – a time in which birth was considered inherently dangerous by many, if not most, practitioners. Interventions such as induction, episiotomies, anesthesia, cord clamping, etc. were routine in many cases – a reality which some evidence suggests may have increased the rate of sensitization reported. We’ll discuss more about why later on, but first let’s talk about the studies themselves.

Of the nine major clinical trials conducted:

We don’t know who paid for seven out of nine of them. Of the two we do know about, both were paid for by pharmaceutical companies. As mentioned in this article, funding bias is a well-documented phenomenon in which the outcomes of studies tend to support the interests of those who paid for it.

Seven out of nine were not double-blind. Of the two that were, one did not have an appropriate number of subjects.

Six out of nine were either not randomized or only quasi-random. This raises concerns that patients could have been cherry-picked to influence the study outcome.

This is not to say that RhoGAM isn’t beneficial in some instances – clearly it is. However, questions remain regarding whether the benefits were exaggerated (either knowingly or unknowingly) and whether a low-intervention birth might reduce sensitization risk. (Again, more on that later.)

What is the optimal dosage?

We don’t know. The standard dose in the UK, France, Ireland and Canada is about 100mg, while the standard dose in the United States is 300 mg. Other than France, most European countries give between 200-300 mg. At a lower dosage there are concerns that if the bleed is large there will not be enough RhoGAM in the bloodstream to cancel it out. At higher dosages there are concerns of increased anaphylactic and other reactions. (Wickam p.26)

What is the likelihood that I will need RhoGAM?

“Overall, the average rate of isoimmunization of women in control groups was 7.5 percent (186/2488), which implies that around 90 percent of the rhesus-negative women who give birth to a rhesus positive baby remain unaffected.” (Wickham p.17)

Or to “put it another way, any given woman has a 1 in 4000 chance of losing a subsequent baby from rhesus disease if she does not have routine antenatal anti-D. [For you non-British folks, this means routine RhoGAM shots during pregnancy.] This does not, of course, mean that [a routine RhoGAM shot during pregnancy] will offer her total protection from this outcome, just as the current postnatal programme offers no absolute guarantee.”

Has there been any research on the long-term health effects of anti-D for mother or baby?

No.

Do I need RhoGAM during my first pregnancy?

According to Dr. Wickham, sensitization “will not affect a woman’s first baby unless iso-immunization has occurred previously (such as from a mismatched blood transfusion, or at the time of an abortion or miscarriage). However, if rhesus antibodies are produced, subsequent rhesus-positive babies may be affected because the antibodies are now able to cross the membrane at the placenta (even though actual blood cannot) and may attack the rhesus proteins in the baby’s blood.”

To clarify, firstborn children are not usually affected unless the mother was sensitized prior to the pregnancy through a blood transfusion or pregnancy loss. However, if sensitization occurred early in the pregnancy for some reason and was not treated, rhesus disease can occur. It’s very rare, though. Here’s the math:

As mentioned previously, the rate of sensitization in control groups is estimated at about 10%, meaning that 90% of Rh-negative women who gave birth to a Rh-positive baby did not experience an immune reaction. Of the 10% that were affected, 86 out of 100 experienced sensitization at birth. That means out of the 10% that may become sensitized, just 14% of those individuals will experience sensitization before the birth process.

Do medical interventions increase the likelihood of fetomaternal hemorrhage?

Certain obstetric procedures, such as amniocentesis, fetal blood sampling, or chorionic villus sampling, are known to increase the likelihood of maternal and fetal blood mixing. However, many midwives believe that other procedures may have similar effects.

When interviewing midwives for her book, Dr. Wickham found the following procedures were of concern:

Ultrasounds

“Ultrasonography was felt to be a risk factor for transplacental haemmorhage in two ways. The first concerns the potential trauma that may be caused to the placenta by the movement of the transducer over the abdomen. Midwives noted that a number of women have their placenta attached to the anterior wall of their uterus, which is where the transducer is moved during the scan. It was argued that the pressure applied to the transducer in order to visualize the relevant parts of the uterus, baby and placenta might in some cases cause a small part of the placenta to separate from the wall of the uterus, and thus cause bleeding from fetal vessels into the maternal circulation.”

As we’ll discuss later, normal detachment of the placenta during birth does not cause bleeding from the fetal side. Wickham also points out that bleeding may only occur if the placenta is not optimally healthy, but also suggests that a baby’s tendency to “jump around” or thrash during an ultrasound may increase the likelihood that a small amount of damage is done to the placenta or cord, which might result in fetomaternal hemorrhage. (Wickham p.79)

Synthetic Oxytocin (Pitocin)

Thoughts on how synthetic oxytocin might cause fetomaternal hemorrhaging are two fold. First, it tends to create unnaturally strong contractions, which may cause the placenta to separate too early. In most cases of normal physiological birth, the placenta will go through a specific detachment process that is thought by some to reduce the likelihood of fetomaternal hemorrhage. Basically, there are two sides to a placenta – the mother’s and the baby’s. The mother’s side is supposed to detach and bleed rather than the baby’s. Early detachment may cause bleeding on they baby’s side of the placenta, which would cause the baby’s blood to enter the mother’s bloodstream.

Second, Pitocin reduces a woman’s production of natural oxytocin, which facilitates placental detachment. The problem here is that if the placenta manages to stay intact through Pitocin-induced contractions, it may then have difficulty detaching at the appropriate time because the woman’s natural regulation of oxytocin has been disrupted.

Intrauterine Catheters

“It is logical that any instrument inserted into the uterus, even with extreme care, may cause slight trauma to the placenta; slight trauma may be all that is needed for fetomaternal bleeding to occur during birth.” (Wickham p.81)

Episiotomy

Episiotomies inhibit a woman’s natural production of oxytocin, which is vitally important for optimal placental separation.

Fundal Pressure

“Fundal pressure may occur either deliberately, where the attendants push on the fundus to attempt to expedite the birth of a baby or the placenta, or accidentally, where the woman is asked to adopt a position which puts unnecessary pressure on the top of her uterus. Again, midwives suggested that this could interfere with placental attachment and physiology, and potentially cause fetomaternal transfusion.” (Wickham p.82)

Directed Pushing

Unlike instinctive pushing, “non-physiological pushing is thought to lead to an increase in intrauterine pressure, which may in turn cause trauma to the placental site or possibly the rupture of small vessels. Directed pushing usually involves the Valsalva manouvre, where the woman is instructed to take a deep breath and push for as long as she can. The fact that the Valsalva manouvre was originally invented as a method for forcibly removing pus from the ear would support the idea that this could create enough force to cause trauma elsewhere in the body.” (Wickam p.82)

Local and Epidural Anaesthesia

Most anesthetics contain vasodilators, which cause blood vessels to widen. “These vasodilators may be carried through the body, potentially causing the dilation of vessels in and around the placenta. Dilation of these vessels may then lead to the escape of blood from fetal vessels,” especially if this occurs around the time the placenta is separating. (Wickham p.83)

The use of anesthesia also often increases a woman’s need for other interventions that may make her more susceptible to fetomaternal hemorrhaging.

Cord Traction

“The use of controlled cord traction was also seen as potentially harmful; again, the effect of an attendant pulling on the cord may be to cause parts or all of the placenta to separate before this would have occurred physiologically, with the same result. The pressure of an attendant’s hand on the uterus, a procedure routinely used with controlled cord traction to ‘guard’ the uterus from being inverted, may also affect the delicate physiology of placental separation or cause fetal vessels to burst.” (Wickham p. 90)

Cord Clamping

“Early clamping may force blood back into the placenta which increases the likelihood of antibody sensitization for RH negative mothers who have an RH positive infant.” (source) It has been suggested that even touching the cord to see if it has stopped pulsing may disrupt the delicate process of transfusion from placenta to baby.

Are there any ways I can reduce the likelihood of becoming sensitized?

Though there haven’t been any formal studies on steps that can be taken to reduce sensitization risk, some midwives suggest certain supplements and lifestyle changes that may strengthen the placenta and support the immune system.

Click here to read my follow-up post on their recommendations.

Did you/would you get a RhoGAM shot? Why or why not?