GENOTYPING
First of all, the terms Rhesus positive and Rhesus negativeare now, more frequently, being described as Rh(D) positive and Rh(D) negative. This section should hopefully explain why the transition has become necessary and, also, provide basic information about the Rhesus factor. Although the initial thought of reading through this may seem daunting, you may prefer to come back to it if you encounter any information which needs reinforcing. Alternatively, for an adequate understanding that can be applied to the other sections, skip to the end of the detailed section and read the simplified explanation below.
Detailed Explanation:
We all inherit a set of three Rhesus (Rh) genes from each parent called a haplotype. You may have heard of the c, d, e, C, D and E genes. The upper case letters denote Rh positive genes and the lower case, negative and we inherit either a positive or negative of each gene from each parent (eg. CDe/cde, cdE/cDe etc.). This means that we then possess two of each gene and can pass either to ouroffspring.
If a person is tested Rh positive, their blood is said to contain the Rhesus factor - if they are tested negative it does not. A person possessing one or more positive Rh genes (C, D or E), anywhere in their inherited haplotypes, has inherited the Rh factor (eg. cdE/De, cde/cDe etc.) and they are tested Rh positive - only a person with a genotype of cde/cde is truly Rh negative.
In this respect, it is now common practice to refer only to the D gene when determining the Rh factor of a person`s blood. The term now used is `Rh(D)` instead of just `Rhesus`. This ensures that we concentrate solely on the D gene, or lack of it, as Rh(D) positive cells contain a substance (D antigen) capable of stimulating Rh(D)negative blood into producing harmful antibodies. These antibodies destroy (hemolyze) red cells containing the D antigen (Rh(D) positive cells). The c, e, C and E genes are of little importance here, as cases where antibodies have been produced against them are very rare, although there have been instances where this has occurred and treatment has become necessary. Information about them is still found in pregnancy booklets.
This may help to explain why the harmful antibody produced by a Rh(D)negative woman`s immune systemagainst Rh(D) positive cells is called `anti-D` (anti-Rh(D) - also the name of the injection given to a woman at delivery - see `The Purpose of Anti-Rh(D) Injections`). This injection is sometimes also referred to as RhoGAM or Anti-D Immunoglobulin.
PLEASE NOTE: A Rh(D) positive woman would never produce an antibody against a Rh(D) negative child, as positive blood does not produce `anti-d` - there is no anti-Rh(d).
A person is Rh(D) negative if they have inherited a d gene from each parent (d/d).
A person is Rh(D) positive if they have inherited either of the following:
- a D gene from each parent (D/D)
- a D from one parent and a d from the other (D/d or d/D)
Therefore, it is possible to have a Rh(D) negative child if the mother is Rh(D) negative and the father Rh(D) positive. The father may have inherited both a D and d and it is possible that the baby could inherit the negatived gene from him. As Rh(D) negative woman definitely possess two d genes, the baby would inherit one of these from her - this combination would produce a negative child (d/d).
If the father possesses two D genes, the baby will definitely inherit a positive from him, together with the Rh(D) negative gene (d) from the mother. This combination will produce a Rh(D) positive child.
PLEASE NOTE: If a Rh(D) negative woman is absolutely certain that her partner is also Rh(D) negative, they will surely produce Rh(D) negative offspring and the baby will not be affected by Rh(D) problems, even if the mother already carries Rh(D) antibodies from a previous pregnancyor miscarriage with another partner or as a result of a transfusion using positive blood cells.
Even though both the d and D gene are referred to here, the term Rh(D) does indicate that the d gene is not really the issue here - the test performed is to determine the presence or lack of the D gene:
If a blood test shows that you do not possess the D gene, you are described as Rh(D) negative.
If this gene is found to be present, you will be described as Rh(D) positive.
So, for example:
If your blood type is B Rhesus positive (B+), the more accurate way of describing this is B Rh(D) positive (D gene is present).
If your blood type is A Rhesus negative (A-), it would be described as A Rh(D) negative (D gene is not present).
So, we can now see that if you possess the D gene and are, therefore, Rh(D) positive, your blood will contain the D antigen which stimulates Rh(D) negative blood into producing antibodies (anti-Rh(D)) against it.
At the risk of complicating this subject even more - a man who has inherited both positive factors (D/D) would be described as being Homozygous - meaning that every one of his sperms must contain the D gene. If a he has both (D/d or d/D) he would be described as being Heterozygous - meaning that 50% of his sperms contain the D gene and 50% contain d.
Simple Explanation:
Whatever our blood type (ie. A, B AB, O), we all have two Rhesus genes, called D or d, depending on whether we are Rhesus positive or negative and babies inherit one of these from each parent.
A person is Rh(D) negative if they have inherited a d gene from each parent (d/d)
A person is Rh(D) positive if they have inherited either of the following:
- a D gene from each parent (D/D)
- a D from one parent and a d from the other (D/d or d/D)
This is why it is possible to have a Rh(D) negative child if the mother is Rh(D) negative and the father Rh(D) positive. If the father has both a negative and a positive gene, the baby may inherit this negative gene and, as all Rh(D) negative women have two negative genes, the baby will definitely inherit a negative from her.
PLEASE NOTE: If a negative woman is absolutely sure that her partner is Rh(D) negative, they will surely produce Rh(D) negative offspring and no harm can come to the baby from any Rhesus antibody the mother`s blood may contain, even if she had already developed Rhesus Iso-immune disease before the pregnancy.
Rh(D) positive blood contains the D antigen which stimulates Rh(D) negative blood into producing antibodies against it. Anti-Rh(D) is also the name of the injection given after delivery (more commonly known as `anti-D`).
PLEASE NOTE: A Rh(D) positive woman would never produce an antibody against a Rh(D) negative child, as positive blood does not produce `anti-d` - there is no anti-Rh(d).
ANTIBODIES/ANTI-RH(D) AND THEIR EFFECTS
Antibodies against Rh(D) positive cells will be present in the mother`s bloodstream if she has previously had a Rh(D) positive baby and received no anti-D - in my experience most unlikely - midwives are just dying to stick a woman with an anti-D after delivery, appearing most disappointed when the baby is found to be negative and the mother is not in need of it! Antibodies will also be present if the mother has unknowingly had a placental bleed during pregnancy, causing fetal Rh(D) positive blood to mix with the mother's. If the mother has previously had a miscarriage or received a transfusion where Rh(D) positive blood was used, it is very likely that, if an adequate dose of anti-D was not administered at the time, her blood will contain Rh(D) antibodies.
PLEASE NOTE: A placental bleed (feto-maternal hemorrhage (FMH)) can occur during any pregnancy but, before we go any further, I would like to explain why it is much more unlikely for a woman to develop Rhesus (Rh) problems during her first:
The first time the Rhesus immune system encounters Rh(D) positive blood cells, it produces antibodies (IgM class antibodies) that are capable of destroying them. However, these antibodies are too large to travel through the blood vessel linking mother and baby`s blood and cannot harm the unborn child. They are only effective in removing the positive cells from the mother's own bloodstream. It is the second and subsequent times such positive cells are encountered that the immune system will begin to produce a different type of antibody (class IgG antibodies) and, each time this occurs these antibodies react more `angrily` than the time before. Even though the `linking' blood vessel is only one cell wide, and not even the fetal and maternal bloods can mix this way, these new antibodies are of a shape and size that can easily pass through it, from the mother`s bloodstream to the baby. So, if a woman expecting her first child has a placental bleed during the pregnancy, she will produce the larger antibodies which can only destroy the positive cells circulating in her own blood. She would only start producing the more harmful antibodies if she suffered a further placental bleed. However, this is possible and the same care should be taken during a first pregnancy as with a second or subsequent pregnancy.
When Rh(D) positive cells find their way into a negative bloodstream for the first time, they remain `unnoticed` for about three days. After this time, the D antigen contained in these cells begins to stimulate the immune system into producing antibodies against them. When a woman`s own immune system has been stimulated into producing these antibodies, she is described as having been sensitized, which means that the first larger (IgM class) antibodies have been produced to destroy the positive red cells circulating in her own bloodstream. The immune system then `lays in wait` for the next shower of such cells to be encountered, ie. during a next pregnancy, so that the immediate production of the more harmful (IgG class) antibodies can begin. This is when the woman becomes Rh(D) Iso-immune - immunized against Rh(D) positive cells, even if they belong to her unborn child. Although the amount present may decrease over a period of time, these antibodies will remain in her bloodstream throughout her life, waiting to destroy any future invasion of Rh(D) positive red cells.
THE PURPOSE OF ANTI-RH(D) INJECTIONS
After delivery, a blood test is performed to determine whether the baby is Rh(D) positive or negative. If the baby is tested Rh(D) positive, the mother will be given an injection of specially prepared anti-Rh(D), within three days (72 hours), in order to help her own blood destroy all the positive blood cells released into the bloodstream after the placenta comes away from the womb. This way, the blood cells are destroyed before the three days are up and her own immune system is not provoked into producing its own anti-Rh(D). Antibodies are only harmful if produced by the mother - the small amount injected after delivery is only there to do the job of `mopping up` the positive blood cells before they get to the immune system - they disappear from the bloodstream after a time.
100 micrograms of anti-Rh(D) will protect a woman from around 4ml of fetal blood. If the fetal-maternal hemorrhage (FMH) is more than 4 ml, a higher dosage is calculated and administered.
PLEASE NOTE: An anti-Rh(D) injection given at delivery is not a vaccine and does not make a woman immune to Rhesus (Rh) disease, but, provided she is found to be free of antibodies at the time it is administered, it can ensure that the woman begins the next pregnancy clear of antibodies.
Some Rh(D) negative women receive injections of anti-Rh(D) during pregnancy - especially at around 28 and/or 34 weeks - these would help to prevent antibodies being produced if an unsuspected placental bleed were to then occur, or had already occurred within the preceding 72 hours of the injection.
The amount injected is effective unless an unusually high amount of fetal blood enters the maternal bloodstream, thus `using up` the injected antibodies. In this respect, blood tests are still necessary throughout pregnancy to make sure that all is still well.
Each doctor follows guidelines set out by his/her own practice so a woman may find that she is not offered this treatment. However, administering anti-Rh(D) during pregnancy has been proved beneficial and it would be wise for a woman to discuss this with her doctor if she has any concerns about the welfare of her baby.
PLEASE NOTE: It is highly recommended that an anti-D injection be given after any incident which could result in red Rh(D) positive cells becoming present in the mother`s bloodstream, whether this be medical intervention where Rh(D) blood has been used, a fall which may cause a placental bleed, or a miscarriage.
ALSO NOTE: If a woman already has antibodies present in her blood a further administration of anti-D would be pointless and completely ineffective.
Although anti-Rh(D) is extremely effective, it is specially prepared using donor blood possessing high amounts of antibodies, the widespread use of this treatment has led to a number of women becoming immunized against red cell antigens unrelated to the Rhesus factor which, in rare circumstances, could also cause problems during a pregnancy, as well as there being a delay in providing blood for the mother herself in an emergency. However, the risks involved are outweighed enormously by the benefits of anti-Rh(D) and the injection should not be refused unless a woman is certain that her blood already contains Rh(D) antibodies.
If a Rh(D) negative woman is thought to be carrying a Rh(D) positive baby whose blood group differs from her own, you might ask why it is that her own in-built mechanism for destroying other blood types does not eliminate these cells from her bloodstream (Allo-immunization) before the D antigen contained in the Rh(D) positive cells stimulates her into producing Rh antibodies. While this would be so for some women, each person`s blood reacts in so many different ways, that it should never be assumed that the cells have been destroyed in time (within 72 hours). It is, therefore, standard procedure that every Rh(D) negative
woman has an anti-Rh(D) injection after delivery when the baby is found to be Rh(D) positive, whatever her blood group.
IMPORTANCE OF BLOOD TESTS
At the beginning of a pregnancy, a woman`s blood is tested for the Rh(D) factor and, if she is found to be Rh(D) negative, further tests will be performed throughout the pregnancy to ensure that her blood is not producing Rh antibodies against her baby`s blood (see Antibodies and Their Effects).
If a bleed from the placenta should occur at any time during pregnancy and the fetal blood is Rh(D) positive, this would result in antibodies being produced. This is why it is essential to keep a note of when blood tests are due and what the results are. If results have not been received within a week after the test is performed, they should be `chased up` - blood tests have been known to go astray. And, if a blood test is missed, it is vital that another one be arranged as soon as possible.
These tests are set out at carefully planned intervals throughout pregnancy to ensure that, if any antibodies are found in the bloodstream, the baby will not have been affected by them to such a degree that it would present a life threatening situation. Rhesus (Rh) disease (also called Hemolytic disease or Erythroblastosis Fetalis) takes weeks rather than days to affect the unborn child, so there would be ample time to check on the baby`s welfare and act accordingly.
It is written in pregnancy booklets that a Rh(D) negative woman should not be left to continue her pregnancy past her due date. The reason behind this is that, after the last carefully planned blood test, it is expected that the baby will be born on or before that date and, rather than perform another blood test, the baby will be delivered and any problems dealt with. It seems that this is not common practice.
In this respect, a woman who has not delivered by her due date should ask that a blood test be performed to put her mind at rest. While her doctor may insist that this is not necessary, babies suffering from Rh(D) disease have been known to die at full term and, even though this is a rare occurrence, this simple precaution should be taken.
PLEASE NOTE: If a baby`s blood is Rh(D) negative, it will not contain the D antigen and, therefore, cannot stimulate the mother`s immune system into producing antibodies throughout pregnancy or at labor and an anti-D is not necessary. Also, any antibodies already present in the mother`s blood cannot harm the baby`s negative cells. However, unless it is 100% certain that the partner is also Rh(D) negative, there will be no way of knowing the baby`s Rh factor during pregnancy and regular blood tests are still of utmost importance.
A recently developed test to determine the Rh factor of the baby by testing the amniotic fluid has been proving very effective. However, this test is only performed if a woman is already Rh(D) Rhesus iso-immune and her partner is known to possess both a positive and negative gene (d/D or D/d). This development is quite recent, but has proved very accurate and, although further blood tests will be performed regularly, a woman who is found to be carrying a Rh(D) negative baby will most probably be allowed to proceed with her pregnancy as normal.
TREATMENT
Rh(D) antibodies attack the baby`s positive blood cells by coating and bursting them (hemolyzing), causing the baby to become slowly more and more anemic - a baby affected in this way would be described as having Rhesus ( Rh) disease (also called Hemolytic Disease of the Newborn (HDN), Hyperbilirubinemia or Erythroblastosis Fetalis). Each time a red blood cell is destroyed, a substance called bilirubin is released into the amniotic fluid, which causes these waters to become increasingly yellowed as more positive cells are destroyed.
The term `Rhesus disease` may lead you to believe that the condition is an illness which could affect the mother`s health. This is not true - her Rh antibodies cannot attack her own negative blood cells and will lie dormant in the bloodstream, and even decrease, until they encounter the next invasion of Rh(D) positive cells which would contain the D antigen capable of stimulating her into producing more. The only implications of the disease are those described on these pages and the only harm is to the unborn child.
If a blood test reveals that a dangerously high level of Rh(D) antibodies are present in the mother`s bloodstream, an amniocentesis will be performed - a sample of the amniotic fluid is taken and run through a machine which determines the level of bilirubin - the higher the degree of yellowing, the more the baby is affected. The results are compared carefully to a special chart (Liley chart), which shows whether the degree of yellowing proves the baby to be at risk.
These tests will be performed by a specialist, to whom the woman will have been quickly referred and who deals with Rhesus disease on a very regular basis. He/she will decide what action to take depending on the degree of anemia. The results may show that the baby is not so anemic, that action needs to be taken at that time. However, the woman would be asked to return every two weeks, or at intervals specified by the specialist, to retest the waters and keep a close check on how the anemia is progressing.
If, however, the results of the amniocentesis are plotted as high or higher than a line on the chart, called the Liley line, this would indicate that the baby is at risk and a transfusion into the umbilical cord will be performed under local anesthetic, whereby Rh(D) negative blood cells will be used to replace the positive ones destroyed. The amount of blood cells needed is cleverly determined by testing a sample of blood taken, by needle, from the cord (cordocentesis), guided using ultrasound. These results are quickly analyzed and the transfusion is performed there and then, using the already inserted needle, to minimize risk factors. This method is very successful and is sometimes repeated at intervals throughout the pregnancy, depending on subsequent test results. However, there may be occasions where the specialist is unable to insert the needle into the cord, or where the baby is in a position where the needle poses a risk and, in these circumstances, the needle will be inserted into the baby's abdominal cavity and injected slowly. Instead of being transfused directly into the baby's circulation, the blood will be absorbed over a small period of time. The mother would have been asked to arrive at the hospital an hour or so earlier than the transfusion is scheduled, in order that a sample of her blood can be taken and tested. This process is called cross-matching and enables the hospital's Hematology Department to find the closest match of donor Rh(D) negative blood. Not only does the donor blood have to be Rh(D) negative, it also has to be screened for any antigens, other than those related to the Rhesus Factor, which would stimulate the mother's immune system into destroying the newly transfused cells.
Although the mother's Rh antibodies cannot attack the transfused blood, the cells will diminish after a time and another test will be required two weeks later, again, to determine the amount of negative cells the baby needs to replace the positive ones destroyed. Even though the mother's antibody level is still checked at each stage of the treatment, it will most definitely rise to an extremely high level after the first and further transfusions.
It may be felt that it would be safer to deliver the baby and manage the baby's condition more directly, especially if the woman is more than 32 weeks into her pregnancy and the baby is at risk of developing severe Hemolytic Anemia. This is a very carefully made decision and one that depends on which situation
would give the baby a better chance of survival. As Pediatric medicine has progressed to a very high standard, it is usually considered much safer to do this. However, if transfusions proceed until later in the pregnancy, say, 35 weeks, this increases the chance of a successful delivery nearer to full term and lessens the need for blood exchanges and other treatments.
If the baby is born early due to this condition, a transfusion is performed immediately to replace the baby`s blood with negative blood cells which remain in the system for about 40 days. About 9g of the baby`s blood is withdrawn and replaced at a time. Rh(D) negative cells are used to ensure that they cannot be harmed while helping the baby`s system to perform normally, which they do quite efficiently. They give the baby time to produce new positive cells, supplying enough blood to keep vital organs in good working order while this takes place. These Rh(D) negative cells will not harm the baby`s own newly produced cells, as there is no immune system to back them up. The blood used for this purpose is normally O Rh(D) negative and is cross-matched in the same way, to ensure that the transfused cells have no antigens to which the baby`s blood will take exception. Within as little as 72 hours the antibodies passed to the baby from the mother will have been eliminated.
If the anemia does not progress to the level that would require transfusions into the womb and a transfusion is not required at delivery, a special UV-ray lamp (Bililight) will be placed over the baby to combat any jaundice present (phototherapy). Close monitoring will ensure that the baby`s condition remains satisfactory.
PLEASE NOTE: Since the object of an anti-Rh(D) injection, is to prevent a woman from becoming sensitized and so becoming Rh(D) Iso-immune, the procedure would never benefit a woman with this condition. She will have plenty of anti-Rh(D) being manufactured by her own immune system and the injected antibodies would simply join forces with those already resident.
ISO-IMMUNIZATION AND FUTURE PREGNANCY
As the Rh(D) antibody can cross the placenta from around 12 weeks, it is assumed that a baby would begin to become affected by the antibodies already present in the mother`s bloodstream from this time forward. For subsequent pregnancies a woman who is Rh(D) Iso-immune will have her blood tested at this time to check the level of antibodies present in her blood. This is measured in International Units (I/U). Obviously, it would be preferable to have no antibodies at all but, unfortunately, this would not be the case. However, if the level is measured to be less than 5 I/U, no action will be taken and further blood tests will be performed frequently to check this level. If the antibody level rises above 5 I/U, an amniocentesis is performed and, since it is possible that the baby may be Rh(D) negative, extra fluid will also be taken and tested at the same time to determine the Rh factor. This will also be the case if the mother is known to already have a higher level of antibodies than 5 I/U. An amniocentesis will be performed, along with a test to determine the baby's Rh factor, if necessary, along with an antibody check.
For reasons unknown, the woman`s antibody level still fluctuates slightly in response to a Rh(D) negative baby - not to such a high degree as during a Rh(D) positive pregnancy and, of course, no harm would come to a Rh(D) negative child.
Throughout the rest of the pregnancy, tests are done at intervals specified by the specialist taking care of that particular case. The length of time between testing depends on the degree by which the baby is affected, but can be as often as every two weeks. Also taken into consideration are the results of blood tests performed on the mother to determine the level of Rh(D) antibodies in her blood, which will rise as a Rh(D) positive pregnancy progresses and will be plotted on a Liley chart (see `Treatment`). It is usually at around 20 weeks, or later, that any intervention in respect of a transfusion is necessary.
Throughout the rest of the pregnancy, tests are done at intervals specified by the specialist taking care of that particular case. The length of time between testing depends on the degree by which the baby is affected, but can be as often as every two weeks. Also taken into consideration are the results of blood tests performed on the mother to determine the level of Rh(D) antibodies in her blood, which will rise as a Rh(D) positive pregnancy progresses and will be plotted on a Liley chart (see `Treatment`). It is usually at around 20 weeks, or later, that any intervention in respect of a transfusion is necessary.
Regarding transfusions and delivery, the same applies as when a placental bleed occurs during pregnancy (see `Treatment`), except that everybody is already totally aware of the situation and ready for action straight away.
PLEASE NOTE: When a woman is found to be carrying Rh(D) antibodies, the pregnancy is never allowed to go past full term. Once she has been diagnosed has being Rh(D) Iso-immune, and the specialists become involved, they take NO chances and, as they deal with this condition everyday, they have become experts in their field, with overwhelming success rates.
NEW TREATMENTS - TRIALS
A new treatment, whereby the mother is transfused with non-specific (normal) human antibodies, is currently being used in trials.
If the mother's partner is known to be heterozygous (has both negative and positive genes), the baby's Rhesus factor is determined by either chorionic villus sampling (CVS) at around 11-12 weeks or amniocentesis at around 12-14 weeks. CVS is performed by taking a small sample of cells from the placenta, outside the amniotic sac and analyzing it. This method is often used early into the pregnancy, as an amniocentesis cannot always be performed at this time and the results of a CVS are available within a few days - the results of an amniocentesis take a little longer. If the baby is found to be Rh(D) positive, the mother will immediately receive a transfusion of these normal antibodies on a daily basis for one week, after which the transfusions will be administered weekly until around 28 weeks. These transfusions take around 2 hours and are stopped immediately if the mother develops any adverse reaction to the treatment, such as a rash etc. So far, the only common side effect reported has been an occasional headache just after treatment, which has not caused any further problems for the mother. The normal antibodies help to protect the baby's red blood cells from the mother's harmful Rh(D) antibodies.
It has been considered that a safer option would be to begin treatment without CVS and perform an amniocentesis a few weeks later, to determine the Rh factor of the baby. This would be a decision that needs to be made between the specialist and the patient.
NOTE: If the mother's partner is known to be homozygous (having only Rh(D) positive genes), she will automatically go ahead with the transfusions, as there will be no need for CVS.
The same routine checks are still used to monitor the baby throughout the pregnancy - ie. amniocenteses and the mother's antibody check, as this treatment is still only being carried out in trials.
At present, this treatment is only offered to women whose condition has become so severe that their baby could be at risk. The trials have so far been very successful, in that a transfusion into the womb becomes necessary much later in pregnancy, if at all, giving the baby a far greater chance of survival.
Unfortunately, even though this treatment has been very successful in severe cases, it has not yet been clinically proven as a definite advantage and is, therefore, very expensive and not widely available as a result. Until a much larger number of women participating in these trials have delivered successfully, it will be a long time before any significant benefits are seen.
Another recent success had been seen in China, where a blood test is performed on the mother, to determine the baby's Rh factor. The immature genes from the baby are detected in her blood and analyzed. This test has been unreliable in the first trimester (up to around 13 weeks) but very accurate during the last two trimesters. The test will not be widely available for a while, but it is a real step forward.
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