The immune system has various methods of destroying invaders and we will not go into detail regarding these pathways today. However, in the case of Rh-sensitization, the fetal RBCs are predominantly destroyed by cells that attack, nonspecifically, whatever antibody has attached to. Most of the destruction of Rh-sensitized fetal RBCs occurs by cells, such as macrophages, comprising what is termed the ‘reticuloendothelial (RE) system’ that is highly concentrated in organs such as the liver and spleen. Fortunately, these cells are not capable of mounting a permanent immune response to these antibody-sensitized fetal RBCs, which is a GOOD thing for the baby. (In other words, after birth, once the mother’s Rh-antibodies are eliminated, the baby will no longer attack its own RBCs, although the destruction can continue after birth until such time as the antibodies are gone). There are several consequences of the RE system’s response that contribute to the course and physical changes associated with what we then term ‘Rh-disease’ in the fetus.
First, the RE system begins to break down the fetal RBCs at a faster rate than RBCs usually turn over. RBCs contain the hemoglobin that is necessary for carrying oxygen throughout the body. When RBC destruction exceeds the ability of the baby to make sufficient quantities of new RBCs to keep up with the needs of the growing fetus, then anemia begins to develop. As the baby grows its need for more RBCs increases rapidly; and, as the placenta develops throughout gestation, it becomes more efficient at transferring maternal antibodies (including anti-Rh antibodies) to the baby. Unfortunately, in the case of Rh-disease, this accelerates the destruction of fetal RBCs. This combination of events places the baby at greater risk for severe anemia as the pregnancy progresses.
In addition to the destruction of fetal RBCs, the primary organs in which this occurs, the liver and spleen, also begin to enlarge. This enlargement is the consequence of several factors. First, the cells of the RE system proliferate (to some extent) and enlarge as the result of destruction and consumption of the fetal RBCs. Secondly, while the baby is in the womb, the liver, in particular, and the spleen are important sites for the production of fetal RBCs, an event that usually shifts more to the bone marrow as pregnancy progresses. As the baby becomes anemic, the production of RBCs in these organs (called extramedullary hematopoiesis) actually accelerates, rather than diminishes, and the proliferation of precursor cells responsible for the production of new RBCs contributes significantly to enlargement of the liver and spleen. As the liver and spleen increase, abnormally, in size, the growing cell mass begins to compress blood vessels (particularly veins) and lymphatic channels, resulting in 'congestion' (retention of blood and fluid) of these organs, contributing to further enlargement and accelerating the ‘congestion’ in a vicious cycle.
Severe anemia in Rh-disease rarely occurs before about 20 weeks, although the fetal RBCs strongly express the Rh-antigen by 30 days’ gestation. Many factors play into the risk for severe anemia including the maternal antibody titer, the type of IgG antibodies to which the baby is exposed, and the baby’s genetic background. Baby’s can usually tolerate very low RBC counts. However, when the anemia becomes so profound that the baby’s ability to supply oxygen to its tissues diminishes, the baby begins to accumulate lactic acid as the consequence of having to use metabolic pathways to support its tissues that do not require oxygen (anaerobic metabolism). The resulting ‘acidosis’ is probably one of the primary mechanisms by which the fetal heart begins to function less efficiently and, if this continues long enough, the baby goes into ‘heart failure,’ resulting in the terminal stages of Rh-disease (unless corrective measures are taken) in which the baby retains fluid throughout its body, a condition called hydrops fetalis. It is also thought that the congestion of the fetal liver, by impairing venous blood flow from the placenta to the heart (remember, it is the umbilical vein, not a high pressure artery, that carries oxygenated blood from the placenta and through the fetal liver before going to the heart) contributes to the heart failure as well.
There is at least one other event that occurs during Rh-disease that can put the baby at long-term risk for complications, or even death. When the baby’s RBCs break down and release hemoglobin, the hemoglobin is then also broken down, primarily into a substance called bilirubin. Indeed, elevated circulating levels of bilirubin can usually be detected even before the baby begins to develop anemia. Some of the bilirubin is converted into a ‘water soluble’ form that can be excreted in the fetal urine and, as we will discuss in the final post on this subject, the detection of this becomes the basis for assessing, indirectly, the degree of fetal anemia. Unfortunately, due to the immaturity of its metabolic pathways, the baby is not very efficient at converting bilirubin to this excretable form and a water insoluble form of bilirubin can begin to accumulate in the fetal blood. This form of bilirubin, called indirect bilirubin, has the ability to penetrate the lipid membranes of nerve cells and is toxic to them, causing cell damage and death. At extremely high levels of bilirubin, the baby can suffer permanent brain damage (kernicterus) and death as a result of that damage, but this is rarely seen today with the management protocols currently used to follow pregnancies and the babies who are the products of Rh-sensitized women.
I fully realize that today’s post is fairly complicated (it is even for most providers), but having a basic understanding of Rh-disease is essential to understanding the options (and importance) for evaluation and management of an Rh-sensitized pregnancy that will be presented in my next post on this subject…