What is Rh Hemolytic Disease?
The Rhesus factor, or Rh factor, is a protein found on the surface of red blood cells. This name came about when the factor was first discovered in rhesus monkeys. The Rh blood group is made up of lots of individual components (over 50), but the most commonly known ones are D, C, c, E, and e. The ‘D’ component is particularly important, as it causes what is known as Rhesus disease due to how strongly it can induce an immune response. If a person’s red blood cells carry the D component, they are considered Rh-positive; if their red blood cells don’t carry it, they are Rh-negative.
Rh-hemolytic disease (also known as Rh incompatibility) is a condition that happens when a woman with Rh-negative blood is exposed to Rh-positive blood cells. This exposure results in the woman’s body producing anti-D antibodies, something known as isoimmunization. Once a woman’s body has produced these antibodies, they can last a lifetime. If the woman becomes pregnant again, these antibodies can get to the baby via the placenta. When they find the D component on the baby’s red blood cells, they bind together and destroy the cells, causing a condition known as erythroblastosis fetalis, where the baby’s body isn’t producing enough red blood cells. The severity of the condition depends on how many antibodies are in the woman’s body, the gestational age of the baby (how far along in the pregnancy it is), and the baby’s enzymatic activity (the functionality of their enzymes).
If Rh-hemolytic disease goes undiagnosed, it can be very dangerous, with a mortality (death) rate of 24% in newborn babies. However, steps can be taken to significantly reduce this risk. For instance, parents can be screened to see if they carry the Rh factor. If a pregnancy is likely to be affected, the woman can receive a treatment called Rh immunoglobulin. This has greatly reduced the number of babies who die from this condition.
What Causes Rh Hemolytic Disease?
Rh hemolytic disease, a type of blood disease, is usually caused by two main events. The first cause is when a pregnant mother with Rh-negative blood gets exposed to her baby’s Rh-positive blood cells. This can happen during various events in pregnancy or delivery, like normal childbirth, a miscarriage, an ectopic pregnancy (when a fertilized egg implants outside the uterus), placenta previa (a condition where the placenta covers the opening of the cervix), lack of prenatal care, specific medical procedures, an external cephalic version (a procedure to turn a breech baby), cesarean section, or a sudden, forceful event or injury that can cause internal damage.
Once a mother is exposed to this Rh-positive blood, her body creates antibodies that can attack Rh-positive blood cells. For future pregnancies, if the unborn baby is Rh-positive, these antibodies can cross over to the baby through the placenta. These antibodies can then destroy the baby’s blood cells, causing serious issues like severe anemia (low red blood cells), hyperbilirubinemia (too much bilirubin, a waste product, in the baby’s blood), which can lead to neurological damage or even death.
The second, less common cause of Rh incompatibility happens when an Rh-negative woman receives a transfusion of Rh-positive blood, especially during an emergency. This can occur primarily in emergency circumstances when there isn’t time to test the woman’s blood type.
Risk Factors and Frequency for Rh Hemolytic Disease
The percentage of people with Rhesus negative blood type varies significantly across different regions of the world, influencing global disease rates. In North America and Europe, 15% of the white population has Rh-negative blood, while only 4% to 8% of Africans and 0.1% to 0.3% of Asians share this blood type. Despite improvements in prenatal screening and prevention, each year, Rh-hemolytic disease still affects 276 newborns for every 100,000 live births all over the world, especially in developing countries.
In the southwest United States, the number of cases is 1.5 times higher than the national average. This difference might be due to immigration factors. In newborns affected by Rh-hemolytic disease, 24% risk death and 11% are stillborn. Furthermore, 13% develop a condition known as kernicterus. The highest death rates from this disease are recorded in Eastern Europe and Central Asia, with 38 deaths for every 100,000 live births. Interestingly, if a mother has ABO incompatibility – another blood condition where she possesses anti-A/anti-B antibodies against the fetus – it can lower the chance of developing this disease.
Signs and Symptoms of Rh Hemolytic Disease
In cases related to Rh incompatibility, it’s crucial to gather detailed information, including the parents’ blood types, any past blood transfusions, and the history of prior pregnancies. This should particularly focus on any history of Rh-hemolytic disease, traumas or interventions during pregnancy, past miscarriages, and any administration of Rh IgG. The physical exam results depend on how severely the disease has affected the patient.
Newborn babies lightly affected by Rh-hemolytic disease will show signs of mild jaundice in their first few days. They usually recover fully without any long-term issues. More moderately affected babies can show signs of anemia and jaundice simultaneously.
Where severe affliction occurs, newborns develop a condition named kernicterus, a few days after being born. This is due to the buildup of a type of bilirubin in their central nervous system tissues. Symptoms of kernicterus include loss of early neurological reflexes, such as the Moro reflex or posturing reflex, a bulging fontanelle (the soft spot on a baby’s head), arched back, limp body, high-pitched cry, difficulties feeding, and generalized seizures. This condition is more frequent in premature babies and around 83% of children who develop kernicterus face permanent neurological damage.
Severe cases of Rh-hemolytic disease can also lead to a highly dangerous condition called erythroblastosis fetalis in infants, marked by jaundice and severe anemia. The most intense form of this condition is hydrops fetalis, which involves symptoms like generalized swelling, buildup of fluid around the lungs or heart, cardiac failure, and abnormal blood production outside of the bone marrow. Infants with this condition typically have a very low hematocrit (a measure of red blood cells in blood) and face a mortality rate greater than 50%.
Testing for Rh Hemolytic Disease
The first step for every pregnant woman is to determine her Rh blood type, as per recommendations made by the United States Preventive Services Task Force (USPSTF).
If a pregnant woman tests Rh-positive, no further testing is required. But if she’s Rh-negative, the next step involves testing for anti-D antibody, which fights off Rh-positive blood cells, in the woman’s blood. This testing process starts with a basic test called a rosette test and is later confirmed with a more quantifiable test known as the Kleihauer-Betke test. This test is particularly necessary when there’s a significant amount of bleeding. A Coomb’s test, another type of blood test, confirms the result. If antibody levels exceed a specific threshold, further testing in the form of repeated amniocentesis, a procedure for removing small amounts of fluid from around the baby in the womb, may begin as early as 16-20 weeks to determine the Rh status of the fetus.
The monitoring protocol for the baby depends on whether the Rh status of the baby is positive or negative. For instance, if an Rh-negative mother is carrying an Rh-positive fetus, fetal growth is monitored using various types of ultrasound scans, and middle cerebral artery (MCA) dopplers, which measure blood flow in the baby’s brain, to check for anemia (low red blood cell count). This is usually performed every 1-2 weeks starting from 24 weeks into the pregnancy.
If the test for anti-D antibodies is negative, the next step is to determine the father’s Rh blood type. If the father is Rh-negative, no more testing is required. However, if the father has both Rh-negative and Rh-positive genes (heterozygous Rh-positive), the baby has a 50% chance of being either Rh-negative or Rh-positive. In these cases, further genetic testing of the baby might be required. Fetal Rh genotyping can be done through various non-invasive methods or invasive techniques, such as amniocentesis and chorionic villus sampling, which are procedures for obtaining fetal DNA for analysis.
Should a woman come into the emergency room to deliver and she has not undergone prior prenatal tests, blood samples from the baby’s umbilical cord are taken for blood grouping and Rh typing, measurement of hematocrit (red blood cell concentration), hemoglobin (oxygen-carrying protein in red blood cells), and the presence of bilirubin. The direct Coombs test is performed to confirm potential cases of antibody-induced anemia, which is more likely due to Rh-incompatibility than ABO incompatibility. Signs such as elevated bilirubin, low hematocrit, and simultaneous significant count of reticulocytes (young red blood cells) may indicate the need for emergency blood transfusion.
Imaging studies including pelvic ultrasound scans can show signs of fluid in the baby’s body cavities, soft tissue swelling, scalp swelling, fluid around the lungs and heart, enlarged heart and liver, and high blood pressure in the liver’s blood vessels in cases of severely affected fetuses.
Treatment Options for Rh Hemolytic Disease
Rh immunoglobulins (RhIVIG), first introduced around fifty years ago, have proven to be a highly effective preventive treatment for Rh incompatibility, a condition where a mother’s Rh blood factor and the baby’s Rh factor are incompatible. After this treatment was established in 1968, there has been a significant decrease in the occurrence of Rh-hemolytic disease, a condition where the mother’s immune system attacks the baby’s red blood cells. At the same time, the mortality rate has also reduced by two-thirds.
This treatment is given to Rh-negative women, who don’t carry the Rh protein, when they have babies who are Rh-positive (carrying the Rh factor) and the mother hasn’t developed immunities against Rh yet. It can be given preventively, following abortion, or if the mother’s and baby’s blood have mixed (fetomaternal hemorrhage). Rh immunoglobulins work by covering the baby’s red blood cells that contain the D antigen, preventing them from activating the mother’s immune system. Since Rh immunoglobulins have a short life of 3 months in the body, the treatment is given once between 28 to 32 weeks of pregnancy, and again within 72 hours after the baby’s birth.
The dose can be adjusted based on the amount of bleeding, which can be estimated by testing for the presence of baby’s red blood cells in the mother’s circulation. In the case of an abortion before 13 weeks, a smaller dose should be given, with a full dose given in the event of a miscarriage.
Jaundice, a common condition where a baby’s skin and the whites of the eyes turn yellow, can be treated using phototherapy. However, with the administration of a high dose of IVIG, the duration of phototherapy treatment has significantly reduced.
Exchange transfusion is a treatment method used after phototherapy to treat high levels of bilirubin in a newborn baby’s blood, which reduces the risk of the baby developing kernicterus, a severe form of brain damage.
If a baby in the womb is severely anemic, a blood transfusion may be required. The extent of the anemia can be calculated precisely before birth by using a special kind of ultrasound called middle cerebral artery Doppler. Once the baby is born, if their hematocrit level (the proportion of red blood cells to the total blood volume) is less than 30%, a blood transfusion is indicated. This can be done through a blood vessel, or into the abdominal cavity as an alternative.
What else can Rh Hemolytic Disease be?
Rh-hemolytic disease manifests as yellow skin discoloration, known as jaundice, and anemia. These symptoms stem from an excess of a specific type of bilirubin in the blood, known as unconjugated hyperbilirubinemia. For removing bilirubin from the body, it is converted or ‘conjugated’ by an enzyme known as UDP-glucuronosyltransferase (UGT) 1A1. This disease can occur as a result of either not enough of this enzyme or an overproduction of bilirubin.
It is crucial to figure out whether the jaundice is normal or pathological. Normal jaundice starts on the second or third day after birth, with bilirubin levels no more than 12mg/dl. It’s 20% more common in premature babies and usually fades away after one week without any harm. On the other hand, jaundice that shows up within the first day after birth or comes with significantly high bilirubin levels is considered pathological and requires further investigation.
The most prevalent cause of pathological hyperbilirubinemia is breast milk-induced jaundice, often attributed to the possible lack of nutrients in these breastfed infants and how breast milk affects the UDP-glucuronyltransferase enzyme system.
However, there are other significant factors that could lead to this condition:
- Blood group (ABO) incompatibility
- Inherited conditions like spherocytosis and enzyme deficiencies
- Blood leakage from the fetus to the mother (fetomaternal hemorrhage)
- Blood transfer between twins (twin transfusion syndrome)
- Thalassemia, specifically alpha thalassemia
- Thrombotic microangiopathies
It is important to differentiate these conditions from Rh-incompatibility through a series of tests such as full blood count, peripheral blood smear, measuring conjugated and unconjugated bilirubin levels, liver function tests, and specific blood markers.
What to expect with Rh Hemolytic Disease
The use of Rho (D) immune globulin, a type of medicine, has greatly reduced the occurrence of Rh-hemolytic disease, which is a condition where red blood cells are destroyed faster than they can be replaced. A study showed that from the time this medicine was introduced, the rate of this disease dropped from 40.5% to 14.3% for every 10,000 births in the first ten years.
Furthermore, advanced prenatal checkups, modern diagnosis techniques, and high-quality healthcare facilities, particularly in developed countries like the United States, have lowered the occurrence of Rh-hemolytic disease and related death rates to a very small percentage. Nonetheless, higher rates are still seen in developing countries where close to 276 babies out of every 100,000 live births are affected. Newborns showing signs of fluid buildup, a condition known as hydrops, have a slightly higher risk than those without these signs.
Possible Complications When Diagnosed with Rh Hemolytic Disease
The possible complications of certain conditions during pregnancy and childbirth may include:
- An early miscarriage or fetal death in the womb due to specific changes in the fetus.
- Fetal or newborn anemia: This can cause severe blood disorder (hemoglobin level less than 7 g/dL) due to excessive immune response from the mother’s body. This disorder reduces the oxygen levels and hinders the development of lungs in the fetus, and may lead to certain health complications in the newborn, such as changes in heart cells due to reduced oxygen supply in the blood.
- Kernicterus: This is a serious condition where a substance called unconjugated bilirubin gets lodged in the newborn’s brain, potentially resulting in permanent damage to the nervous system. This can happen to a high percentage of newborns (83%) and can persist later in life, even after the resolution of blood disorder and jaundice.
- The potential for recurrence of these complications in future children the mother may have.
Preventing Rh Hemolytic Disease
Rh disease, a condition that can cause serious illness or death, can actually be prevented. This is why it’s so crucial for doctors to teach patients about the importance of regular screenings during pregnancy and getting special treatments in the last few months of pregnancy. These measures can help avoid this health problem. It’s now much easier for doctors to find out parents’ Rh status earlier because of better access to healthcare services. This early detection has led to significantly improved results and overall health outcomes.
