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|link comment||answered Jul 21 '11 at 21:54 Kimberly Expert|
Discuss the current and future practice in prevention, diagnosis and treatment of haemolytic disease of the fetus and newborn (HDFN)
Hemolytic disease of the newborn
Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis fetalis, is an alloimmune condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta. The underlying cause of HDFN is incompatibility between the maternal and fetal blood. This incompatibility results in the formation of antibodies in the maternal blood, which attacks the fetal red blood cells (RBCs). During pregnancy, maternal antibodies are transported across the placenta and enter the fetal circulation and attack the red blood cells in the fetal circulation; the red cells are broken down and the fetus can develop reticulocytosis and anemia. This fetal disease ranges from mild to very severe, and fetal death from heart failure (hydrops fetalis) can occur. When the disease is moderate or severe, many erythroblasts are present in the fetal blood and so these forms of the disease can be called erythroblastosis fetalis.
There are approximately 40 antibodies to RBCs that have been reported to cause HDFN but many are infrequent and do not cause severe disease. Three antibodies—Rhesus (Rh) D antibodies (anti-D), Kell antibodies, and antibodies to Rhc—are the main players that cause significant problems in the great majority of cases of HDFN. In particular, anti-D is the most common cause of severe HDFN.
In the majority of cases, the risk of HDFN arises when an Rh D-negative mother becomes pregnant with an Rh D-positive child. This can occur when the child inherits the D antigen from the father. The maternal immune response to the fetal D antigen is to form anti- D antibodies against it. These antibodies are usually of the immunoglobin G (IgG) type, which traverse the placental barrier, and hence delivered to the fetal circulation. Maternal anti-D antibodies in the fetal circulation attach to Rh antigen on fetal RBCs. Lysosomal enzymes released by macrophages and natural killer lymphocytes attack the antibody-coated RBCs.
Symptoms of HDFN
During pregnancy symptoms may include:
• With amniocentesis, the amniotic fluid may have a yellow coloring and contain bilirubin.
• Ultrasound of the fetus shows enlarged liver, spleen, or heart and fluid buildup in the fetus' abdomen.
After birth, symptoms may include:
• A pale coloring may be evident, due to anemia.
• Jaundice or yellow coloring of amniotic fluid, umbilical cord, skin, and eyes may be present. The baby may not look yellow immediately after birth, but jaundice can develop quickly, usually within 24 to 36 hours.
• The newborn may have an enlarged liver and spleen.
• Babies with hydrops fetalis have severe edema (swelling) of the entire body and are extremely pale. They often have difficulty breathing.
Complications of hemolytic disease of the newborn can range from mild to severe. The following are some of the problems that can result:
• Mild anemia, hyperbilirubinemia, and jaundice: The placenta helps rid some of the bilirubin, but not all.
• Severe anemia with enlargement of the liver and spleen: When these organs and the bone marrow cannot compensate for the fast destruction of red blood cells, severe anemia results and other organs are affected.
• Hydrops fetalis: This occurs as the baby's organs are unable to handle the anemia. The heart begins to fail and large amounts of fluid buildup in the baby's tissues and organs. A fetus with hydrops is at great risk of being stillborn.
• Severe hyperbilirubinemia and jaundice: The baby's liver is unable to handle the large amount of bilirubin that results from red blood cell breakdown. The baby's liver is enlarged and anemia continues.
• Kernicterus: Kernicterus is the most severe form of hyperbilirubinemia and results from the buildup of bilirubin in the brain. This can cause seizures, brain damage, deafness, and death.
Causes of HDFN
HDN most frequently occurs when an Rh negative mother has a baby with an Rh positive father. When the baby's Rh factor is positive, like the father's, problems can develop if the baby's red blood cells cross to the Rh negative mother. This usually happens at delivery when the placenta detaches. However, it may also happen anytime blood cells of the two circulations mix, such as during a miscarriage or abortion, with a fall, or during an invasive prenatal testing procedure (i.e., an amniocentesis or chorionic villus sampling). Although it is not as common, a similar problem of incompatibility may happen between the blood types (A, B, O, AB) of the mother and baby in the following situations:
Mother's Blood Type O A B
Baby's Blood Type A or B B A
In a first pregnancy, Rh sensitization is not likely. Usually it only becomes a problem in a future pregnancy with another Rh positive baby. During that pregnancy, the mother's antibodies cross the placenta to fight the Rh positive cells in the baby's body. As the antibodies destroy the red blood cells, the baby can become sick. This is called erythroblastosis fetalis during pregnancy. In the newborn, the condition is called hemolytic disease of the newborn.
Generally HDFN can be caused by:
1. Fetal-maternal hemorrhage because of:
Abdominal injury, abortion, Stillbirth, ruptures in the placenta during pregnancy
Invasive prenatal diagnosis e.g. amniocentesis, chorionic villus sampling
2. Therapeutic blood transfusion. ABO blood group system and the D antigen of the Rh blood group system typing are routine prior to transfusion.
3. If the there is ABO incompatibility especially when the women of blood type is O. This leads to the production of IgM anti-A and IgM anti-B antibodies early in life. On rare occasions, IgG antibodies are produced. Then IgG antibodies can cross the placenta and damages the fetus erythrocytes.
Diagnosis of HDFN
Because anemia, hyperbilirubinemia, and hydrops fetalis can occur with other diseases and conditions, the accurate diagnosis of HDFN depends on determining if there is a blood group or blood type incompatibility.
1. Prenatal testing
• To detect the presence of any IgG antibody that could cause HDFN in order to identify, monitor, and treat the infant as soon as possible.
• To determine which women are candidates for RhIg in order to prevent the production of anti-D.
• Maternal antibody titer is a good indicator of severity of HDFN.
• Ultrasound - to detect organ enlargement or fluid buildup in the fetus. Ultrasound is used to view internal organs as they function, and to assess blood flow through various vessels.
• Amniocentesis - to measure the amount of bilirubin in the amniotic fluid..
• Sampling of some of the blood from the fetal umbilical cord during pregnancy to check for antibodies, bilirubin, and anemia in the fetus.
2. Father testing
• Investigative tests on the father depend on which maternal antibodies are present. Mother has anti-D ABO and Rh typing with anti-D, -C, -E, -c,-e to determine probable Rh genotype to predict the chance the fetus has of being Rh positive and affected by HDFN;
• Test for weak D if initial Rh typing appears to be D-negative. For D positive fathers, the probable Rh genotype can be determined using serologic tests, i.e., DCEce typing to determine if the father is probably homozygous or heterozygous for D.
• Other maternal clinically significant antibodies Phenotype father for the corresponding antigen and its antithetical antigen (e.g., K and k)
3. Molecular Genotyping -
• Molecular methods exist for typing Rh (RHD and RHCE), Kell (K & k), Duffy (Fya & Fyb), and Kidd (Jka & Jkb) loci. In prenatal testing programs, molecular typing can determine the Rh type of the mother, father, and fetus and may be done if the mother has anti-D or another antibody known to cause HDFN. DNA methods are typically used in these circumstances:
For women who type as weak D in serologic tests, to determine the Rh genotype of the mother to identify if she is partial D or weak D;
For women who have made anti-D, to determine the Rh genotype of the father to see if fetal monitoring is needed;
For women who have made anti-D, to determine the Rh type of the fetus if the father is heterozygous for RhD or unavailable for testing.
Fetal blood typing can be done using fetal DNA from cells obtained by amniocentesis or by testing cell-free, fetal-derived DNA present in maternal plasma at 5 weeks gestation and later.
• In the case of a mother with anti-D and a father who is D positive using serologic methods, molecular typing can determine the father's RHD heterozygosity or homozygosity. If the father is homozygous for the RHD allele, all of his offspring will be Rh positive, negating the need for fetal D testing, but indicating that the fetus should be monitored for HDFN. If the father is heterozygous for RHD, the Rh type of the fetus should be determined to see if HDFN is possible.
4. Postnatal testing
Once a baby is born, diagnostic tests for HDFN may include the following:
• Testing of the baby's umbilical cord blood for blood group, Rh factor, red blood cell count, and antibodies
ABO blood group system (anti-A and anti-B)
Rhesus system (Rhesus D, E, e ,C and antibody combinations (ie anti-Rhc and anti-RhE antibodies occurring together) - can be severe
Kell system (anti-Kell , anti-K 1 antibodies – common and also anti-K 2 ,anti-K 3 and anti-K 4 antibodies - rare
Other blood group antibodies (Kidd, Lewis, Duffy, MN, P and others).
Fetal blood (or umbilical cord blood)
• The direct Coombs test is used to confirm that the fetus or neonate has an immune mediated hemolytic anemia.
• Full blood count - the hemoglobin level and platelet count are important
• Peripheral blood morphology shows increased reticulocytes. Erythroblasts (also known as nucleated red blood cells) occur in moderate and severe disease
• Biochemistry tests for jaundice: Bilirubin (total and indirect)
• The Acid elution technique of Kleihauer-Betke test or flow cytometry on a postnatal maternal blood sample can confirm that fetal blood has passed into the maternal circulation and can also be used to estimate the amount of fetal blood that has passed into the maternal circulation.
• The indirect Coombs test is used to screen blood from antenatal women for IgG antibodies that may pass through the placenta and cause hemolytic disease of the newborn.
Treatment for hemolytic disease of the fetus and newborn:
Once HDFN is diagnosed, treatment may be needed. Specific treatment for hemolytic disease of the newborn will be determined based on: Baby's gestational age, overall health, and medical history, extent and expectations of the disease, baby's tolerance for specific medications, procedures, or therapies
Antenatal (During pregnancy), treatment for HDFN may include:
• Serial Ultrasound and Doppler examinations- to detect signs of fetal anemia such as increased blood flow velocities and monitor hydrops fetalis
• Quantitative analysis of maternal anti-RhD antibodies - an increasing level is a sign of fetal Rh disease
• Intrauterine blood transfusion
This is done by placing a needle through the mother's uterus and into the abdominal cavity of the fetus or directly into the vein in the umbilical cord.
Intraperitoneal transfusion - blood transfused into fetal abdomen
Intravascular transfusion - blood transfused into fetal umbilical vein
• Early delivery (usually after about 36 wks gestation)
If the fetus has mature lungs, labor and delivery may be induced to prevent worsening of HDN.
Postnatal (After birth), treatment may include:
• Blood transfusions (for severe anemia)
• Intravenous fluids (for low blood pressure)
• Help for respiratory distress using oxygen or a mechanical breathing machine
• Phototherapy: Intensive phototherapy has also been used to treat moderate and severe HDFN and decrease the need for exchange transfusion. The newborn is placed under a "blue light" which chemically alters the bilirubin in the surface capillaries to a harmless substance.
• Exchange transfusion to replace the baby's damaged blood with fresh blood:
The exchange transfusion helps increase the red blood cell count and lower the levels of bilirubin. An exchange transfusion is done by alternating giving and withdrawing blood in small amounts through a vein or artery.
• Human Serum Albumin: Human serum albumin can also be transfused, either separately or as part of an exchange transfusion in place of FFP. Albumin binds unconjugated bilirubin, thus preventing its deposition in the fat-rich brain cells. Albumin must be used judiciously, because it can aggravate congestive heart failure.
Prevention of hemolytic disease of the newborn:
Determine Rh status of the mother
As part of routine prenatal or antenatal care, the blood type of the mother (ABO and Rh) is determined by a blood test. A test for the presence of atypical antibodies in the mother's serum is also performed.
If the mother is not sensitized, reduce the risk of future sensitization
To find out whether a pregnant Rh D-negative mother has been sensitized to the Rh D antigen, an indirect Coombs test is done. If anti-D is not found in the mother's serum, it is likely that she has not been sensitized to the Rh D antigen. The risk of future sensitization can be greatly reduced by giving all unsensitized mothers anti-D Ig, which "mops up" any fetal RBCs that may have leaked into the maternal circulation, reducing the risk of first-time exposure to the D antigen.
Usually, Rh D-negative mothers given a drug called Rh immunoglobulin (RhIg), also known as RhoGAM. This is a specially developed blood product that can prevent Rh negative mother's antibodies from being able to react to Rh positive cells. This anti-D Ig is given at about 28 weeks gestation, which is about the time when fetal RBCs start to express the D antigen, and mothers receive another dose at about 34 weeks, a few weeks before labor begins during which the risk of feto-maternal hemorrhage is high. A final dose of anti-D Ig is given after the baby has been delivered within 72 hours.
If the mother is sensitized, determine whether the fetus is at risk and monitor accordingly
Once the presence of maternal anti-D has been confirmed, the next step is to determine whether the fetal RBCs are a target, i.e., confirm the Rh status of the fetus. If the father is homozygous for the D allele (D/D), the fetus will be D positive. If however the father is heterozygous (D/d), there is a 50:50 chance that the fetus is D positive, and the only way to know the blood type for sure is to test a sample of fetal cells taken from the amniotic fluid or umbilical cord.
If the fetus is Rh D-positive, the pregnancy is carefully monitored for signs of HDN. Monitoring includes regular ultrasound scans of the fetus and monitoring of the amount of anti-D in the mother's serum. Active hemolysis is indicated by a rise in anti-D. If a fetal blood test confirms fetal anemia, depending upon its severity, a blood transfusion can be done in utero to replace the lysed fetal RBCs.
RhIG remains the treatment of choice for the prevention of HDFN. Its use, prophylactically, has dramatically reduced the incidence of HDFN, particularly severe cases that were responsible for stillbirth and neonatal death. However, there is still an unmet need for patients who are already sensitized, where RhIG is no longer effective. If patient does become sensitized, clinicians have a battery of diagnostic tools to follow these pregnancies. But procedures, such as amniocentesis and intrauterine transfusions, still carry a level of risk.
A number of new approaches look promising for the future. One such approach is the regulation of the maternal immune system, whereby a therapeutic vaccine could be used to down-regulate the immune system in sensitized patients, which potentially will stop production of anti-D antibodies. In that scenario, intrauterine transfusions would not be necessary.
Furthermore, Molecular methods exist for typing Rh (RHD and RHCE), Kell (K & k), Duffy (Fya & Fyb), and Kidd (Jka & Jkb) loci. In prenatal testing programs, molecular typing can determine the Rh type of the mother, father, and fetus and may be done if the mother has anti-D or another antibody known to cause HDFN. Fetal blood typing can be done using free fetal DNA from cells obtained by amniocentesis or by testing cell-free, fetal-derived DNA present in maternal plasma at 5 weeks gestation and later.
|link comment||answered Nov 15 '11 at 08:06 fikir New member|
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