Rh incompatibility
Introduction
Rh blood group incompatibility The Rh blood group antigen is determined by three pairs of closely linked alleles on the first pair of chromosomes, and there are six antigens, namely C and c; D and d; E and e. Among them, D antigen was first discovered and the antigenicity was the strongest, so it is called Rh positive when it has D antigen. The anti-d has not been determined so far, so it is difficult to confirm the existence of the d antigen, and the lack of D is now only indicated by d. Both DD and dD are Rh-positive, dd is Rh-negative, and the frequency of Rh-negative differences in ethnicity: approximately 15% in the Caucasian population and 5% in the African American. China's Han population is less than 0.5%, and some ethnic minorities in China, such as the Uzbek and Tatar, Rh negative accounted for more than 5% of the population, Rh blood system has 6 antigens, namely C, c, D, d, E , e, in which d antigen has no antiserum at present, so only 5 kinds can be detected. The D antigen is the strongest among the 6 antigens, and the pathogenic rate is also the highest, accounting for more than 80% of the Rh factor, so it is often clinically The Rh blood group was determined by anti-D serum. basic knowledge The proportion of sickness: 0.01% Susceptible population: pregnant women Mode of infection: non-infectious Complications: jaundice, neonatal bilirubin encephalopathy
Cause
Rh blood group incompatibility
Causes
Rh blood type is not contracted with ABO blood group incompatibility (30%):
Since the fetal red blood cells entering the mother are affected by the ABO antibody, they are quickly neutralized and the Rh antibody is not produced, so Rh hemolytic disease is not easy to occur, even if the disease is mild, Douohoe et al. (1964) found that the mother and child AO are incompatible ( The neutralizing force of the mother O, sub-A) is stronger than that of the mother BO (parent O, sub-B). The former can protect 90% of women from sensitization, and the latter can only protect 55% of women from sensitization.
The amount of antigen in red blood cells (30%):
This is determined by the amount of fetal red blood cells and the number of Rh-positive erythrocyte antigen clusters entering the mother. Rh-positive heterozygous erythrocytes are less than half of the antigenic clusters of Rh-positive homozygous erythrocytes, but this is not important for the onset of Rh hemolytic disease because of Rh The neonates with hemolytic disease are Rh-positive heterozygotes (because their mother is Rh-negative homozygotes), and are Rh-positive heterozygotes, but the antigen clusters are different, such as CDe/cde red blood cells and CDE/cde red blood cells, the former is the latter. The antigenic cluster is more than 1/3, so CDe/cde newborns are prone to disease, and their condition is also heavier than CDE/cde. Because there are various factors affecting the incidence of Rh hemolytic disease, Rh-negative women, although bred Rh A positive fetus, which accounts for only about 1/10 of its hemolysis.
Pathogenesis
1. Blood group incompatibility: Red blood cells with Rh(+) antigen enter the blood of Rh(-) mother through the placenta, and produce corresponding blood group antibodies. This antibody enters the fetal circulation through the placenta, acts on red blood cells and causes hemolysis, and has nucleated red blood cells. Thus hyperplasia, revealed in the fetal blood, hence the name erythroblastosis fetalis.
Transplacental blood loss (transplacental blood loss), fetal blood into the mother, is not uncommon, HbF can be detected by acid elution method, which can prove that there is indeed a placental blood loss, only blood contains only 0.1 ~ 0.2ml of fetal blood, Not enough to sensitize the mother, but repeated small doses of placental blood loss can still be sensitized, it is known that the Rh system immune sensitization only needs a cumulative amount of 1ml, many obstetric factors increase the chance of blood loss through the placenta, such as high pregnancy Blood pressure disease, cesarean section, hip production, placenta previa, early exfoliation of the placenta, external reversal or amniocentesis, abortion, especially abortion will also occur a greater transplacental blood loss.
When the Rh blood group is incompatible, the fetal red blood cells enter the maternal circulation through the placental blood loss, and are swallowed by the mother spleen macrophages. It takes a considerable time to release a sufficient amount of Rh antigen, which reaches the corresponding antigen receptor of the spleen lymphocytes. The production of Rh antibody, this initial immune response develops slowly, often lasts for more than 2 months and even up to 6 months, and the antibody produced is often weak and IgM, does not pass through the placenta, because fetal red blood cells enter the mother more At the end of pregnancy or at the time of labor, the first fetus is only in the latent stage of the primary immune response. Even if the placental blood loss occurs earlier, the incidence of the first child is generally low due to the above reasons. After the primary immune response, pregnancy again, even if the amount of blood lost through the placenta is small, secondary immune can occur quickly, IgG antibodies rise rapidly, and hemolysis is caused by the combination of the placenta and fetal red blood cells.
2. The mechanism of allogeneic hemolysis caused by Rh blood group incompatibility is as follows (taking anti-D as an example):
(1) The mother is Rh negative.
(2) The fetus is Rh positive.
(3) Fetal red blood cells pass through the placenta into the maternal circulation.
(4) The mother is sensitized by the D antigen of fetal red blood cells to produce an IgM antibody to the mother.
(5) A small amount of cells enter the mother again after pregnancy.
(6) Rapid production of a large amount of IgG antibodies.
(7) The mother produces anti-D, IgG antibodies into the fetal circulation.
(8) The maternal anti-D antibody sensitizes the fetal red blood cells.
(9) The sensitized fetal red blood cells are destroyed.
A small number (about 1%) of Rh hemolytic disease occurs in the first child, because some pregnant women have received Rh blood group incompatibility, or a small number of Rh-negative pregnant women when she is still a fetus, because her mother is Rh is positive, so there is a blood group incompatibility. If at this time (pregnant) mother's blood has a small amount of placenta into the fetus, the initial immune response occurs, so that when the pregnant woman is positive in the first pregnancy, as long as her fetus is positive, as long as A small amount of fetal blood can enter the pregnant woman to have a secondary immune response, and a sufficient amount of IgG antibody is produced to cause the disease. This is the so-called "grandmother theory."
Rh blood group incompatibility mainly occurs when the mother is Rh negative, and the fetal Rh positive is anti-D antigen positive, which is caused by anti-E (mother is ee), anti-C (mother is cc) or anti-e, c, etc. Anti-E is more common, because RhCCee or CcDee accounts for almost half of the Han population in China, and RhE antigenicity is second only to RhD. In Shanghai, China has diagnosed 122 cases of Rh hemolytic disease in 18 years, of which 47 cases (38.5%) are Rh was positive, and 42 cases were caused by anti-E hemolytic disease.
Prevention
Rh blood group incompatibility prevention
In addition to D antigen can cause neonatal hemolytic disease, other Rh antigens can also sensitize the mother, can also cause neonatal hemolytic disease, but its antigen intensity is weak, the incidence is less. The order of Rh antigenicity is D>E>C>c>e>d. There are many CCDee blood types in China, so there are relatively many cases of neonatal hemolytic disease caused by anti-E and anti-c. However, due to the strong antigenicity of D antigen, it is easy to produce anti-D antibody, so most of them still take anti-D antibody to take the lead, but compared with other ethnic groups, the role of E and c is more important in Chinese Han women. Generally speaking, the Rh-positive blood type refers to the D-antigen. Therefore, the mother may be Rh-positive due to anti-E or anti-c. Therefore, Rh hemolytic disease does not necessarily occur in Rh-negative mothers.
Complication
Rh blood group incompatibility Complications, jaundice, neonatal bilirubin encephalopathy
Nuclear jaundice is the main complication of this disease. As early as 1904, Schmorl found that the basal nucleus of the brain was yellow-stained in a case of a newborn who died of severe jaundice, and was named for the first time as kernicterus. This yellow-stained substance is determined to be unbound bilirubin, which can cause toxic lesions of nerve cells, so it is also called bilirubin encephalopathy.
The most obvious bilirubin encephalopathy is the basal nucleus of the brain, which is bright yellow or dark yellow; other parts such as hippocampus, hypothalamic, hypothalamic nucleus, globus pallidus, putamen, apical nucleus, caudate nucleus, ventricular nucleus, cerebellum The lobules and the anterior horn of the spinal cord are pale yellow; the cerebellum, the cerebral ventricle, and the white matter and gray matter of the cerebral hemisphere can also be affected, but are lighter.
Basal nucleus neurons are most active in the physiological and biochemical metabolism in the neonatal period. The oxygen consumption and energy are the most needed, so the basal nucleus is the most vulnerable. The bilirubin may oxidize the mitochondria of brain cells after entering the brain cells. The joint action is out of contact, so the energy production of brain cells is inhibited and the brain cells are damaged.
1. Neonatal bilirubin encephalopathy and maturity of the blood-brain barrier: The intact blood-brain barrier has a barrier effect that restricts certain substances (such as bilirubin) from entering the central nervous system, so it protects the brain tissue. Role, but when the effects of hypoxia, infection, hypoglycemia and acidosis, the permeability changes, the barrier effect is destroyed, the so-called blood-brain barrier is open, at this time not only free bilirubin can enter the brain Tissue, and unbound bilirubin associated with albumin can also enter, some drugs can affect the blood-brain barrier, especially when the neonatal blood-brain barrier is not mature enough, especially in premature infants with insufficient gestational age, In the first few days, the blood-brain barrier of the newborn is more permeable, and bilirubin is easy to pass through. Therefore, it can be considered that the neonatal blood-brain barrier is immature and prone to nuclear jaundice.
2. Free bilirubin gradient: Unbound bilirubin (UCB) is fat-soluble. It has affinity with phosphatidyl-rich nerve cells. When UCB and albumin are combined into a complex, due to the large molecular weight, it is generally impossible. UCB that passes through the blood-brain barrier but is not associated with albumin can pass through into the central nervous cells to cause bilirubin encephalopathy. Any factors that increase the serum free bilirubin concentration, such as: 1UCB concentration is too high; 2 albumin The content is too low; 3 the existence of competition to seize the albumin on the junction can lead to bilirubin encephalopathy, the higher the blood and brain free bilirubin gradient, the more the amount of brain into the brain, the incidence of bilirubin encephalopathy The higher it is.
3. Concentration of bilirubin: When there is no other complication in full-term neonates, bilirubin encephalopathy rarely occurs when the total bilirubin concentration is below 307.8-342.0 mol/L (18-20 mg/dl). Total bilirubin >342.0mol/L (20mg/dl) may cause bilirubin encephalopathy in some neonates, and the total bilirubin concentration in immature children is 256.5mol/L (15mg/dl) or lower. It is possible to have bilirubin encephalopathy.
4. Bilirubin encephalopathy and other factors: Some high-risk factors may directly or indirectly contribute to bilirubin encephalopathy, such as premature infants with more oxygen in the brain nucleus and higher metabolic rate, when bilirubin passes through the blood-brain barrier It is susceptible, the serum albumin content of premature infants is low, resulting in a decrease in the junction of bilirubin and albumin; as well as suffocation, hypoxia, infectious meningitis, acidosis and hypoproteinemia can reduce bilirubin The amount of binding to albumin; drugs, hunger and hypoglycemia can capture the junction and reduce the protective effect of the blood-brain barrier. When dealing with neonatal hyperbilirubinemia, these factors should be considered in time for the blood-brain barrier. The impact of the function.
Symptom
Rh blood group incompatibility Common symptoms Nuclear jaundice convulsions, snoring, snoring, dyspnea, ascites, obstructive jaundice, fetal heart failure, pleural effusion
The clinical manifestations and severity of neonatal hemolytic disease caused by different Rh antigens are similar. The most serious cases are stillbirth and edema. The main symptom is jaundice, which occurs in almost every child. Anemia can occur within 1 to 2 days after birth. However, most of them gradually became pale after 5 days of birth. Other symptoms were apathetic, manifested as lethargy, eating less, crying less, some suffering from heart failure due to anemia, manifested as shortness of breath, convulsions and cyanosis, severe jaundice Bilirubin encephalopathy (nuclear jaundice) may occur, and convulsions, gaze or tremors may occur and eventually die.
The clinical symptoms of this disease are caused by hemolysis, the severity of symptoms and the amount of maternal antibodies, fetal erythrocyte sensitization and fetal compensatory ability and other factors.
1. Fetal edema: more common in patients with severe illness, edema, pale skin, skin freckle, pleural effusion, ascites, low heart sound, fast heart rate, difficulty breathing, liver and spleen, most of the edema of live birth are premature If not treated promptly, it will die soon after birth. Many fetal edema are stillbirths. The occurrence of edema is related to low plasma protein. Because extramedullary hematopoiesis and hypoxia affect liver function, some children still have heart failure. Edema, the ratio of placental edema weight to neonatal weight in this type of child can reach 1: (3 ~ 4) (normal 1: 7).
2. Astragalus: The bilirubin produced by hemolysis in the fetus is treated by the mother liver. Therefore, the cord blood of the newborn is generally free of jaundice. The severe one can have 0.3mg of bilirubin. The responsibility for treating bilirubin after birth is all in the fetus itself. In addition, the liver function is not yet sound, and the jaundice is seen 4 to 5 hours after birth, and it is rapidly deepened, reaching a peak at 3 or 4 days after birth. It is not uncommon for those who exceed 340 mol/L (20 mg/dl) to appear early and rise. Fast, is the characteristic of jaundice in children with Rh hemolytic disease, bilirubin is mainly unconjugated bilirubin, but a small number of children in the course of recovery of the disease combined with bilirubin increased significantly, cholestasis syndrome occurs, because the liver There are extensive extramedullary hematopoietic foci, giant cell formation, bile duct proliferation, siltation of bile liver area, necrosis of the bile duct, etc., as well as fetal edema with severe anemia, capillary obstruction caused by extramedullary hematopoiesis, and obstructive jaundice.
Astragalus begins to appear on the face (serum bilirubin is 68-102 mol/L). If the bilirubin value rises, jaundice appears in the limbs and trunk, and finally the palm and sole are affected. Bilirubin is >256.5-307.8 mol/ L (15 ~ 18mg / dl), the facial torso is orange yellow but the heart of the hand is still yellow, but if the bilirubin > 324mol / L (20mg / dl), the bottom of the hand and the foot also turned orange, 10 days of neonatal biliary The erythromycin had no damage to liver function at 231 mol/L, and blood glucose decreased by 43.5%.
Compared with ABO hemolysis, Rh has more cases of jaundice within 24h, and ABO is more than 2,3 days after birth. Chongqing reported that all Rh hemolytic disease jaundice appeared within 24h, and 15 cases occurred within 12h.
3. Anemia: varying degrees, mild hemolysin umbilical cord hemoglobin >140g / L; moderate hemolyzed cord blood <140g / L, severe cases can be less than 80g / L, and often accompanied by fetal edema, after birth Hemolysis continues, anemia is more obvious than when it was born. Some Rh hemolytic disease children have obvious anemia (Hb<80g/L) 2 to 6 weeks after birth, which is called late anemia. This is because some children have early symptoms. Severe, no need for blood transfusion therapy, but Rh blood group antibodies are persistent in the body (more than 1 to 2 months), continue to hemolyze and lead to advanced anemia, even if some children with early symptoms are exchanged for transfusion, there are still some children Late anemia occurs, because exchange of blood transfusion can only switch out some blood group antibodies, in addition, the red blood cell oxygenation curve of adult red blood cells is shifted to the right of the newborn, which is easier to release oxygen, which can reduce tissue hypoxia, but the red blood cell production is reduced.
Examine
Rh blood group incompatibility check
1. Blood antibody determination: Rh negative pregnant women should check their husband's Rh blood type, if not, measure maternal antibodies, the first measurement is generally carried out at the 16th week of pregnancy, which can be used as the basic level of antibodies, then at 28-30 Weekly re-measurement, repeated once every 2 to 4 weeks, the increase in antibody titer suggests that children are likely to be affected, when the antibody titer is 1:16, it should be used for amniocentesis, and the plasma antibody is mostly IgG antibody. The ratio of IgG1 and IgG3 antibodies was only IgG1, fetal edema appeared at 20 weeks, and only IgG1 appeared at 27 weeks, only 4/5 of IgG1 antibody was sick, while both IgG1 and IgG3 were onset, IgG2 and IgG4 could not. Immunization, as well as red blood cell phagocytosis in blood tests, 50% positive is severe, 20% positive is mild.
2. Polymerase reaction (PCR): Detection of fetal RhD type, the results of PCR detection in the literature from 1991 to 1996 were confirmed by fetal or neonatal serology, a total of 500 cases, the sensitivity and specificity were 98.7% and 100%, respectively. Positive and negative predictive values were 100% and 96.9%, respectively. Compared with umbilical cord puncture and serology, amniocentesis PCR technology can reduce fetal RhD by 4 times perinatal mortality. In 2001, it was confirmed that PCR can not only detect RhD. And a comprehensive examination of the blood around the parents, amniotic fluid and umbilical cord blood can identify 8/14 heterozygous father D gene for infants and 26/26 homozygous father D gene for infants and 26/26 homozygous father D gene For babies, this method can be used to comprehensively identify children with type D in order to properly treat the pregnancy.
3. Amniocentesis examination: Normal amniotic fluid is transparent and colorless. Severe hemolytic disease amniotic fluid is yellow. The hemolysis of the fetus is higher, the higher the amniotic fluid is, the higher the amniotic fluid is. The amniotic fluid examination results have reference value for further treatment. The optical density at 450 nm is related to the bilirubin content in amniotic fluid. The increase in optical density may result in bilirubin bulge. The height of this bulge is related to the severity of fetal disease, but The optical density readings of the amniotic fluid at 450-460 nm in the optical density bulging are not consistent at different stages of pregnancy, so the readings of the optical density bulging at the same 450 nm have different meanings at different stages of pregnancy, where the bulging value is in I. The district indicates that the fetus is not ill or the condition is mild. The condition in the second area is moderate. In the third area, the condition is serious. The spectrophotometer is used to measure 450 nm. The equipment requirements are higher. The bilirubin method is also used to determine amniotic fluid. Bilirubin <8.55mol / L, it is estimated that fetal red blood cell damage is not serious, can be regarded as pregnant women health, consider waiting for natural childbirth, greater than this value, such as L / S value 2.0 should consider termination of pregnancy, such as >17.1 mol / L by L / S2.0 i.e., termination of pregnancy.
Erythrocyte and hemoglobin decrease, reticulocytes increase (reticulocyte can exceed 0.06 on the first day after birth), and nucleated red blood cells increase (1 to 2 days after birth, peripheral blood can find more than 2 to 10/100 white blood cells) Etc. only suggests that the child may have hemolysis, can not be diagnosed by this, the main basis for diagnosis after birth is the examination of serum-specific immune antibodies.
(1) Check if the mother's Rh blood type is different.
(2) To check whether the baby red blood cells are sensitized, the anti-human globulin test direct method positive indicates that the baby red blood cells are sensitized by the blood group antibody, and can be used as a release test to know which Rh blood group antibody.
(3) Check the presence and type of blood group antibodies in the serum of infants, and compare the infant serum with each standard cell (CCDee, ccDEE, ccDee, Ccdee, ecdEe, ccdee) as an anti-human globulin indirect test.
(4) Check the presence or absence of blood group antibodies in the maternal serum. It can be confirmed by indirect anti-human globulin test that since Rh blood group antibodies can only be caused by human red blood cells, there is a diagnosis of neonatal Rh hemolytic disease by the presence of Rh blood group antibodies in the mother. There is a certain reference significance, but to be diagnosed, the above point (2) should be positive, and only the baby red blood cells are sensitized.
4.B-ultrasound examination: severe fetal edema complicated with ascites B-ultrasound can detect the dark side of the fetus abdomen, in which the fluttering of the intestines, liver and other organs can be seen; fetal edema, the skin of the fetus including the thickness of the scalp increases, Double line echo.
5. The sensitivity of positive blood cells to patients with red blood cells for blood mononuclear cell stratification is 91%, while the accuracy of positive is 100%, while the accuracy of control amniotic fluid 450 in the 0 to II layer is 60%. Separation with monocytes also saves B-ultrasound or amniocentesis, and can be used for preliminary screening tests.
6. End-tidal carbon monoxide: a good indicator for monitoring the production of endogenous CO. The hemoglobin produced by aging red blood cells and hemoglobin releases C0 during the process of converting heme into biliverdin by heme oxidase. Metabolism of one gram of methemoglobin produces equal amounts of CO. In clinically, neonates with severe hyperbilirubinemia, monitoring endogenous CO production can more intuitively predict serum bilirubin Generation.
Diagnosis
Rh blood group incompatibility diagnosis
diagnosis
Prenatal and postpartum diagnosis can be based on medical history, clinical manifestations, laboratory tests, and B-ultrasound.
Differential diagnosis
Mainly differentiated from ABO hemolysis.
