Rh incompatibility

from Wikipedia, the free encyclopedia
Classification according to ICD-10
P55.0 Rh isoimmunization in the fetus and newborn
O36.0 Care of the mother because of Rhesus isoimmunization
- anti-D antibodies (Rh antibodies)
- Rh incompatibility (with hydrops fetalis)
ICD-10 online (WHO version 2019)

The rhesus incompatibility ( synonyms Rh incompatibility , rhesus incompatibility ) is a blood group incompatibility against the Rhesus - antigen "D" between Rh-negative (Rh - , Rh, genotype dd) mother and Rh-positive (Rh + , Rh, genotype Dd, dD) child.

It can cause red blood cells ( erythrocytes ) in children to break down ( haemolysis ). In severe cases, neonatorum haemolytic disease with hydrops fetalis develops .

Immune serological peculiarities

The Anti-D antibody is an irregular erythrocyte antibody that rhesus-negative people can produce if they have been immunized by rhesus-positive erythrocytes. This is because irregular antibodies are antibodies which (in contrast to isoagglutinins or blood group antigens ) were formed by unnatural sensitization (e.g. through blood transfusions , pregnancy). The laboratory examination shows that any irregular antibodies in the serum can bind to the surface of so-called test erythrocytes . If these are irregular antibodies of the immunoglobulins of the IgM class , agglutination will already occur at this stage . A Coombs serum is also added to detect irregular antibodies of the immunoglobulins of the IgG class (indirect Coombs test). If agglutination occurs at this stage, irregular antibodies of the IgG class are considered to be detected.

Epidemiology

In Europe, around 15% of all people are Rh negative (dd, always homozygous ), 50% heterozygous (Dd) and the remaining 35% homozygous Rhesus positive (DD). In connection with the dominant inheritance of the Rh factor (Rh positive), this results in a constellation in about every tenth pregnancy in which the mother is Rh negative and the fetus Rh positive.

  • If the mother is Rh negative (dd) and the father is homozygous Rh positive (DD), then each fetus is heterozygous Rh positive (Dd).
  • If the mother is Rh-negative (dd) and the father is heterozygous Rh-positive (Dd / dD), then there is a 50% probability that the fetus is heterozygous Rh-positive (Dd) and a 50% probability is Rh-negative (dd ).

Pathogenesis

The rhesus factor is inherited dominantly , which is why the blood group characteristic rhesus-negative is relatively rare with around 15% of the population. The erythrocytes of rhesus-positive people have a "D antigen" (rhesus factor "D") on their surface. Rh-negative people do not have this antigen. The antibodies against Rhesus factor D are only formed in people without this factor when they come into contact with it, i. H. when rhesus-positive blood components (erythrocytes and constituents) from one person get into the bloodstream of another rhesus-negative person.

This can happen during blood transfusions or, under certain conditions, during pregnancy or childbirth. Rh-positive blood is now usually only transfused to Rh-negative people in an emergency (no suitable canned food is available). Normally, the bloodstream of mother and child is separated from one another by the placental barrier during pregnancy . This prevents the child's blood cells from entering the maternal circulation (or vice versa). If this is still the case, for example during invasive , prenatal interventions in the uterus and / or on the child, or z. B. in the case of an injury to the child, the umbilical cord or the placenta at birth - the condition is in each case the introduction of the child's blood into the maternal bloodstream - the mother can be sensitized and form antibodies against the rhesus antigen of the child. Furthermore, so-called microtraumas or pathological opening processes of the placenta are assumed to be the cause .

Depending on the type and extent of the invasiveness of the procedure considerably more likely is a sensitization in induced abortion or termination of pregnancy and other invasive procedures in the uterus, such as during the prenatal the chorionic villus sampling (CVS); Amniocentesis (AC) and umbilical cord puncture . This also applies to abdominal injuries during pregnancy, bleeding of the placenta, implantation of the germ cells outside the uterus , miscarriages and, if necessary, scraping and blood transfusions that are incompatible with Rh factor. The risk of the initiation of the formation of antibodies and immunization increases depending on the extent of the invasiveness or the risk of injury and bleeding or the amount of blood introduced into the bloodstream (see frequency in Rh-negative pregnant women ).

The connection between, on the one hand, the detection of beta cells with the genome of the test person's mother in the pancreas (so-called microchimerism ), and, on the other hand, the significantly increased incidence of the autoimmune disease type 1 diabetes mellitus in people who had previously delivered by caesarean section suggests that there is During caesarean sections, the child's blood circulation is more often contaminated with the mother's body cells.

If the mother is immunized during the first pregnancy, it happens relatively slowly and usually does not lead to problems during the first pregnancy. However, if the mother is “sensitized” from the first child, that is, her immune system has formed memory cells, then renewed blood contact in the next pregnancy with a Rhesus-positive child can very quickly lead to the formation of antibodies in the mother ( boosting ). In contrast to erythrocytes, these D antibodies can easily pass through the placental barrier into the child's bloodstream as type G immunoglobulins (IgG immunoglobulins; after T-cell help and immunoglobulin class change the anti-D antibodies from IgM to IgG). They bind to the child's Rh-positive erythrocyte antigens. Such erythrocytes, which are loaded with antibodies from the mother, are broken down prematurely in the child's spleen . Haemolytic anemia occurs in the child - to a greater or lesser extent .

First, the hemolysis of the erythrocytes in the child leads to a compensatory increase in the formation of new blood cells, also outside the bone marrow (extramedullary blood formation), in the liver and spleen. Depending on the severity, hypoxia and acidosis , decreased albumin synthesis, and in some cases edema and pleural effusions can occur. This prenatal picture of haemolyticus fetalis disease, called haemolyticus neonatorum disease (MHN) after birth , can lead to hydrops fetalis and, in the worst case, to malformations or death of the child (see therapy ). From an immunohematological point of view, the severity of haemolyticus neonatorum essentially depends on the concentration of maternal antibodies , the proportion of IgG antibodies passing through the placenta and their subclass distribution as well as the antigen density and distribution on the child's tissue. The degree of hemolysis follows from this . Whether there are health consequences for the child depends on the time and degree of hemolysis, further on whether it can be adequately compensated (month of pregnancy, constitution and state of health of the child) and thirdly - if necessary - on the therapeutic measures taken (see symptoms and therapy ).

Another form of maternal intolerance to blood cells of the unborn child is fetal and neonatal alloimmune thrombocytopenia (F / NAIT) and neutropenia (F / NAIN), in which the child's blood platelets or white blood cells are destroyed.

Frequency in Rh-negative pregnant women

Before the introduction of anti-D prophylaxis (rhesus prophylaxis), between 1.96% (3/153) and 13.39% (15/112) of the women in the control groups were immunized in various studies, resulting in an average immunization rate of 7, 5% results. Before anti-D prophylaxis was introduced, Morbus Haemolyticus Neonatorum (MHN) was found in 0.6% of all pregnancies, 60% of which required treatment and 12% were fatal.

The above Figures also include those women who previously had - possibly multiple - invasive interventions such as induced abortion, injuries, bleeding, extrauterine pregnancy, incompatible blood transfusions, etc. Anti-D prophylaxis for abortions (illegal until 1976 and therefore quantitatively and qualitatively unknown) and other invasive interventions, injuries, after administration of Rh-incompatible blood transfusions, etc. - d. H. Indications in which this is done today - (see prophylaxis ) was not available at that time.

Prophylaxis with anti-D immunoglobulin

This article or paragraph presents the situation in Germany . Help us to describe the situation in other countries.

The drug administered preventively against the immunization process described under pathogenesis and its consequences is a blood product . It is referred to as "anti-D" or "anti-D prophylaxis", while the "active ingredient" contains anti-D or rhesus factor antibodies (human anti-D immunoglobulin).

Blood transfusions with Rh-positive blood to Rh-negative people are now usually only carried out in an emergency (lack of suitable canned food). In this case, significantly higher doses of anti-D prophylaxis are administered than are usual for pregnant women.

A blood group determination in early pregnancy is one of the usual prenatal measures. As a preventive measure, all Rh-negative mothers receive anti-D immunoglobulin antibodies in the 28th week of pregnancy and no later than 72 hours after the birth of a Rh-positive child. Antibodies are not formed and subsequent pregnancies are not at risk.

Anti-D prophylaxis is also carried out in Rh-negative pregnant women before invasive interventions in the uterus, for example as part of prenatal diagnosis or after injuries. This includes

In addition, antibody screening tests are carried out during pregnancy, with which Rhesus antibodies can also be detected. If their concentration increases during pregnancy or if the fetus shows signs of the onset of hydrops on the ultrasound , an intrauterine blood transfusion can be carried out if necessary .

history

The anti-D prophylaxis vaccine was developed in the 1960s by a British group ( Ronald Finn , Cyril A. Clarke ) in Liverpool and an American group ( William Pollack , Vincent J. Freda , John G. Gorman , Columbia- Presbyterian Hospital) and introduced the vaccine in 1969. The scientists involved received the Lasker ~ DeBakey Clinical Medical Research Award in 1980 .

Hepatitis C contamination

In the GDR in 1978 and 1979, around 6,800 rhesus-negative mothers were infected with hepatitis C after the birth of rhesus-positive children during an anti-D prophylaxis, which was then legally prescribed for this constellation, to protect subsequent children against better knowledge. The people responsible for the scandal were convicted of violating the GDR Drugs Act. However, the public and the victims were initially not informed about these events. Compensation that had finally been started by the GDR was interrupted by the GDR's accession to the FRG and only resumed in 2000 by the Federal German Anti-D-Aid Law.

Mode of action and effectiveness

Even if there are hypotheses in this regard , according to the manufacturer, “the mechanism of action by which the anti-D immunoglobulin suppresses the immunization by Rh (D) positive erythrocytes (…) is not known.” Regarding the effectiveness, “passive immunization with specific IgG -Antibodies against the Rh (D) antigen (...) prevent the Rh (D) negative mother from being actively immunized in> 99% of cases. "However, under the" condition (...) that a sufficient dose is received early enough is administered after exposure to fetal Rh (D) -positive erythrocytes. ”Efficacy studies have not yet been published by the manufacturers.

Criticism of anti-D prophylaxis

The general use of anti-D immunoglobulins in Rh-negative pregnant women has been criticized by critics. It is stated that with the general introduction and general administration of anti-D prophylaxis to Rh-negative pregnant women, research into the causes of immunization with anti-D has not yet been carried out or has been omitted due to lack of interest. Although more than 90% of Rh-negative women pregnant with Rh-positive children (see frequency in Rh-negative pregnant women ), this occurs naturally, i. H. Even without the administration of anti-D prophylaxis, no antibodies develop and the administration of these blood products (anti-D immunoglobulin) is not without its risks. It is unknown to what extent pregnancy or birth-related factors, particularly prenatal invasive procedures, influence the likelihood of immunization. On the other hand, it has long been known that their probability is increased by such invasive interventions, on which the determination of numerous indications for the preventive administration of anti-D prophylaxis (see prophylaxis) is based.

Symptoms

As a result of the improved preventive measures, around half of the newborns with a rhesus intolerance with proven rhesus antibodies only have mild hemolysis with mild neonatal jaundice . The other part usually has more pronounced anemia and, due to the compensatory increase in blood formation outside the bone marrow, an enlarged liver and spleen ( hepatosplenomegaly ). The jaundice is correspondingly more severe and the children are often born yellow ( jaundice gravis et praecox ). Generalized water retention ( edema ) and effusions in the chest and abdominal cavity ( pleural effusion and ascites ) can be found in the full picture of the hydrops fetalis .

In erythroblastosis, biliverdin and bilirubin are released through hemolysis and are also deposited in the dentin of the tooth. This causes the crown and roots to turn blue-green. This so-called chlorodontia decreases after a few years due to the further formation of dentin.

Diagnosis

Determining the blood group of mother and child is crucial for diagnosis. The Coombs test is used to detect IgG antibodies that cross the placenta in the maternal serum , whereas the direct Coombs test detects antibodies on the child's erythrocytes. In order to assess the severity and plan further treatment, it is also necessary to determine a blood count of the child, various hemolysis parameters ( LDH , reticulocytes ) and bilirubin.

The RhD status of the fetus can now be reliably determined from the mother's blood using the polymerase chain reaction (PCR). If the fetus is RhD negative, anti-D prophylaxis no longer has to be carried out.

therapy

Half of the children with mild symptoms do not need therapy or phototherapy is sufficient . In severe cases, however, a blood exchange transfusion may have to be carried out. Hydrops fetalis is always an emergency for the neonatologist , which entails a variety of intensive care measures even in the delivery room. As a rule, the children must be intubated and ventilated immediately, receive blood transfusions immediately, and the effusions in the chest and abdominal cavity are punctured for relief .

Web links

  • Hemolytic Disease of Newborn (HDN), McGraw-Hill Companies, Inc. Graphic of maternal sensitization processes [1]

Individual evidence

  1. ^ C. Mueller-Eckhardt, V. Kiefel: Transfusionsmedizin. 3. Edition. Springer, 2004.
  2. ↑ Guidelines of the German Medical Association…. 2005, under: "Notation" in Chapter 4.2.5.13, to be found on the Internet: bundesaerztekammer.de ( Memento from July 1, 2007 in the Internet Archive )
  3. ^ A b R. Roos et al.: Checklist neonatology. The neo-ABC. Stuttgart 2000, ISBN 3-13-125051-8 .
  4. ↑ a b Microchimerism in the pancreas of diabetics - cause of disease or therapeutic approach? In: Ärzteblatt. January 23, 2007.
  5. ↑ Caesarean section increases the risk of diabetes in children. In: Ärztezeitung. March 12, 2012.
  6. ↑ WQ Ascari, AE Allen, WJ Baker et al: Rho (D) immune globulin (human) evaluation in women at risk of Rh immunization. In: JAMA. 205 (1), 1968, pp. 1-4.
  7. ↑ GJ Bishop, VI Krieger: One milliliter injections of RHo (D) immune globulin in prevention of Rh immunization. A further report on the clinical trial. In: Medical Journal of Australia. 2, 1969, pp. 171-174.
  8. ↑ CA Clarke, WTA Donohoe, R. Finn et al. a .: Prevention of Rh haemolytic disease: final results of the 'high risk' clinical trial. In: Br Med J. 2 (5762), 1971, pp. 607-609.
  9. ↑ B. Chown, A. Duff, J. James et al .: Prevention of Primary Rh Immunization: First report of the Western Canadian Trial. In: Canadian Medical Association Journal. 100, 1969, pp. 1021-1024.
  10. ↑ C. Dudok de Wit, E. Borst-Eilers, CHM Weerdt et al: Prevention of Rh immunization. A controlled trial with a comparatively low dose of anti-D immunoglobulin. In: BMJ. 211 (4), 1968, pp. 477-479.
  11. ^ JG Robertson, CM Holmes: A clinical trial of anti-Rho (D) immunoglobulin in the prevention of Rho (D) immunization. In: Journal of Obstetrics an Gynecology of the British Commonwealth. 76, 1969, pp. 252-259.
  12. ↑ MA Stenchever, IJ Davies, R. Weisman et al: Rho (D) immunoglobulin. A double blind clinical trial. In: AJOG. 106 (2), 1970, pp. 316-317.
  13. ↑ CA White, RD Visscher, HC Visscher et al.: Rho (D) immune prophylaxis: A double blind cooperative study. In: O&G. 36 (3), 1970, pp. 341-346.
  14. ↑ JC Woodrow, CA Clarke, RB McConnell et al.: Prevention of Rh-haemolytic disease. Results of the Liverpool 'low risk' clinical trial. In: BMJ. 2, 1971, pp. 610-612.
  15. ↑ Axel Seltsam, Tobias J. Legler, Eduard K. Petershofen: Rhesus-D diagnostics in pregnancy. (PDF) In: Haemotherapy. 7/2006, p. 3.
  16. ^ Lasker Foundation
  17. ↑ Stefan Günther: Hepatitis C Vaccine Damage Case: Long Overdue Compensation for Victims , Dtsch Arztebl 2000; 97 (39): A-2517 / B-2149 / C-2013
  18. ↑ Instructions for use and specialist information Rhophylac 300 under 5.1: Pharmacodynamic properties. ( Memento of the original from December 8, 2015 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF) @1@ 2Template: Webachiv / IABot / www.cslbehring.de
  19. ↑ Instructions for use and specialist information on the product Rhophylac 300 from CSL Behring. ( Memento of the original from December 8, 2015 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF) @1@ 2Template: Webachiv / IABot / www.cslbehring.de
  20. ↑ E. Lachman, SM Hingley, G. Bates, AM Ward, CR Stewart, SL Duncan: Detection and measurement of fetomaternal haemorrhage: serum alpha-fetoprotein and the Kleihauer technique. In: British medical journal. Volume 1, Number 6073, May 1977, pp. 1377-1379, PMID 67873 , PMC 1606867 (free full text).
  21. ↑ Peter Gängler: Conservative Dentistry and Periodontology: 66 tables . Georg Thieme Verlag, 2005, ISBN 3-13-593702-X , p. 75 ( google.com ).
  22. ↑ LADR informs: Targeted rhesus prophylaxis - syringes only when necessary , edition 258 01/2018