Rhesus-conflict between mother and fetus: probability, when it occurs, what is dangerous, what to do

Part of the body's humoral immunity is the system of blood antigens. So, on the plasma membranes of erythrocytes there are glycoprotein corpuscular antigens, among almost fifty of which the rhesus-conflict during pregnancy is most often capable of causing agglutinogen D or Rh (Rh).

[1], [2]

Epidemiology

It is believed that the negative Rh factor has no more than 15% of the European population, that is, about one in every tenth future mother - Rh-.

In the Basques of Spain, the prevalence of Rh blood of the negative type reaches 35%; Africans - 4%; for residents of Near East - 2-4%; the population of South-East Asia and the Asia-Pacific region - less than 1%.

According to official data, in the United States Ph- is defined in 16-17% of white, 7-8% of African Americans, 2-3% of American Indians. In this case, according to experts from the American Pregnancy Association, Rh-incompatible pregnancies leading to isoimmunization (alloimmunization) and Rh-conflict, account for almost 20% of all gestations in the country. In 13 marriages out of a hundred children were born to mothers with Rh- from fathers with Rh +; one in a thousand babies is born with fetal hemolytic disease.

In Europe, about 13% of newborns are at risk of Rhesus incompatibility, and half of them have complications, but in preventive treatment this number does not exceed 1%.

The risk of conflict in the blood group ABO during pregnancy is estimated in different sources in different ways: from 2% to 16%.

[3], [4], [5]

Causes of the rhesus Conflict

The conditions for the occurrence of rhesus-incompatibility of the mother and fetus, that is, the causes of rhesus-conflict in pregnancy, are due to the fact that in a pregnant woman the Rh rhesus is negative (Rh-), and in the future child it is positive (Rh +) as a father.

Although the majority of the population has Rh +, in the blood of some people this agglutinogen D (cluster of differentiation of CD240D), which has a high degree of immunogenicity, is simply absent. This is a recessive trait that is inherited with the d-allele of the RHD gene, which encodes the transmembrane protein of red blood cells RhD.

The presence of D-antigen in the blood of the unborn child and determines the incompatibility of the fetus and the mother - Rh-conflict. The inheritance of the Rh factor of the child and the likelihood of a rhesus-conflict are more graphically represented in the table:

Rhesus factor of the mother	Rhesus factor of the father	Rhesus factor of the child	Probability of Rhesus Conflict
Ph +	Ph +	Ph + (75%) or Ph- (25%)	Absent
Ph-	Ph +	In 50% of pregnancies Ph +, in 50% of Ph-	50%
Ph +	Ph-	Ph + or Ph-	Absent
Ph-	Ph-	In 100% of pregnancies Ph-	Absent

The Rh blood factor is one of the most important for the ABO blood group and is of paramount importance not only in obstetrics. There may be a rhesus-conflict in blood transfusion: when a patient with Rh- is transfused with donor blood with Rh +. This leads to the development of antibodies to erythrocyte antigens and forms an increased reactivity of humoral immunity (sensitization), which during subsequent transfusion of blood plasma provokes erythrocyte agglutination and is fraught with blood transfusion shock.

In addition, incompatibility can arise as conflict over ABO blood group. This system of erythrocyte antigens takes into account the presence of antibodies that are endogenous alloagglutinins: G-globulin antigens A (α-agglutinin) or B (β-agglutinin). They can be produced during any pregnancy, including at the first. Unlike the formation of Rh antibodies in the Rh rhesus conflict, they do not need the stimulus of the second conflict pregnancy, that is, the factor of sensitization of the organism.

This table for ABO blood groups gives an idea of the inheritance of a blood group by a child and the combinations of blood groups of the mother and father that cause incompatibility between the mother and the fetus. Recall that the zero blood group (0) corresponds to the traditional I group, A - II, B - III and AB - IV.

Mother's blood group	Father's blood group	Blood group of a child	The likelihood of conflict
0	0	0	Absent
A	0	A or 0	Absent
AT	0	B or 0	Absent
AB	0	A or B	Absent
0	A	0 or A	Not more than 50%
A	A	0 or A	Absent
AT	A	0, A, B or AB	Not more than 50%
AB	A	A, B or AB	Absent
0	AT	0 or B	Not more than 50%
A	AT	0, A, B or AB	Not more than 50%
AT	AT	0 or B	Absent
AB	AT	0, B or AB	Absent
0	AB	A or B	High
A	AB	A, B or AB	Not more than 50%
AT	AB	A, B or AB	Not more than 50%
AB	AB	A, B or AB	Absent

However, as it turned out, up to 30% of patients with negative Rh do not show any signs of isoserological incompatibility, even when a significant amount of Rh-positive blood enters their bloodstream.

The risk of Rh sensitization after the first pregnancy lowers the simultaneous incompatibility of the ABO blood group (by almost 5%), which hematologists suggest may be the result of rapid utilization of incompatible erythrocytes and the subsequent weakening of the overall effect on D-antigen.

[6], [7], [8]

Risk factors

In addition to the actual negative Rh factor of the mother's blood and the positive Rh blood of the fetus, as well as its zero blood group and blood groups A or B in the child's father, obstetrician-gynecologists call such risk factors for the development of sensitization and the subsequent occurrence of Rh-conflict as previous miscarriages, ectopic (ectopic) or frozen pregnancy; develop a rhesus-conflict after abortion, after detachment of the placenta; Rhesus-conflict after childbirth, and also after delivery by cesarean section; after invasive prenatal diagnostic procedures (puncture of the bladder and fetal amniotic fluid for research, etc.).

Significant risk of Rh-conflict in the presence of an anamnesis of a pregnant transfusion of blood plasma with Rh +, as well as getting blunt abdominal injuries (severe bruises).

According to clinical observations, amniotic intrauterine hemorrhage is observed in 15-50% of pregnancies, and their frequency increases with the development of pregnancy and in most cases occurs during childbirth.

The situation is complicated by a significant amount of transplacental hemorrhage and a very high degree of maternal immunoreactivity.

[9], [10], [11], [12], [13]

Pathogenesis

Blood from Rh + from the circulatory system of the embryo and fetus can enter the bloodstream of a mother with Rh-, which doctors call a transplacental passage of embryonic erythrocytes. And the pathogenesis of Rhesus conflict is that the absence of D-antigen in the blood in the mother causes a reaction to its presence in the blood of the unborn child similar to allergic - with sensitization and the formation of RhD IgG antibodies.

The main immunoglobulin in the Rh factor is IgG, which accounts for almost 80% of all isotypes of serum antibodies that provide a secondary immune response. And the higher the density and antigenic determinant of D-antigen on the surface of the fetal erythrocytes, the more pronounced the reaction of the maternal immune system - isoimmunization (isoserological incompatibility or alloimmunization). Also read the article -  Rhesus-sensitization during pregnancy

During the current and all subsequent pregnancies, antibodies are able to penetrate the fetal blood, and if their level is high enough, antigen-antibody complexes with Rh-positive embryonic erythrocytes are formed, and the hemolysis (destruction) of erythrocytes in the blood of the child occurs. Fetal fetal hemolytic anemia develops with Rh-conflict.

At the same time, Rhesus-conflict during the first pregnancy is usually not threatened, and the difference Rh-factors of parents does not cause problems with the health of the child. Immunologists explain this by the fact that when the first child is born in the organism of the future mother, the corresponding antibodies simply do not have time to be developed (recall the physiological immunosuppression characteristic of the period of pregnancy). However, this can only be if there were no specific circumstances in the pregnancy history (which are in the Risk Factors section).

In most cases, there is a rhesus-conflict in the second pregnancy, Rh-conflict in the third pregnancy, etc. Associate this with the fact that over time there is an isoimmunization: in the blood of a woman with Rh- there are already enough antibodies that can attack the red blood cells of a child. And each time problems can be more serious. The risk increases with multiplicity, when the Rhesus-conflict develops in the pregnancy of twins - if inherited Rh + father.

[14], [15], [16],

Symptoms of the rhesus Conflict

Immediately it should be noted that the symptoms of Rh syndrome in a pregnant woman are absent, that is, isoimmunization in a future mother does not manifest itself, and its Rh-incompatibility with the fetus does not betray itself. And the course of pregnancy in case of rhesus-conflict in physiological respect practically does not differ from that of gestation in women with Rh +. In the same way, there is a change in the hormonal background characteristic of the period of gestation, the toxicosis of Rh-conflict or swelling of soft tissues does not become stronger, etc.

But the management of pregnancy with Rhesus-conflict requires from the obstetrician-gynecologist not only high professionalism, but also maximum attention to the state of the future mother and strict fulfillment of all medical prescriptions by the pregnant woman, in particular, the timely delivery of blood tests. Since the only objective evidence of the maturing problem is elevated antibodies in the Rh syndrome, which are beginning to be produced in the body of the future mother by the D-antigen in the fetal blood (see further on - Diagnosis of Rhesus Conflict in Pregnancy).

Rhesus-conflict in the early stages of pregnancy (from 6-8 weeks) is possible, since the fetal blood production begins about three weeks after implantation of the embryo in the uterus, and Rh-antigen is identified on the membranes of red blood cells at an early stage through 40 days after conception.

Typically, the initial response to the RhD IgG antigen is slow, sometimes it occurs after five to six months. In this case, Rhesus-conflict is diagnosed in late pregnancy. But in subsequent pregnancies, the effect of mother antigens on fetal erythrocyx begins 4-8 weeks earlier.

Also, a competent specialist fears about the development of Rh-conflict at the end of the second trimester will necessarily cause polyhydramnios (increased volume of amniotic fluid), characteristic of rhesus-sensitization of the fetus and the development of  fetal erythroblastosis.

Usually births with Rh-conflict (in the absence of contraindications due to other pathologies) are natural. However, when a child is in serious condition, a planned cesarean section is prescribed for Rh-conflict (at week 37). But in both cases, breastfeeding with Rh-conflict is prohibited.

The first signs of the development of Rh-conflict in the fetus can be determined by ultrasound examination of the condition of such internal organs as the spleen, liver, heart (they will be increased). There may also be a thicker placenta, and in the abdominal cavity of the fetus on the ultrasound is visualized the accumulation of fluid.

Complications and consequences

Undoubtedly, the most negative and life-threatening consequences and complications of Rhesus-conflict during pregnancy undergoes the child's organism.

Consequences for the child (as during fetal development, neonatal and infantile period) are manifested in IgG-mediated hematological disorders:

• hemolytic disease of the newborn or fetal erythroblastosis (P55 in ICD-10);
• Rh-isoimmunization of fetus and newborn (P55.0 according to ICD-10);
• AB0-isoimmunization of fetus and newborn (P55.1 according to ICD-10).

Anemia develops in case of Rhesus conflict, heart failure and dropsy with edema of the subcutaneous tissue of the fetal head, soft tissues of the trunk, with pleural and pericardial effusions and ascites. In severe cases, hemolysis can lead to extramedullary hemopoiesis and reticuloendothelial clearance of embryonic erythrocytes - with hepatosplenomegaly and a decrease in liver function (a decrease in the production of blood proteins).

A slightly elevated serum bilirubin level is manifested by the development of jaundice in newborns with Rh-conflict, but the levels of bilirubin (the pigment of erythrocytes, the product of their hemolysis) must be constantly monitored.

Significantly increased bilirubin in newborns with Rh-conflict can lead to nuclear jaundice (P57.0 in ICD-10), which is manifested not only by jaundice of the skin and sclera, muscle stiffness, convulsions, difficulty in feeding, etc.

Unconjugated hyperbilirubinemia during the neonatal period can lead to brain damage and partial dysfunction. This is due to the neurotoxic effect of high concentrations of bilirubin in the blood on the gray brain substance. Damage can be either minor or fatal, leading to a fatal outcome.

Rhesus-conflict during pregnancy has consequences for the mother. First, the development of antibodies RhD IgG continues throughout life and has a negative effect on all subsequent pregnancies - if the future child has a Rh factor positive. And this threatens a more severe course of fetal erythroblastosis of the fetus and newborn.

Secondly, because of fetal edema in the first months of pregnancy, miscarriages often occur with Rh-conflict. A fetal death of a fetus - a stagnant pregnancy due to rhesus-conflict - is noted by midwives in 8-10% of cases.

By the way, IVF can be performed with Rh-conflict, however, when pregnancy occurs, the same problems can arise as with natural conception.

[17], [18]

Diagnostics of the rhesus Conflict

The analysis for the blood group and Rh factor is dealt with once - at the first visit to the antenatal clinic about pregnancy. If Rh women is negative, the father of the baby should also take a blood test and accurately establish Rh.

Diagnosis of rhesus-conflict during pregnancy is carried out on the basis of numerous laboratory tests of blood of the future mother.

Blood test for Rh-conflict is an antiglobulin test by Coombs, for which the venous blood of a pregnant woman is examined; this analysis allows to detect serum antibodies of the mother on the fetal D-antigen, and its positive result is a sign of their rhesus incompatibility. And in newborns with Rh-conflict this analysis is performed immediately after birth to reveal hemolytic anemia.

On what week are the tests for Rh-conflict? At the first visit of an obstetrician-gynecologist, pregnant women with Rh- are placed on a special account and receive a referral for an analysis of blood for antibodies in the Rhesus-conflict. It is supposed to be handed over for a period of 7-8 weeks.

Regularly determining titres for Rh-conflict, the doctor monitors the development of Rh-sensitization and its intensity. If the initial result is negative (analysis did not show the presence of antibodies IgG-anti-D), then repeat should be done at the 20th week of pregnancy. Over the next 10 weeks, titers are determined every four weeks; from the 30th to the 36th week - once every two weeks; in the last month - weekly.

Below is a table of titers of antibodies RhD IgG in Rh-conflict (with a standard interpretation of the indicators):

1: 4	The rhesus sensitization of a pregnant woman is determined.
Above 1: 8	An increase in the level of Rh-sensitization, which does not require invasive diagnostic intervention
1:16	Increased risk to fetal life; it is necessary to study amniotic fluid (amniocentesis)
1:32	Development of intrauterine hemolysis and hydrocephalus of the fetus, high risk of his death; Amniocentesis and umbilical cord blood analysis for bilirubin is required.
1:64 and above	Requires dopplerometry of the blood flow in the middle intracranial artery of the fetus; there may be a need for termination of pregnancy or early delivery

Analysis of cord blood is done to determine the blood group and rhesus of the fetus; hematocrit; the level of hemoglobin, bilirubin and ferritin in his blood, as well as the amount of albumin, reticulocytes, platelets and neutrophils. It may be necessary to analyze the amniotic fluid for the content of bilirubin in it.

Instrumental diagnostics includes dopplerography, dopplerometry of blood flow velocity (in the heart, umbilical and intracranial arteries of the fetus); KTG (cardiotocography) is performed to evaluate the fetal heart.

From the 18th week they start to do ultrasound in case of Rh-conflict - at least five to six times, and if necessary, more to monitor the fetus, do not miss its deterioration (increase edema) and avoid such a measure as premature termination of pregnancy - abortion in case of Rh-conflict.

More information in the material -  Rhesus-conflict during pregnancy - Diagnosis

[19], [20], [21]

Treatment of the rhesus Conflict

What does the treatment of Rh-conflict in pregnancy mean? These are measures aimed at preventing the consequences of Rh-incompatibility in the mother and the development of hemolytic disease in the fetus.

Sensitization in the mother and the production of antibodies due to Rh rhesus can be stopped by the introduction of the Rh human immunoglobulin Rho (D). This is a specially created immunoglobulin for the prevention of Rh-conflict, consisting of IgG-antibodies of human blood plasma and capable of penetrating the placenta. The mechanism of action is to block the human immune system from recognizing this Rhesus antigen.

The trade names of this medication are RhoGAM, KamRho, Rhophylac (R), Partobulin SDF, Resonative, Gamulin Rh, HypRho-D, etc. Introduced in / m - 300 μg; the duration of a single dose is 2-4 weeks. The drug is usually prescribed from 26-28 weeks at regular intervals throughout the second half of pregnancy, and also during the first three days after delivery. Possible side effects include pain at the injection site, allergic reactions, fever, headache, a decrease in the level of erythrocytes in the blood.

Prevention of Rhesus Conflict during pregnancy in the hospital is carried out in those cases when the examination showed an increase in antibody titers and it is required to purge the maternal blood from them, that is, to carry out plasmapheresis in the Rh syndrome.

In addition, in-patient fetal blood transfusion is performed in the clinic, which is a replacement haematransfusion through the umbilical vein and is considered in obstetric practice as the method of choice for the last three decades. The period is from the 22nd to the 34th week of pregnancy.

The treatment of hemolytic disease in a newborn begins immediately after childbirth. Read more about this -  Hemolytic disease of newborns

Prevention

To date, the prevention of rhesus-conflict arising during pregnancy, is the use of the same immunoglobulin RhO (D).

Some may think that this is a vaccination or inoculation against Rh-conflict during pregnancy. But this is not so. This immunoglobulin is prescribed to prevent an immune response to Rh-positive blood in people with Rh-negative blood type. The drug can also be used to treat immune thrombocytopenic purpura.

Immunoglobulin is administered to women with Rh- immediately after abortion, miscarriage, ectopic pregnancy and any other manipulation, somehow related to conception and the threat of isoimmunization. Its action is limited to 4-6 weeks.

[22], [23], [24], [25]

Forecast

Despite all the achievements of modern medicine, 100% positive prognosis for the birth of healthy children in couples in which a woman has a negative Rh blood, and a man - a positive, is impossible. Rhesus conflict is a consequence of the reaction of the immune system of the blood, and the red blood cells not only carry oxygen into tissues, remove carbon dioxide from them, provide all the biochemical processes in the body with adenosine triphosphate (ATP), but also show immunomodulatory activity.

[26], [27], [28]