List of Abbreviations
HDN | hemolytic disease of the newborn |
|---|---|
HDF | hemolytic disease of the fetus |
MoM | multiple of the median |
MCA-PSV | middle cerebral artery peak systolic velocity |
PISS | potentially immunizing sensitizing event |
PCR | polymerase chain reaction |
ultrasound | ultrasound examination |
Terms and Definitions
See Section 1.1.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Rh isoimmunization is the presence of maternal Rh antibodies (anti-Rh (D) antibodies) in the blood as a manifestation of a secondary immune response in sensitized patients due to maternal-fetal blood group incompatibility for the Rhesus system [1]. Synonyms: Rh conflict, Rh sensitization, Rh alloimmunization.
Hemolytic disease of the fetus (HDF) is a condition characterized by hemolysis of Rh(D)-positive fetal red blood cells caused by maternal anti-Rh (D) antibodies crossing the placental barrier into the fetal circulation due to maternal-fetal Rhesus incompatibility, and manifesting as anemia and an increased number of erythroblast forms [2]. Synonyms: erythroblastosis fetalis, hemolytic jaundice.
Potentially immunizing sensitizing event (PISE) is a group of specific physiological and pathological conditions in which Rh-positive fetal red blood cells may enter the circulation of an Rh-negative woman and induce Rh isoimmunization.
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
Rh isoimmunization mainly develops due to maternal-fetal incompatibility for the RhD antigen. HDF can also develop due to maternal-fetal incompatibility for C, c, E, e antigens. A woman with a Rhesus-negative blood type becomes sensitized either during pregnancy when the fetal RhD antigen, inherited from the biological father, enters her circulation, or outside of pregnancy following a transfusion of Rhesus(D)-positive donor blood components.
During pregnancy, fetal red blood cells cross the placental barrier into the maternal circulation in 5–7% of women during the 1st trimester, 15–16% during the 2nd trimester, and 29–30% during the 3rd trimester [3]. The first stage of the maternal immune response is the production of IgM antibodies, which have a high molecular weight and do not cross the placental barrier into the fetal circulation. Subsequent stages of isoimmunization involve the production of IgG antibodies, which have a low molecular weight and freely cross the placental barrier from the mother into the fetal circulation, including immunoglobulin G1 and G3 subclasses that actively interact with Fc receptors (FcR) of lymphocytes and macrophages, which play a major role in fetal red blood cell hemolysis.
HDF is rare during the 1st pregnancy because fetal red blood cells enter the maternal circulation mainly in late pregnancy or during labor, and the primary immune response does not have time to develop. HDF in a 1st pregnancy may be the result of pre-existing isoimmunization, for example, from a history of administration of Rhesus-positive blood components to a Rhesus-negative woman.
In subsequent pregnancies, the entry of fetal red blood cells into the maternal circulation triggers a rapid immune response, IgG antibodies cross over to the fetus, leading to hemolysis, anemia, activation of extramedullary hematopoiesis sites, and hepatosplenomegaly. Due to 'overload' of liver cells with iron and globin breakdown products, its protein-synthetic function is impaired, leading to hypoproteinemia, hypoalbuminemia, and subsequently increased vascular wall permeability. Against the background of progressive anemia, hypoxemia develops, causing a hyperdynamic circulation type in the fetus, with the gradual development of heart failure and portal hypertension, which promotes further enlargement of the liver and the onset of anasarca. This is how severe anemia with fetal hydrops develops. In the absence of intrauterine treatment, antenatal fetal death may occur [3, 4].
1.3 Epidemiology of the Disease or Condition
Hemolytic disease of the newborn (HDN) (resulting from hemolytic disease of the fetus and newborn) is diagnosed in approximately 0.6%–1% of newborns in the Russian Federation, while the incidence of Rhesus isoimmunization has not yet shown a significant downward trend in recent years [3]. Perinatal mortality from HDN is 0.037‰. According to Rosstat Form No. 32 6 in 2023, HDN was diagnosed in 1.2% of newborns in Russia. The case fatality rate for HDN in Russia is approximately 0.22%. The incidence of bilirubin encephalopathy worldwide ranges from 0.4 to 2.7 per 100,000 newborns [5].
1.4 Features of Coding the Disease or Condition
O36.0 – Rhesus isoimmunization, requiring care of mother.
O36.1 – Other forms of maternal isoimmunization requiring medical care.
P55.0 – Rh isoimmunization of fetus and newborn.
P55.8 – Other forms of hemolytic disease of fetus and newborn.
P55.9 – Hemolytic disease of fetus and newborn, unspecified.
P56.0 – Hydrops fetalis due to isoimmunization.
P56.9 – Hydrops fetalis due to other and unspecified hemolytic disease.
1.5 Classification of the disease or condition
Forms of HDFN according to the nature of the immunological conflict between maternal and fetal blood:
Rh incompatibility;
incompatibility with other erythrocyte antigens;
ABO system incompatibility.
Forms of HDFN by anemia severity and presence of hydrops fetalis:
moderate anemia;
severe anemia;
severe anemia with hydrops fetalis.
Forms of HDFN according to fetal hemoglobin level:
mild anemia – hemoglobin deficit up to 20 g/L compared to mean values for gestational age (Hb <0.84 MoM);
moderate anemia – hemoglobin deficit of 20–70 g/L (Hb <0.65 MoM);
severe anemia – hemoglobin deficit greater than 70 g/L (Hb <0.55 MoM).
1.6 Clinical presentation of the disease or condition
The primary role in the diagnosis of HDFN is assigned to laboratory and functional research methods, which diagnose HDFN and establish its form.
2. Diagnostics, medical indications and contraindications for diagnostic methods
Diagnostic criteria
The diagnosis of HDFN is established in a pregnant woman with Rh-negative blood, discordant with the biological father of the child regarding the Rh factor, based on the clinical picture of polyhydramnios in the patient, anemia and/or hydrops fetalis according to fetal ultrasound and Doppler ultrasound of fetal blood flow, as well as laboratory data showing anemia and an increased number of nucleated red blood cells in the fetus.
2.1 Complaints and Anamnesis
Specific symptoms are absent. With the development of severe anemia and hydrops fetalis, the pregnant woman may note a decrease in the intensity of movements, which reflects weak motor activity of the fetus against the background of developing heart failure.
Before conception or in early pregnancy, history-taking is recommended to assess HDFN risk factors [2], [6].
Grade of Recommendation CLevel of Evidence 5Grade of Recommendation C (Level of Evidence – 5).
Comment: History-taking includes: information on the ABO blood group and Rh factor of the pregnant woman, blood group and Rh factor of the biological father; in women with Rh-negative blood – history of blood component transfusions, analysis of data on the number of pregnancies, their course and outcomes, prevention of Rh isoimmunization by administration of anti-Rh₀(D) human immunoglobulin**, anamnestic data on the birth of previous children with signs of HDN, treatment methods, gestational age at delivery, severity of the disease in newborns. Risk factors for HDFN include potentially Rh-sensitizing events (PRSE): transfusion of blood components without regard to Rh status in women with Rh-negative blood; in women with Rh-negative blood pregnant by an Rh-positive partner – delivery, medical abortions, miscarriages, ectopic pregnancies, invasive diagnostic and therapeutic procedures (chorionic villus sampling, amniocentesis, cordocentesis, cervical cerclage, reduction of embryo number in multiple pregnancy, amnioreduction, external cephalic version for breech presentation), bleeding during pregnancy, retrochorionic/placental hematoma, intrauterine fetal death in the current pregnancy, abdominal trauma.
2.2 Physical Examination
Physical examination is performed in accordance with the clinical guidelines «Normal Pregnancy» [7].
2.3 Laboratory Diagnostics
For the purpose of timely diagnosis of Rh isoimmunization, it is recommended to refer a pregnant woman with Rh-negative blood for the determination of anti-erythrocyte (anti-Rh) antibodies (preferably by gel agglutination method) at the 1st visit, then in the absence of antibodies at 18–20 weeks of gestation and at 28 weeks of gestation [8, 9], [10].
Grade of Recommendation CLevel of Evidence 5Grade of Recommendation C (Level of Evidence – 5).
Comment: If prevention of Rh isoimmunization is performed after 28 weeks of gestation, anti-Rh antibodies must be determined prior to the administration of human anti-Rh₀(D) immunoglobulin** [11]. More frequent testing for anti-Rh antibodies is impractical. The Rh blood type of the husband/partner should be determined. If the husband/partner is Rh-negative, anti-Rh antibody testing is not performed. If the husband/partner's blood type is unknown or Rh-positive, it is advisable to perform non-invasive fetal Rh genotyping using cell-free fetal DNA circulating in maternal blood, which has a sensitivity and specificity of 98–100%. This test can be recommended at 12 weeks of gestation during the first prenatal screening. If the fetus is found to be Rh-negative, maternal blood is not tested for anti-Rh antibodies. If determining the fetal Rh genotype is not possible, the pregnancy is managed as a pregnancy with an Rh-positive fetus. In the European population, complete deletion of the RhD gene predominates, which allows the fetal RhD gene to be detected in maternal circulation in the absence of the maternal gene. However, in 3–5% of Rh-negative Europeans, the RhD gene is detected either completely or as a result of gene conversion between the exons of the RhD and RhCE genes (hybrid RhD-CE-D genes). Such hybrid genes are unable to encode the synthesis of the D antigen on the erythrocyte membrane surface. In this case, a discrepancy occurs between the phenotypic and genotypic Rh blood type. The presence of the RhD gene in the mother hinders the detection of the fetal RhD gene. If the RhD gene is detected in the mother, non-invasive determination of the fetal Rh blood type is impossible, and such a pregnancy must be managed as a pregnancy with an Rh-positive fetus.
2.4 Instrumental Diagnostics
To diagnose fetal anemia, it is recommended to refer pregnant patients with Rh isoimmunization for Doppler ultrasound of fetal blood flow to determine the peak systolic velocity in the fetal middle cerebral artery (MCA-PSV) starting from 18–19 weeks of gestation [4], [10], [12,13].
GCR ALoE 2Grade of Recommendation A (Level of Evidence – 2).
Comment: An increase in MCA-PSV for the corresponding gestational age with high sensitivity and specificity indicates the development of fetal anemia of varying severity. An MCA-PSV of less than or equal to 1.29 MoM indicates the absence of fetal anemia or a mild form of the condition. An MCA-PSV from 1.29 MoM to 1.5 MoM indicates moderate anemia, and an MCA-PSV greater than 1.5 MoM indicates severe fetal anemia [Table 4]. [44]
The sensitivity of MCA-PSV for predicting moderate fetal anemia (hemoglobin concentration less than 0.65 MoM) and severe anemia (hemoglobin concentration less than 0.55 MoM) in the absence of fetal hydrops reaches 100%, with a false-positive rate of 12% [Table 5]. [4,14-17]
The use of fetal MCA-PSV has significantly reduced the need for diagnostic cordocentesis.
To detect fetal anemia and determine its severity, it is recommended to refer pregnant patients with Rh isoimmunization for repeat Doppler ultrasound of fetal blood flow with determination of MCA-PSV [2], [4].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: When MCA-PSV is <1.29 MoM, the ultrasound is repeated in 2 weeks; when MCA-PSV is from 1.29 MoM to 1.5 MoM, it is repeated in 1 week. When MCA-PSV values are 1.5 MoM or greater, given the high probability of severe fetal anemia, a repeat ultrasound is performed in 2–3 days. If MCA-PSV values are rising, cordocentesis followed by intrauterine blood transfusion is indicated [2], [4]. There is a possibility of premature emergency delivery due to complications during intrauterine interventions, which may require specialized and high-tech neonatal care.
It is not recommended to diagnose the severity of hemolytic disease of the fetus (HDF) based on ultrasound fetometric parameters (hepatomegaly, splenomegaly), increased placental thickness, polyhydramnios, Doppler blood flow parameters in the fetal aorta, umbilical vein and artery, or the pulsatility index in the MCA, as these are not specific to this pathology [4].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: The detection of ascites and anasarca (a combination of hydropericardium, hydrothorax, and edema of the subcutaneous tissue of the head, trunk, and extremities of the fetus) on fetal ultrasound indicates an extremely severe course of HDF.
To diagnose the severity of HDF during cordocentesis, it is recommended to perform fetal blood testing, which includes: determination of ABO blood groups, Rh factor (D antigen), total blood hemoglobin level, hematocrit evaluation, acid-base balance and blood gas analysis, and direct antiglobulin test (direct Coombs test) [2], [18-20].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comment: A decrease in hematocrit by >15% and/or a hemoglobin deficit of more than 70 g/L (Hb <0.55 MoM) from the normal value for the given gestational age indicates the development of severe anemia and is an indication for intrauterine transfusion of washed erythrocytes to the fetus. Reference hemoglobin values are presented in Table 1 (Appendix B).
It is not recommended to diagnose HDF by assessing the optical density of bilirubin in amniotic fluid obtained via amniocentesis, as this procedure is invasive, has low informativeness, and may lead to iatrogenic complications [12].
GCR ALoE 2Grade of Recommendation A (Level of Evidence – 2).
2.5 Other Procedures
Not applicable.
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1. Non-pharmacological treatments
Not applicable.
3.2. Pharmacotherapy
For the treatment of Rh isoimmunization and HDF, desensitizing therapy, immunocytotherapy, skin graft transplantation from the husband, hemosorption, plasmapheresis, immunosorption, and other similar methods are not recommended, as their use leads to a loss of time and the consequent development of extremely severe forms of HDF [2], [4].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: There are currently no effective drug therapies for Rh isoimmunization and HDF.
3.3. Intrauterine fetal packed red blood cell transfusions
It is recommended to treat severe forms of HDF using intrauterine intravascular transfusions of washed erythrocytes to the fetus [5, 21] (Appendix B).
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: Intrauterine transfusions can be performed multiple times; the last transfusion is usually performed at 32 weeks of gestation with a fetal weight of >2000 g, although in recent years there has been a trend toward performing transfusions at 35–36 weeks of gestation, allowing delivery at 37 weeks. This approach reduces the number of complications associated with neonatal prematurity. Before performing an intrauterine fetal blood transfusion or when planning delivery prior to 34 weeks of gestation, respiratory distress syndrome prophylaxis is administered once according to the standard protocol [22].
3.4. Delivery in Rh isoimmunization
In HDF, it is recommended to determine the timing and method of delivery individually, taking into account the obstetric history, fetal condition, and the capabilities of the obstetric and neonatal services of the maternity hospital [2].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: In cases of severe fetal anemia, hydrops fetalis, or following intrauterine transfusion of washed erythrocytes, operative delivery is preferred, as cesarean section avoids additional trauma and fetal distress during labor.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
Not applicable.
5. Prevention and Dispensary Observation
5.1. Non-specific prophylaxis
Patients with an Rh-negative blood type are recommended to be provided with information on the importance of maintaining the pregnancy and preventing abortions [4], [23].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comment: In the United Kingdom, the implementation of Rh isoimmunization prevention programs reduced the incidence of HDF 30-fold over 20 years (from 46 to 1.6 cases per 100,000 births) [24–27]. For the healthcare system, the costs of preventive measures for Rh isoimmunization are significantly lower compared to the costs of treating HDF/hemolytic disease of the newborn [24–28].
It is recommended to inform patients with a history of Rh isoimmunization and HDF/hemolytic disease of the newborn about the possibility of selection and selective transfer of embryos with an Rh-negative genotype within preimplantation genetic testing programs using assisted reproductive technologies [4], [29].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
5.2 Specific antenatal prevention of Rhesus isoimmunization
For pregnant women with an Rh-negative blood type and the absence of anti-Rh antibodies at 28 weeks, it is recommended to administer human anti-Rh₀(D) immunoglobulin** at 28–30 weeks of gestation at a dose according to the manufacturer's instructions, intramuscularly, for the prevention of Rh isoimmunization [26, 30], [31].
GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).
Comment: If the husband/partner has an Rh-negative blood type or if the fetus is found to be Rh-negative by non-invasive testing, human anti-Rh₀(D) immunoglobulin** is not administered at 28–30 weeks. If prophylaxis was not performed at 28 weeks, it is indicated after 28 weeks of gestation provided that anti-Rh antibodies are absent.
In a pregnant woman with Rh-negative blood type and absence of anti-Rh antibodies, during PRSS: invasive diagnostic and therapeutic procedures (chorionic villus sampling, amniocentesis, cordocentesis, cerclage, multifetal pregnancy reduction, amnioreduction, external cephalic version for breech presentation), bleeding during pregnancy, retrochorionic/placental hematoma, abdominal trauma, it is recommended to administer an additional dose of human anti-Rho[D] immunoglobulin** intramuscularly, in the dose specified in the package insert [32, 33].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
5.3. Specific postnatal prophylaxis in patients with negative blood type without isoimmunization
To determine the indications for specific postnatal prophylaxis after delivery, it is recommended to determine the main ABO blood groups and the Rh system D antigen (Rh factor) in the newborn [2, 6].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: If the newborn has an Rh-negative blood type, specific prophylaxis of maternal Rh isoimmunization is not indicated.
If the newborn has an Rh-positive blood type, it is recommended to perform specific prophylaxis of maternal Rh isoimmunization by intramuscular administration of anti-RhO(D) human immunoglobulin** at a dose of 1500 IU (300 mcg) immediately after receiving the newborn's blood test results, and preferably no later than 72 hours after delivery (preferably within the first two hours) to prevent Rh isoimmunization [4, 11, 21, 10].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: To calculate the dose of anti-RhO(D) human immunoglobulin**, the Kleihauer-Betke test is recommended [40, 41, 42, 43]. The test is based on the phenomenon of elution of maternal hemoglobin (HbA) and the absence of elution of fetal hemoglobin from erythrocytes in a citrate-phosphate buffer. Following appropriate processing of the maternal peripheral blood smear, the volume of fetomaternal hemorrhage is determined by counting the number of fetal cells [42, 44]. If the volume of fetomaternal hemorrhage does not exceed 25 ml, a standard dose of anti-RhO(D) human immunoglobulin** of 1500 IU (300 mcg) is administered; for volumes of 25–50 ml, the dose is doubled to 3000 IU (600 mcg). If technical facilities for the Kleihauer-Betke test are unavailable, it is recommended to double the dose of anti-RhO(D) human immunoglobulin** in the following cases: placental abruption, manual exploration of the postpartum uterus, and cesarean section accompanied by increased blood loss. If for any reason prophylaxis was not administered, anti-RhO(D) human immunoglobulin** may be administered up to 10 days postpartum [40, 45].
A pregnant woman with an Rh-negative blood type and absence of anti-Rh antibodies undergoing pregnancy termination in the 1st and 2nd trimesters, antenatal fetal death, or ectopic pregnancy is recommended to be administered an intramuscular dose of anti-RhO(D) human immunoglobulin** according to the manufacturer's instructions for the purpose of preventing Rh isoimmunization [4, 37-39, 40].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: Additional prophylaxis of Rh isoimmunization in early pregnancy should be carried out immediately after pregnancy termination or upon confirmation of fetal death [40]. Following antenatal prophylactic administration of anti-RhO(D) human immunoglobulin**, anti-Rh antibodies in various titers may be detected within 12 weeks.
6. Organization of Medical Care
Upon detection of anti-Rh antibodies, the pregnant woman should be referred for consultation to a Level III medical organization for further follow-up.
Medical care for patients with hemolytic disease of the fetus (HDF) requiring intrauterine transfusion of washed red blood cells must be provided in facilities equipped for the care of premature newborns (Level III facilities).
Indications for hospital admission to a medical organization:
Severe fetal anemia (>1.5 MoM) – for intrauterine transfusion of washed red blood cells up to 34 weeks of gestation (inpatient, emergency).
Moderate fetal anemia (1.3–1.4 MoM) – for monitoring, prevention of fetal respiratory distress syndrome, and deciding on intrauterine transfusion of washed red blood cells up to 34 weeks of gestation (inpatient, elective).
The need for monitoring and preterm delivery of a pregnant woman with Rh isoimmunization and mild/moderate fetal anemia combined with other obstetric and/or somatic pathology to prepare the birth canal at 36–37 weeks of gestation (inpatient, elective).
7. Additional Information
The course and outcome of HDF/hemolytic disease of the newborn (HDN) are influenced by the following factors:
prematurity
severity of anemia at birth;
presence of fetal hydrops;
presence of associated fetal/neonatal pathology;
presence of severe fetal hypoxia;
concomitant fetal/neonatal infection.
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Yes/No |
|---|---|---|
1 | The pregnant woman with Rh-negative blood type was referred for anti-Rh antibody testing at the first visit, and subsequently in the absence of antibodies at 18–20 weeks and at 28 weeks of gestation | Yes/No |
2 | Administration of anti-RhO(D) human immunoglobulin** at a dose according to the manufacturer's instructions was prescribed intramuscularly at 28–30 weeks of gestation to a pregnant woman with Rh-negative blood type in the absence of anti-Rh antibodies | Yes/No |
3 | An additional administration of anti-RhO(D) human immunoglobulin** at a dose according to the manufacturer's instructions was prescribed intramuscularly during pregnancy upon the occurrence of a potentially Rh-sensitizing event in a pregnant woman with Rh-negative blood type in the absence of anti-Rh antibodies | Yes/No |
4 | Administration of anti-RhO(D) human immunoglobulin** at a dose according to the manufacturer's instructions was prescribed intramuscularly to a postpartum woman with Rh-negative blood type in the absence of anti-Rh antibodies upon the birth of an Rh-positive newborn within the first 72 hours after delivery | Yes/No |
5 | Administration of anti-RhO(D) human immunoglobulin** at a dose according to the manufacturer's instructions was prescribed intramuscularly in cases of: pregnancy termination in the 1st and 2nd trimesters, antenatal fetal death, or ectopic pregnancy in a pregnant woman with Rh-negative blood type and absence of anti-Rh antibodies | Yes/No |
6 | Fetal anemia was diagnosed by determining the peak systolic velocity of the middle cerebral artery in the fetus | Yes/No |
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Qureshi H, Massey E, Kirwan D, Davies T, Robson S, White J, Jones J, Allard S, British Society for Haematology. BCSH guideline for the use of anti-D immunoglobulin for the prevention of haemolytic disease of the fetus and newborn. Transfus Med. 2014;24(1):8–20. doi:10.1111/tme.12091.
Bennardello F, Coluzzi S, Curciarello G, Todros T, Villa S, Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) and Italian Society of Gynaecology and Obstetrics (SIGO) working group. Recommendations for the prevention and treatment of haemolytic disease of the foetus and newborn. Blood Transfus. 2015;13(1):109–34. doi:10.2450/2014.0119-14.
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Appendix A1. Working Group Composition
Konopliannikov Alexander Georgievich – MD, PhD, Professor, Department of Obstetrics and Gynecology named after Academician G.M. Savelieva, Pediatric Faculty, Pirogov Russian National Research Medical University (Moscow). No conflict of interest.
Tetruashvili Nana Kartlosovna – MD, PhD, Head of the 2nd Department of Obstetric Pathology of Pregnancy, Deputy Director of the Institute of Obstetrics, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Ministry of Health of Russia (Moscow). No conflict of interest.
Gagayev Chelebi Gasanovich – MD, PhD, Professor, Department of Obstetrics and Gynecology with a Course in Perinatology, Medical Institute, Peoples' Friendship University of Russia (Moscow). No conflict of interest.
Natalia V. Dolgushina – MD, PhD, Professor, Deputy Director for Research, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Chief freelance specialist in women's reproductive health of the Russian Ministry of Health (Moscow). No conflict of interest.
Stanislav V. Pavlovich – PhD, Associate Professor, Scientific Secretary, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.
Vladimir N. Serov – Academician of the Russian Academy of Sciences, MD, PhD, Professor, Chief Researcher, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, President of the Russian Society of Obstetricians and Gynecologists (ROAG) (Moscow). No conflict of interest.
Roman G. Shmakov – MD, PhD, Professor, Director, Moscow Regional Research Institute of Obstetrics and Gynecology named after Academician V.I. Krasnopolsky, Chief freelance specialist in obstetrics of the Russian Ministry of Health (Moscow). No conflict of interest.
Natalia V. Artymuk – MD, PhD, Professor, Head of the Department of Obstetrics and Gynecology named after Professor G.A. Ushakova, Kemerovo State Medical University of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics, Gynecology, and Women's Reproductive Health of the Russian Ministry of Health in the Siberian Federal District (Kemerovo). No conflict of interest.
Nadezhda V. Bashmakova – MD, PhD, Professor, Chief Researcher, Ural Research Institute for Maternal and Infant Care of the Russian Ministry of Health, Chief freelance specialist in obstetrics, gynecology, and women's reproductive health of the Russian Ministry of Health in the Ural Federal District. No conflict of interest.
Tatiana E. Belokrinitskaya – MD, PhD, Professor, Head of the Department of Obstetrics and Gynecology, Faculty of Advanced Training and Professional Retraining, Chita State Medical Academy of the Russian Ministry of Health, Honored Doctor of the Russian Federation, Chief freelance specialist in obstetrics, gynecology, and women's reproductive health of the Russian Ministry of Health in the Far Eastern Federal District (Chita). No conflict of interest.
Natalia V. Kosovtsova – MD, PhD, Head of the Department of Biophysical and Radiation Research Methods, Ural Research Institute for Maternal and Infant Care of the Russian Ministry of Health (Yekaterinburg). No conflict of interest.
Mark A. Kurtser – MD, PhD, Professor, Academician of the Russian Academy of Sciences, Head of the Department of Obstetrics and Gynecology named after Academician G.M. Savelieva, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health (Moscow). No conflict of interest.
Malyshkina Anna Ivanovna – Doctor of Medical Sciences, Professor, Director of the V.N. Gorodkov Ivanovo Research Institute of Motherhood and Childhood of the Russian Ministry of Health, Head of the Department of Obstetrics and Gynecology, Medical Genetics, Faculty of General Medicine, Ivanovo State Medical Academy of the Russian Ministry of Health, Chief Freelance Specialist of the Russian Ministry of Health for Obstetrics, Gynecology and Women's Reproductive Health in the Central Federal District (Ivanovo). No conflict of interest.
Tatiana V. Markova – PhD, Senior Researcher, Department of Fetal Antenatal Protection, Ural Research Institute for Maternal and Infant Care of the Russian Ministry of Health (Yekaterinburg). No conflict of interest.
Mikhailov Anton Valerievich – MD, Professor, Chief Physician, Maternity Hospital No. 17 of St. Petersburg, Professor of the Department of Obstetrics and Gynecology, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, and the Department of Obstetrics, Gynecology and Perinatology, First Saint Petersburg State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the North-Western Federal District (St. Petersburg). No conflict of interest.
Nikolai N. Nikishov – PhD, Associate Professor, Department of Obstetrics and Gynecology, Immanuel Kant Baltic Federal University, Obstetrician-gynecologist of the highest qualification category, Regional Perinatal Center of the Kaliningrad Region
Irina A. Panova – MD, PhD, Associate Professor, Head of the Department of Obstetrics, Gynecology, Neonatology, Resuscitation and Anesthesiology, Ivanovo Research Institute of Motherhood and Childhood named after V.N. Gorodkov of the Russian Ministry of Health (Ivanovo). No conflict of interest.
Victoria A. Popandopulo – MD, PhD, Professor, Head of the Department of Obstetrics and Gynecology, Maykop State Technological University, Professor of the Department of Obstetrics and Gynecology, Faculty of General Medicine, Astrakhan State Medical University of the Russian Ministry of Health, Chief Medical Officer, Kuban Medical Center LLC, Chief freelance specialist in obstetrics, gynecology, and women's reproductive health of the Russian Ministry of Health in the Southern Federal District (Krasnodar). No conflict of interest.
Lali G. Sichinava – MD, PhD, Professor, Professor of the Department of Obstetrics and Gynecology named after Academician G.M. Savelieva, Pediatric Faculty, Pirogov Russian National Research Medical University of the Russian Ministry of Health (Moscow). No conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience of these clinical guidelines:
Obstetrician-gynecologists.
Neonatologists
Resident obstetricians and gynecologists.
Table 1. Grading of levels of evidence certainty (LEC) for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)
LoE | Definition |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
C | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Appendix A3. Reference Materials
Not applicable.
Appendix B. Physician Action Algorithms
Table 4. Peak systolic velocity in the fetal middle cerebral artery at various periods of gestation
Gestational age (weeks) | MCA PSV (MoM) | |||
|---|---|---|---|---|
1.00 | 1.29 | 1.50 | 1.55 | |
cm/s | ||||
18 | 23,2 | 29,9 | 34,8 | 36,0 |
20 | 25,5 | 32,8 | 38,2 | 39,5 |
22 | 27,9 | 36,0 | 41,9 | 43,3 |
24 | 30,7 | 39,5 | 46,0 | 47,5 |
26 | 33,6 | 43,3 | 50,4 | 52,1 |
28 | 36,9 | 47,6 | 55,4 | 57,2 |
30 | 40,5 | 52,2 | 60,7 | 62,8 |
32 | 44,4 | 57,3 | 66,6 | 68,9 |
34 | 48,7 | 62,9 | 73,1 | 75,6 |
36 | 53,5 | 69,0 | 80,2 | 82,9 |
38 | 58,7 | 75,7 | 88,0 | 91,0 |
40 | 64,4 | 83,0 | 96,6 | 99,8 |
Table 5. Normal fetal hemoglobin concentration values.
Fetal anemia is classified as mild (Hb <0.84 MoM); moderate (Hb <0.65 MoM), and severe (Hb <0.55 MoM)
Fetal hemoglobin concentration (g/L)
Gestational age (weeks) | 1.0 MoM | 0.84 MoM | 0.65 MoM | 0.55 MoM |
|---|---|---|---|---|
18 | 106 | 89 | 69 | 58 |
19 | 109 | 91 | 71 | 60 |
20 | 111 | 93 | 72 | 61 |
21 | 114 | 95 | 74 | 62 |
22 | 116 | 97 | 75 | 64 |
23 | 118 | 99 | 76 | 65 |
24 | 120 | 100 | 78 | 66 |
25 | 121 | 102 | 79 | 67 |
26 | 123 | 103 | 80 | 68 |
27 | 124 | 104 | 81 | 68 |
28 | 126 | 106 | 82 | 69 |
29 | 127 | 107 | 83 | 70 |
30 | 128 | 108 | 83 | 71 |
31 | 130 | 109 | 84 | 71 |
32 | 131 | 110 | 85 | 72 |
33 | 132 | 111 | 86 | 72 |
34 | 133 | 111 | 86 | 73 |
35 | 134 | 112 | 87 | 74 |
36 | 135 | 113 | 87 | 74 |
37 | 135 | 114 | 88 | 75 |
38 | 136 | 114 | 89 | 75 |
39 | 137 | 115 | 89 | 75 |
40 | 138 | 116 | 90 | 76 |
Technique for intrauterine intravascular transfusion of washed red blood cells to the fetus
Washed red blood cells are prepared from donor blood of O(I) Rh-negative group with a high hematocrit of 80–85%, which helps reduce volume overload on the fetoplacental circulation. The transfusion rate is set within 2–4 mL/min depending on the baseline fetoplacental volume. The final volume of washed red blood cell transfusion is calculated based on the fetoplacental volume at the given gestational age, the baseline hematocrit (or hemoglobin) value, and the hematocrit (or hemoglobin) value of the washed red blood cells.
Intravascular fetal transfusion increases hematocrit and hemoglobin levels to normal values, which prevents the development or resolves already developed fetal hydrops, and allows pregnancy to be prolonged to near-term gestation [4, 14–17].
In severe hydrops fetalis due to hemolytic disease, transfusion of washed red blood cells is supplemented by administration of a 20% albumin solution to the fetus. Transfusion of washed red blood cells to the fetus helps weaken the maternal immune response by reducing the relative number of Rhesus-positive red blood cells in the fetal circulation.
To prevent excessive fetal motor activity, which is one of the main causes of complications during cordocentesis and subsequent intravascular transfusion, the neuromuscular blocking agent pipecuronium is administered into the fetal circulation.
The following complications may occur during cordocentesis and intrauterine transfusion of washed red blood cells: bleeding from the umbilical cord puncture site; umbilical cord vessel thrombosis; umbilical cord hematoma formation; placental abruption; acute fetal hypoxia; premature rupture of membranes; preterm birth; infection [46, 47].
Upon completion of the transfusion of the calculated volume of washed red blood cells, fetal blood is sampled to determine post-transfusion hematocrit and hemoglobin levels in order to assess the effectiveness of intrauterine treatment of fetal anemia. The need for repeated fetal blood transfusions is determined by the gestational age at the time of the previous transfusion, the final fetal hematocrit value, and the dynamics of MCA PSV changes [4, 14, 17, 47–49].
Appendix C. Patient Information
If you are Rh-negative, your husband's/partner's Rhesus factor must be determined. If your partner is also Rh-negative, you will not need to undergo any additional tests during pregnancy or receive medication, as your baby will also be Rhesus-negative, and Rhesus isoimmunization will not occur in your case.
If your husband/partner is Rh-positive, or if you do not know his Rhesus factor, fetal Rhesus genotyping can be performed using maternal blood starting from 12 weeks of gestation. If the fetal Rhesus factor is negative, no additional tests during pregnancy or medications are required.
If non-invasive fetal Rhesus testing was not performed, and your husband/partner is Rh-positive, or you do not know his Rhesus factor, or if the test determined the fetus to be Rh-positive, you will be scheduled for Rhesus antibody screening at your 1st antenatal visit, at 18 weeks, and at 28 weeks of gestation. At 28 weeks, in the absence of Rhesus antibodies, you will be offered Rhesus isoimmunization prophylaxis.
After delivery, your baby's Rhesus factor will be determined, and if the baby is Rhesus-positive and you have no Rhesus isoimmunization, you will be prescribed repeated isoimmunization prophylaxis.
If complications arise during pregnancy that require invasive medical interventions (cervical cerclage, amniocentesis, chorionic villus sampling, etc.), additional prophylaxis will be prescribed. You may ask any questions you have to the obstetrician-gynecologist managing your pregnancy.
If rhesus antibodies are detected during your pregnancy, you will be offered a special ultrasound examination to diagnose fetal anemia. This study, called Doppler ultrasound, will be performed repeatedly to assess the condition of the fetus, as it may change as the rhesus conflict progresses.
If Doppler ultrasound reveals signs of fetal anemia, you will be referred to a facility equipped to perform intrauterine fetal blood transfusion—a specialized procedure performed under ultrasound guidance and local anesthesia. The goal of fetal blood transfusion is to maintain normal hemoglobin levels in the fetus and prevent the development of severe anemia by the time of delivery. Such procedures often need to be repeated to achieve the desired effect.
You will be informed about the specific details of your case and the potential risks associated with both the fetal blood transfusion procedure and expectant management. Decisions regarding the timing of delivery are made jointly with you, depending on the condition of the fetus and the obstetric situation.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Not applicable.