REVIEW ARTICLE

https://doi.org/10.5005/jp-journals-10009-1986
Donald School Journal of Ultrasound in Obstetrics and Gynecology
Volume 17 | Issue 3 | Year 2023

Diagnosis and Treatment of Fetus Anemia: Current Status

Liliana S Voto1, Norberto D Margulies2

1,2Department of Maternal and Infant, Juan A Fernández Hospital; School of Medicine, University of Buenos Aires, Buenos Aires, Argentina

Corresponding Author: Liliana S Voto, Department of Maternal and Infant, Juan A Fernández Hospital; School of Medicine, University of Buenos Aires, Buenos Aires, Argentina, Phone: +5491150412871, e-mail: lvoto@intramed.net

Received on: 17 June 2023; Accepted on: 05 August 2023; Published on: 29 September 2023

ABSTRACT

Fetal anemia is defined as the diminished concentration of fetal hemoglobin below two standard deviations for gestational age. In Argentina as well as in most developing countries, this disease is one of the leading causes of fetal-neonatal morbidity and mortality (5% of perinatal deaths) due to the lack of appropriate prophylaxis with postpartum anti-D γ-globulin and inadequate prenatal control. Fetal anemia is originated in the mother due to the presence of specific antibodies–originated In Rhesus factor (Rh)—negative mothers whose husbands are Rh-positive and whose immunization occurred during pregnancy, abortion, postpartum or incompatible transfusions that pass through the placenta agglutinate and hemolyze fetal red blood cells, thus causing fetal anemia and hemolytic disease. In the most severe cases, the fetus can be hydropic or die in utero due to congestive cardiac failure. In our experience, the immunization frequency in Rh-negative patients during their second pregnancy with compatible Rh-positive fetuses is 12–15%. The cornerstone of the follow-up of the sensitized Rh-negative woman is a composite of an appropriate anamnesis, the indirect Coombs test, titration of anti-D antibodies, ultrasound (US) middle cerebral artery (MCA) peak systolic velocity, amniotic fluid spectrophotometry, amniocentesis/cordocentesis, and antenatal fetal monitoring. The pillar of the treatment of severe maternal-fetal Rh-incompatibility to prevent fetal death and allow the fetus to reach viability is intrauterine fetal transfusion (by the intraperitoneal route or intravascular fetal transfusion), high intravenous dose immunoglobulin (HDIVIg) as a single treatment or followed by intrauterine transfusions (IUTs). The neonatal treatment of the newborn is based on phototherapy and HDIVIg, which reduce the frequency of neonatal transfusions needed and the bilirubin maximum levels.

How to cite this article: Voto LS, Margulies ND. Diagnosis and Treatment of Fetus Anemia: Current Status. Donald School J Ultrasound Obstet Gynecol 2023;17(3):223–233.

Source of support: Nil

Conflict of interest: Dr. Liliana S Voto is associated as the International Editorial Board Member of this journal and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of this Editorial Board Member and her research group.

Keywords: Fetal Anemia, Fetal-neonatal morbidity, Mortality

This paper has been previously published as Liliana S Voto, Norberto D Margulies. Diagnosis and treatment of fetus anemia: Current status. In: Chervenak FA, Kupesic Plavsic S, Kurjak A. Donald School; The Fetus as a Patient: Current Perspectives. Jaypee Brothers, New Delhi, 2019, 318–329.

INTRODUCTION

Fetal anemia is defined as the diminished concentration of fetal hemoglobin below 2 standard deviations for gestational age.

Several causes of fetal anemia have been described in Table 1.

Table 1: Etiology of fetal anemia
α-thalassemia
Fetomaternal hemorrhage
Fetal infection (parvovirus B19)
Twin-to-twin fetal transfusion
Congenital leukemia
Fetal tumors (sacrococcygeal teratoma)

Severe hemolytic disease due to Rhesus factor (Rh) incompatibility still constitutes a source of concern for obstetricians and pediatricians. In Argentina, as well as in most developing countries, this disease is one of the main causes of fetus-neonatal morbidity and mortality due to the lack of appropriate prophylaxis with postpartum anti-D γ-globulin and inadequate prenatal control.1

It represents a true model of perinatal pathology: it originated in the mother due to the presence of specific antibodies that pass through the placenta agglutinate and hemolyze fetal red blood cells causing fetal anemia and hemolytic disease. In most severe cases, the fetus can be hydropic or die in utero due to congestive cardiac failure as a consequence of hemolytic anemia.

Perinatal hemolytic disease (PHD) represents one of the most significant examples in medicine of successful disease management and adequate prophylaxis.

By the first half of the century, PHD accounted for 45% of all perinatal deaths. Nowadays, this rate has significantly decreased to 5% as a result of a depth understanding of the etiology and pathogenesis of the disease, progress in perinatal technology, the creation of sophisticated centers for high-risk perinatal care, and, mainly as a result of its prophylaxis.

HISTORY

The PHD was described for the first time in 1609 in France by a midwife that described the stillbirth of an extremely edematous twin, and the second one died some days after due to hydrops.

In 1932 Diamond et al.2 described fetal hydrops, icterus gravis neonatorum, and neonatal anemia as different phases of the same disease, all of them with the presence of erythroblasts, thus naming it erythroblastosis fetalis.

Darrow, in 1938,3 introduced concepts relative to physiopathology and described the presence of a maternal antibody against fetal blood, but he wrongly estimated that the antibody was fetal hemoglobin.

Classic blood groups have already been described in the 1930s, and in 1940, Landsteiner and Wiener4 described the agglutination of red blood cells of Caucasian human beings in contact with rabbit serum inoculated with red blood cells of Rhesus monkeys: the 85% that agglutinated were called “Rh” positive.

In 1941 Levine5 in the United States of America described the role of isoimmunization in PHD when he associated the generation of fetal hydrops with blood transfusions incompatible in the mother and most of them due to the Rh factor.

With this knowledge, many groups started to work to find possible fetal and neonatal therapies in order to reduce the high mortality associated with this pathology. This is how in 1946, Wallerstein6 communicated his experience with neonatal red blood cell transfusion, being 1950, shown by Allen et al.7 as capable of modifying the evolution of a newborn at risk of kernicterus.

All initial treatments tended to neutralize or inactivate circulating maternal antibodies. The intention was to minimize the hemolytic effect of a pre-existing sensitization. The Rh hapten used by Carter in 1947 was intended to inhibit by means of a fraction of human red blood cells the agglutinating property of anti-Rh serum.

The use of corticoids in 1955 was intended by means of their immunosuppressive effect, unknown at that moment, to prevent the reaction of the maternal immunologic system and reduce in that way hemolysis.

Another action capable of modifying the natural course of the disease published by Allen in 19508 and Chown in 19589 was premature delivery that reduced the impact of anemia and hyperbilirubinemia serious complications, thus introducing premature interruption of pregnancy as a therapeutic option. In 1958, Cremer et al.10 published his experience with phototherapy after seriously considering the empirical observations of nurse Ward of Rochford General Hospital, Essex, England, who observed that icteric premature babies who received direct solar light recovered their skin color faster than those who were not exposed to it.

In 1952 Bevis11 started to perform amniocentesis and observed the relationship between the yellowish color of the amniotic fluid and the severity of hemolytic disease, and in 1961, Sir Liley12 in the United Kingdom ended up defining it when he measured bilirubin levels by spectrophotometry in amniotic fluid obtained by amniocentesis. He drafted a chart to which the result obtained when the amniotic fluid of amniocentesis is subject to spectrophotometry is extrapolated, relating each zone to an adequate perinatal prognosis and management according to mortality risk, which is still in use nowadays.

After 2 years, Liley himself13 communicated his experience with intraperitoneal intrauterine transfusion (IUT) in the management of severely ill fetuses without extrauterine viability as a therapeutic measure. Almost simultaneously, Freda et al.14 released his results in the prevention of the disease by the administration of anti-D γ-globulin after inoculating RhD-negative subjects with RhD-positive red blood cells.

PATHOGENESIS OF RH-SENSITIZATION MECHANISM

The antigens of the Rh system are located on the surface of the erythrocyte, although they are also thought to be part of the trophoblast.15

Rhesus factor (Rh) system’s anti-D antibodies are responsible for the majority of clinically detectable PHD cases. This situation is observed in Rh-negative mothers whose husbands are Rh-positive and whose immunization occurred during pregnancy, abortion, and postpartum or incompatible transfusion.

In Argentina, 13% of couples are Rh incompatible, and it is estimated that there is one PHD case in every 150 deliveries. On the other hand, according to different statistics, the immunization rate is between 7 and 14%.

The passage of fetal red blood cells to maternal circulation is considered normal during pregnancy. Using the Kleihauer-Betke technique, it was established that the passage of fetal red blood cells should not be higher than 0.1–0.2 mL. In this case, the competent immunological system would not be activated; however, the chances of it being stimulated are much higher if the transplacental hemorrhage is greater than the established values.

There are certain obstetric events that can increase the risk, such as placenta previa, ruptured placental membranes, external version, Cesarean section, manual removal of placenta, and in the early stages of pregnancy, abortion, and ectopic pregnancy.

All invasive procedures during pregnancy cause the passage of fetal red blood cells. Chorionic villous sampling performed during the first trimester of pregnancy, which is frequently used nowadays, has been associated with very severe cases of hemolytic disease, even with hydrops. Amniocentesis causes fetomaternal hemorrhage in 2–3% of the cases. Spontaneous or induced abortion is also associated with transplacental hemorrhage.

Antigen D has already developed by the 35th–45th day of gestation, which explains why 4–5% of postabortion patients may become sensitized. Intravenous drug abuse can also lead to isoimmunization.

When an Rh-negative person receives Rh-positive blood, an immunologic response takes place in 50% or more of the cases.

The primary immunologic response is usually weak. The initial antibodies are of IgM nature, with a high molecular weight, and are unlikely to cross the placenta. As a result, they do not produce fetal hemolysis labels in pregnancy; the IgG antibodies cross the placenta and produce hemolysis.

The IgG antibodies involved in the etiology and pathogenesis of PHD due to anti-D are mainly subtypes IgG I and III. The former crosses the placenta early in pregnancy and therefore plays a role in most severe PHD cases.

In our experience, the frequency of immunization in Rh-negative patients during their second pregnancy with compatible Rh-positive fetuses is 12–15%.

ABO incompatibility in an Rh-negative patient provides partial protection against primary anti-Rh isoimmunization but not against a secondary immunologic response. In the former, the anti-A or anti-B incompatibility immunized blood cells are captured by the liver, which is not an immunologically active organ and does not produce anti-Rh antibodies. On the other hand, in a secondary immunologic response, the spleen receives the blood cell stroma and produces anti-Rh antibodies. Therefore, there is a higher incidence of Rh hemolytic disease in children whose parents are HBO compatible.

PATHOGENESIS AND PHYSIOPATHOLOGY OF PHD

According to different studies, the rate of active transport of human IgG varies in the course of normal gestation; before 12 weeks of pregnancy, this transfer is very low, but it has been demonstrated that, in severe Rh disease, the direct antiglobulin test on fetal (Rh-positive) red cells may be positive as early as 6–10 weeks. The IgG antibodies rise exponentially until term. Sometimes, IgG levels in infants could be higher than in the mother. The placental transport of IgG1 and IgG3 in women with Rh (D) immunizations is not diminished compared with normal pregnancy. The placental transport of IgG3 is significantly higher in pregnancies at risk of hemolytic disease of the newborn with IgG3 concentrations in normal pregnancy.16

The pathogenesis of PHD lies in the hemolysis of fetal erythrocytes caused by maternal antibodies. Hemolysis then results in fetal anemia.

According to the severity of hemolysis, PHD will be anemic, icteroanemic, or hydropic. In hydropic PHD, the hepatic parenchyma is partially replaced with secondary erythropoiesis tissue, which causes portal and umbilical venous hypertension syndrome, as well as alterations in the metabolism of proteins and decreased albumin. Both clinical conditions cause edema and ascites, which are typical of hydrops.

Frequently, fetal cardiac failure secondary to severe anemia is observed. Both other forms of PHD, anemic and icteroanemic, are the result of less severe hemolysis that does not compromise either the cardiocirculatory system or the protein metabolism.

FOLLOW-UP OF THE RH-NEGATIVE PREGNANT

The anamnesis will focus on relevant data such as a number of previous deliveries, history of anti-D prophylaxis, history of perinatal morbidity and mortality attributable to hemolysis, history of previous transfusions, and history of neonatal exchange transfusions or luminotherapy in previous deliveries.

If an indirect Coombs test does not detect anti-D antibodies, it should be repeated every 4 weeks until immediate puerperium (Flowchart 1).

Flowchart 1: Rhesus (Rh) isoimmunization: patients with no maternal and/or perinatal history of the disease and/or MCA peak systolic velocity and conventional US

If the test is positive, we will proceed as follows:

Middle cerebral artery (MCA) peak systolic velocity provides a noninvasive modality for determining moderate to severe fetal anemia. This technique does not differentiate between mild fetal anemia and the absence of anemia. The sensitivity of an increased peak systolic velocity in the MCA for the prediction of moderate to severe fetal anemia is 100% either in the presence or the absence of hydrops fetalis, and the false positive is 12%.17,18 On the contrary, amniotic fluid is more direct in predicting fetal status, and it constitutes an intermediate step for cordocentesis when it is difficult to implement it.19 The timing of the initial amniocentesis depends on the patient’s history and antibody titer. If the patient’s antibody titer is just at the critical level and the patient has not had a baby with erythroblastosis fetalis (EBF), the initial amniocentesis can be done at 28–29 weeks gestation. If the titer or the history suggests that the EBF may be more severe, then amniocentesis can be performed earlier. In this way, a fetus that needs an IUT can be identified.

Many methods have been used to evaluate atrial fibrillation (AF) by detecting fetal hemolysis. Liley plotted curves of AF.

Δ optical density (OD) 450 values based on gestational age and derived three zones of fetal disease severity. Therefore, using Liley curves, the fetal condition can be predicted based on the AF ΔOD 450 value.12,20

Flowchart 2: Rhesus (Rh) isoimmunization: patients with no maternal and/or perinatal history of the disease; and/or MCA peak systolic velocity and conventional US; IUT, intrauterine transfusion

NONINVASIVE DIAGNOSIS OF FETAL ANEMIA CAUSED BY HEMOLYTIC DISEASE

Undoubtedly amniocentesis and cordocentesis have been successfully used in the diagnosis and treatment of hemolytic disease. During the last few years, a noninvasive method for the diagnosis of fetal anemia has been developed: the assessment of MCA peak systolic velocity by eco-Doppler.

Fetal US

Ultrasound (US) follow-up is vital to evaluate fetal growth and/or early onset of fetal signs attributable to diseases such as the increase of amniotic fluid, hepatomegaly, ascites, edemas, and pericranial pericardial or soft tissues. The last ones show the severity of the fetal condition to anticipate the next appearance of hydrops fetalis, the peak in intrauterine fetal affection (Table 2) (Figs 1 to 3).20

Table 2: Ultrasound (US) findings suggesting anemia
Hepatosplenomegaly
Subcutaneous cellular tissue edema
Fetal ascites
Pericardial effusion
Hydrops
Cardiomegaly
Polyhydramnios
Placental edema
Buddha position

Fig. 1: Fetal skull edema

Fig. 2: Fetal hydrothorax and edema

Fig. 3: Fetal ascites

Fetal Monitoring

Antepartum fetal monitoring is also useful for assessing fetal health, even considering all the questioning that has arisen around it. As it is a noninvasive, reproducible method that can be repeated as many times as necessary, it provides very important data when detecting a “sinusoidal pattern,” as this indicates we are in the presence of tissue ischemia, in the case of severe PHD, due to tissue hypoxia as a consequence of serious fetal anemia (Figs 4 and 5).

Fig. 4: Fetal monitoring; sinusoidal pattern

Fig. 5: Anemic newborn

Doppler US

Since Mari’s1,22 publications, several studies carried out by different authors have worked on the approval of this method and its results. Based on the increase observed in the MCA systolic peak using Doppler US in fetuses with anemia, this methodology has definitely been incorporated in the follow-up of fetuses with mild or moderate hemolytic disease.

The assessment of the MCA of Doppler vascular flow has become a significant method due to its contribution and safety, thus avoiding the use of amniocentesis as a diagnostic method in cases with previous fetuses affected and therefore reducing the risk of antibodies titers increase.12

Dodd et al. published the results23 of an international, multi-center randomized trial in which women with pregnancies complicated by fetal anemia secondary to red cell alloimmunization as indicated by the need to undergo a single IUT were eligible for inclusion.

Timing of subsequent IUTs involved estimating a fall in fetal hematocrit of 1% per day or a fall in fetal hemoglobin of 0.3 gm/dL/day. The aim of this pragmatic multi-center randomized trial was to evaluate whether Doppler MCA-peak systolic velocity (PSV) in the fetus that has undergone one IUT for anemia secondary to red cell alloimmunization was not inferior to timing IUT by timing based on predicting the fall in fetal hematocrit or fetal hemoglobin, without compromising infant hemoglobin at birth.

There were no statistically significant differences between the two groups in risk of adverse infant outcomes related to alloimmunization or procedure-related complications.

They concluded that both Doppler MCA-PSV measurement and estimating the fall in fetal hematocrit or hemoglobin could be used to time second and subsequent IUTs (Table 3) (Figs 6 and 7).

Table 3: Methodology: a technique for measurement of the systolic peak of the MCA
Baby should still be
Obtain transverse planes of the fetal head
Identify the Willis circle
The MCA should be magnified up to 50% of the screen
The sample volume must be 1 mm maximum
The sample volume must be located near the origin of MCA at the internal carotid artery
The angle between the sample volume and the blood direction must be near 0 degrees
Must insonate 3–5 waves
Absence of fetal breathing during the measurement
The highest peak should be measured

Fig. 6: Willis Circle

Fig. 7: Middle cerebral artery (MCA) measurement technique

TREATMENT OF SEVERE MATERNAL-FETAL RH-INCOMPATIBILITY

In 1963 Liley described IUT as the only possible way to prevent intrauterine fetal death of severely affected Rh-positive fetuses. When pregnancy interruption is indicated, fetal prematurity becomes an aggravating factor that conspires against successful results.

The purpose of all the procedures described below is to allow the fetus to reach viability.

Intrauterine Fetal Transfusion

Intraperitoneal Route

It is estimated that the total amount of blood transfused into the peritoneal cavity flows into the fetal bloodstream within 7–10 days after being injected.

This technique relies on the absorption capability of the fetal peritoneum and sub-diaphragmatic lymphatic, and it is not usually indicated before the 24th week of gestation. US plays an essential role in this procedure: it locates the fetal abdomen and shows the precise point of entry.

The inferior portion of the peritoneal cavity is then accessed, considering the bladder as a reference point to prevent injury to the liver or spleen.

Type O, Rh-negative blood, compatible with maternal blood, with a hematocrit concentration not <75% should be transfused. Blood should have been recently extracted (no more than 48 hours before the procedure).

Ascites, if present, should be evacuated before the procedure, although in this case, the intravascular route is always preferred.

The use of uterine inhibitors is recommended, and the administration of antibiotics in order to prevent possible infections is controversial.

The procedure should be repeated, according to the patient’s evolution, every 14 days or more until fetal viability is achieved.

The amount of blood to be transfused should be estimated as follows: gestational age in weeks minus 20, multiplied by 10. For example, in a 28 weeks pregnancy, (28–20) × 10 = 80, a total of 80 mL of erythrocytes should be transfused.

Intravascular Fetal Transfusion

Indications to using this approach are especially in the case of fetal hydrops or very severe fetal anemia. This technique, which may be used from 18 weeks of pregnancy, involves access to an umbilical vessel near its placental insertion, in the intrahepatic portion of the umbilical vein, or in the fetal heart (fetal rescue operation) (Figs 8 to 10).

Fig. 8: Middle cerebral artery (MCA) measurement technique

Fig. 9: Intravascular fetal transfusion

Fig. 10: Middle cerebral artery (MCA) measurement after intravascular fetal transfusion

Nowadays, this procedure is superior to the former because it allows the immediate reversal of fetal anemia, as it is possible to obtain a sample of fetal blood and determine its hematocrit and hemoglobin values. Also, a faster remission of fetal hydrops is observed in most of the cases.

The amount of blood to be transfused depends on the patient’s gestational age and blood donor and fetal blood hematocrit. The procedure should be repeated according to post-transfusion hematocrit values until fetal extraction is indicated.

If no complications occur, this technique allows the lengthening of intrauterine fetal life until the fetus is viable, which results in a marked decrease in perinatal mortality rates.

High-dose Intravenous Ig (IVIg) G for the Treatment of Severe Rh Alloimmunization

Intrauterine fetal transfusion, either by the intraperitoneal or intravascular routes, has been shown to be an effective treatment of Rh-hemolytic disease. However, some fetuses are already severely compromised at an early stage when it is technically impossible to indicate the procedure.

In agreement with other authors, we have found that repeated invasive techniques result in a significant increase of anti-D titers owing to the variable amounts of fetomaternal bleeding inevitably caused by the procedure itself. As a result, a moderate Rh disease in a present pregnancy can often become a severe one in the subsequent gestation.

It has been reported that transfusion therapy before 32 weeks gestation is associated with a higher fetal mortality rate.22 Early treatment in the first weeks of pregnancy would reduce the severity of fetal anemia, decreasing fetal morbidity and mortality. That is why we started a protocol of treatment with high doses of γ-globulin.1

The use of high doses of IVIg in the treatment of immunologic diseases both in children and adults and recurrent intrauterine fetal loss has been frequently reported in the literature with varying degrees of effectiveness.

Although IVIg action mechanisms remain unclear, several explanations have been proposed during pregnancy: feedback inhibition of antibody synthesis, competition for macrophage or Fc receptors of target cells, and blockade of Fc-mediated antibody placental transport. We have used IVIg therapy in a prospective study in order to analyze its effectiveness in the antenatal treatment of severe Rh-hemolytic disease.

The only Ig which is transferred into the fetal circulation is IgG; the other classes of maternal Igs are either not transferred or only cross the placenta in small quantities. The mechanisms involved in the active transfer of IgG across the human placenta are not yet known. Brambell et al.’s studies in rabbits suggest that the transport of IgG molecules across the placenta is mediated through a receptor for the Fc part of the molecule. Further studies have clarified the role of Fc as a placental Fc receptor for IgG. This receptor has been demonstrated on the surface of the trophoblast at 10 weeks and at term.

The mechanisms of placenta transfer of exogenous IgG infused into the mother are still to be elucidated. It must be emphasized that transplacental IgG transfer is a slow process and requires an intact Fc portion of the IgG molecule. Gitlin et al.’s studies demonstrated that when labeled IgG was injected into pregnant women at various intervals before delivery, even after 12 days, the concentration in the infant’s serum was only about 40% of that in the mother. Studies performed by Contractor et al. about IgG transport in perfused placentas suggest that the trophoblast absorbs a substantial amount of human IgG and all bovine IgG, both broken down in small fractions by a mechanism of nonspecific endocytosis and transmits these fragments to the fetal circulation. A small amount of human IgG, however, would escape this process of lysosomal destruction by diverse protective mechanisms and would be released intact on the fetal side.

There are very few cases in the literature reporting the treatment of severe Rh-hemolytic disease with high doses of IVIG, and the findings are too dissimilar to allow for conclusive generalizations. Rewald and Berlin et al. obtained satisfactory results with the combined use of plasmapheresis and IVIg in four cases of severe Rh-hemolytic disease. De la Cámara et al. reported the successful treatment of two cases with repeated doses of IVIg throughout gestation. Scott et al., on the other hand, used a combined protocol of IVIg and repeated IUTs in one case of hemolytic disease. We have administered IVIg as the only treatment in 24 severely Rh-sensitized patients with a previous history of affected fetuses and/or neonates, with elevated anti-D titers and a high degree of intrauterine hemolysis. Patients in group 1 (<20 weeks, n = 8) fulfilled the first two of these inclusion criteria, whereas in groups 2 (20–28 weeks, n = 7) and 3 (>28 weeks, n = 9), IVIg treatment was indicated on the basis of intrauterine hemolysis.

Intravenous Ig (IVIg) was infused at a daily dose of 0.4 gm/kg maternal body weight for 4–5 consecutive days and repeated every 21 days until delivery.

Group III also included those patients who attended the antenatal clinic very late in pregnancy; as a consequence of this delay, the fetuses in these cases were highly compromised because of the advanced stage of hemolytic disease, and they evidenced major neonatal depression and severe fetal anemia at birth, requiring, in almost all cases- exchange transfusions.

As in group I patients, the indication for IVIg had been a previous history of severe fetal/neonatal hemolytic disease and high maternal anti-D titers; all the fetuses showed good intrauterine recovery, and only half of the neonates required transfusion therapy at birth.

Group II responded more satisfactorily to IVIg treatment, as evidenced by the hematological condition of the neonates and the low degree of postnatal hemolysis.

Three fetuses were hydropic at the onset of treatment (two from group I and one from group II). IVIg administration, which is used to reduce intrauterine hemolysis by preventing the development of severe fetal anemia, was clearly not the right therapeutic indication in those cases.

In view of the advanced gestational age at delivery and the fairly high mean birth weight (2500 gm) in all the groups, neonates did not require mechanical ventilation and responded more satisfactorily to therapy in the immediate neonatal period. The decrease in pre vs posttreatment anti-D antibody quantification, the reduction in intrauterine hemolysis, and the strongly positive direct antiglobulin test in all neonates may indicate that the mode of action of high doses of IVIg in Rh-hemolytic disease is (1) feedback inhibition of antibody synthesis; (2) partial blockade of Fc-mediated antibody transport across the placenta. No adverse effects of the drug were observed either in the mother or neonate.

Our findings show that IVIg treatment was effective in groups I and II when IVIg was administered before the 28th week of gestation, and the fetuses were not hydropic at the onset of therapy. In group III, however, in which fetal anemia was already advanced at the time of treatment, IUTs, and prompt fetal extraction should have been the treatment of choice.

The analysis of the series, including only the 13 most severely affected cases as judged by their history of fetal/neonatal death, demonstrated again the effectiveness of IVIg treatment. It can be inferred from the results in this particular group of patients that; (1) after 28 weeks gestation, the administration of IVIg does not elicit significant reductions in anti-D titers and intrauterine hemolysis. Thus, IUT is the therapy of choice; (2) IVIg treatment is not indicated in the case of hydrops fetalis. Except for these two indications, it is in this series with the poorest history, the highest antibody level, and failure of transfusion therapy in previous gestations where we find the most encouraging therapeutic results of IVIg treatment.

The high cost of IVIg therapy is immediately outweighed by the highly satisfactory perinatal results obtained in our population of extremely severe Rh-sensitized patients. Moreover, babies born after treatment with IUTs, as well as those prematurely delivered because of their severe disease, require a prolonged stay in the neonatal intensive care unit (a mean of 60 days in the latter case), the cost of which greatly exceeds that of IVIg therapy.

To conclude, the results of our study, which to the best of our knowledge is the largest reported in the literature, show the value of high doses of IVIg in the treatment of severe Rh incompatibility when repeatedly administered before 28 weeks gestation and in the absence of hydrops fetalis.

HIGH-DOSE γ-GLOBULIN (IVIG) FOLLOWED BY IUT: A NEW ALTERNATIVE FOR THE TREATMENT OF SEVERE FETAL HEMOLYTIC DISEASE

Intrauterine fetal transfusion is currently the therapy of choice in cases of severe anti-D isoimmunization. However, its efficacy is reduced in patients with early severe hydrops fetalis due to the technical difficulties in performing this procedure before 20 weeks gestation and because the fetuses are already anemic at that term.

The purpose of this study was to determine whether the early onset of high-dose γ-globulin therapy followed by IUTs is more effective than IUTs alone in the treatment of very severe isoimmunized fetuses.

The population studied in this retrospective clinical research was assigned to one of the following two groups: (1) γ-group: 30 patients receiving γ-globulin therapy before 21 weeks gestation and IUTs after 20 weeks; or (2) IUT group: 39 patients receiving IUT treatment starting at a gestational age of 20–25 weeks.

Both groups were statistically similar regarding the history of perinatal deaths and anti-D antibody titers (Flowchart 3). The number of hydropic fetuses at the first IUT and of fetal deaths was significantly higher in the IUT than in the γ-group. No significant differences were observed between the groups in fetal hematocrit at first IUT and at birth. However, the percentage of severely anemic fetuses was higher in the IUT group. The fetal mortality rate was 36% less in the γ-group.

Flowchart 3: Rhesus (Rh) isoimmunization: Patients with maternal and/or perinatal history of the disease; and/or MCA peak systolic velocity and conventional US; IVIg, intravenous immunoglobulin; IUT, intrauterine transfusion

In summary, considering that in very severe cases of Rh-isoimmunization:

Our results show that high-dose γ-globulin therapy followed by IUTs improves fetal survival in these severe cases.24 Conventional treatment has also been modified by the administration of immune globulin to the neonate.25

NEONATAL TREATMENT

Our studies suggest that the frequency of neonatal transfusion therapy can be reduced by a combination of conventional phototherapy and high intravenous dose Ig (HDIVIg). Further studies are needed to determine the optimum timing and dosage of HDIVIg therapy.26

Other studies show that IVIg is effective in decreasing maximum bilirubin levels and the need for repeated exchange transfusions in Rh hemolytic disease of the newborn. However, there is an increased need for blood transfusions for late anemia in babies treated with IVIG.27

GENERAL AND FUTURE MANAGEMENT OF RHD ISOIMMUNIZATION

Future therapy will involve selective modulation of the maternal immune system turning the need for IUTs into a rarity.28

When RhD sensitization occurs, careful follow-up of these mothers and judicious intervention can result in good outcomes for most pregnancies. Both Doppler assessment of MCA peak systolic velocity and spectral analysis of amniotic fluid at 450 nm (ΔOD 450) are useful in the diagnosis and management of fetal anemia.29

REFERENCES

1. Margulies M, Voto LS, Mathet E, et al. High-dose intravenous IgG for the treatment of severe rhesus alloimmunization. Vox Sang 1991;61(3):181–189. DOI: 10.1111/j.1423-0410.1991.tb00944.x

2. Diamond LK, Blackfan KD, Batty JM. Erythroblastosis fetalis and its association with universal edema of the fetus, icterus gravis neonatorum, and anemia of the newborn. J Pediatr 1932;1(3):269–309. DOI: 10.1016/S0022-3476(32)80057-0

3. Darrow RR. Icterus gravis (erythroblastosis neonatorum) examination of etiologic considerations. Arch Pathol 1938;25:378–417.

4. Landsteiner K, Wiener AS. An agglutinable factor in human blood recognized by immune sera for Rhesus blood. Proc Soc Exp Biol Med 1940;43(1):223. DOI: 10.3181/00379727-43-11151

5. Levine P. The role of isoimmunization in transfusion accidents in pregnancy and erythroblastosis fetalis. Am J Obstet Gynecol 1941;42:165. DOI: 10.1093/ajcp/11.12.898

6. Wallerstein H. The treatment of erythroblastosis fetalis by substitution transfusion. Blood 1948;3(2):170–179. DOI: 10.1182/blood.v3.special_issue_number_2.170.170

7. Allen FH, Diamond LK, Vaughan JC. Eryhtroblastosis fetalis: VI. Prevention of kernicterus. Am J Dis Child 1950;80(5):779–791. PMID: 14777158.

8. Allen FH Jr. Induction of labor in the management of erythroblastosis fetalis. Quatr Rev Pediat 1950;12:1–5. DOI: 10.1097/00006254-195708000-00023

9. Chown B, Bowman WD. The place of early delivery in the prevention of foetal death from erythroblastosis. Pediatr Clin North Am 1958;279–285. DOI: 10.1016/s0031-3955(16)30649-6

10. Cremer RJ, Perryman PW, Richards DH. Influence of light on the hyperbilirubinaemia of infants. Lancet 1958;1(7030):1094–1097. DOI: 10.1016/s0140-6736(58)91849-x

11. Bevis DC. The antenatal prediction of haemolytic disease of the newborn. Lancet 1952;1(6704):395–398. DOI: 10.1016/s0140-6736(52)90006-8

12. Liley AW. Liquor amnil analysis in the management of the pregnancy complicated by resus sensitization. Am J Obstet Gynecol 1961;82:1359–1370. DOI: 10.1016/s0002-9378(16)36265-2

13. Liley AW. Intrauterine transfusion of foetus in haemolytic disease. Br Med J 1963;2(5365):1107–1109. DOI: 10.1136/bmj.2.5365.1107

14. Freda VJ, Gorman JG, Pollack W. Successful prevention of experimental rh sensitization in man with an anti-rh gamma2-globulin antibody preparation: a preliminary report. Transfusion 1964;4:26–32. DOI: 10.1111/j.1537-2995.1964.tb02824.x

15. Hohlfeld P, Wirthner D, Tissot JA. Perinatal hemolytic disease: physiopathology. J Gynecol Obstet Biol Reprod 1998;27(2):135–43.

16. Palfi M, Hildén JO, Gottvall T, et al. Placental transport of maternal immunoglobulin G in pregnancies at risk of Rh (D) hemolytic disease of the newborn. Am J Reprod Immunol 1998;39(5):323–328. DOI: 10.1111/j.1600-0897.1998.tb00525.x

17. Mari G, Deter RL, Carpenter RL, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 2000;342(1):9–14. DOI: 10.1056/NEJM200001063420102

18. Zimmerman R, Carpenter RJ Jr, Durig P, et al. Longitudinal measurement of peak systolic velocity in the fetal middle cerebral artery for monitoring pregnancies complicated by red cell alloimmunisation: a prospective multicentre trial with intention-to-treat. BJOG 2002;109(7):746–752. DOI: 10.1111/j.1471-0528.2002.01314.x

19. Nishie EN, Brizot ML, Liao AW, et al. A comparison between middle cerebral artery peak systolic velocity and amniotic fluid optical density at 450 nm in the prediction of fetal anemia. Am J Obstet Gynecol 2003;188(1):214–219. DOI: 10.1067/mob.2003.63

20. Liley AW. Errors in the assessment of hemolytic disease from amniotic fluid. Am J Obstet Gynecol 1963;86:485–494. DOI: 10.1016/0002-9378(63)90174-1

21. In: The perinatal medicine of the new millennium: proceedings of the 5th World Congress of Perinatal Medicine 2001; 23–27.

22. Klumper FJ, van Kamp IL, Vandenbussche FP, et al. Benefits and risks of fetal red-cell transfusion after 32 weeks gestation. Eur J Obstet Gynecol Reprod Biol 2000;92(1):91–96. DOI: 10.1016/s0301-2115(00)00430-9

23. Dodd JM, Andersen C, Dickinson JE, et al. Fetal middle cerebral artery Doppler to time intrauterine transfusion in red-cell alloimmunization: a randomized trial. Ultrasound Obstet Gynecol 2018;51(3):306–312. DOI: 10.1002/uog.18807

24. Voto LS, Mathet ER, Zapaterio JL, et al. High-dose gammaglobulin (IVIG) followed by intrauterine transfusions (IUTs): a new alternative for the treatment of severe fetal hemolytic disease. J Perinat Med 1997;25(1):85–88. DOI: 10.1515/jpme.1997.25.1.85

25. Porter TF, Silver RM, Jackson GM, et al. Intravenous immune globulin in the management of severe Rh D hemolytic disease. Obstet Gynecol Surv 1997;52(3):193–197. DOI: 10.1097/00006254-199703000-00022

26. Voto LS, Sexer H, Ferreiro G, et al. Neonatal administration of high-dose intravenous immunoglobulin in rhesus hemolytic disease. J Perinat Med 1995;23(6):443–451. DOI: 10.1515/jpme.1995.23.6.443

27. Mukhopadhyay K, Murki S, Narang A, et al. Intravenous immunoglobulins in rhesus hemolytic disease. Indian J Pediatr 2003;70(9):697–699. DOI: 10.1007/BF02724308

28. Moise KJ Jr. Management of rhesus alloimmunization in pregnancy. Obstet Gynecol 2002;100(3):600–611. DOI: 10.1016/s0029-7844(02)02180-4

29. Harkness UF, Spinnato JA. Prevention and management of RhD isoimmunization. Clin Perinatol 2004;31(4):721–742, vi. DOI: 10.1016/j.clp.2004.06.005

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