Key Points
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Fetal hydrops is defined as the accumulation of fluid in two fetal compartments (abdominal ascites, pleural effusion, pericardial effusion, skin or scalp oedema). It may also be associated with polyhydramnios and placental oedema.
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Immune hydrops is the result of alloimmunisation to red blood cell antigens.
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Rhesus (Rh) immunoglobulin has decreased the relative frequency of RhD disease.
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Kell alloimmunisation is associated with the least predictable and most severe degree of fetal anaemia.
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Doppler measurement of fetal middle cerebral artery peak velocity has transformed the diagnosis and treatment of fetal anaemia and greatly reduced the use of invasive procedures.
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Intravascular fetal blood transfusions in cases of severe anaemia and hydrops have dramatically improved the outcome of these pregnancies.
History
The history of haemolytic disease of the fetus and newborn (HDFN) is an example of how modern medicine can both treat and prevent a disease process with significant perinatal morbidity and mortality. In the 1950s 15% of all alloimmunised gestations ended in stillbirth. Work by Bevis and Walker in Rh-sensitised pregnancies correlated amniotic fluid levels of bilirubin with the incidence of postnatal kernicterus and the severity of anaemia in affected infants. William Liley in New Zealand furthered this work and created the Liley curve, a chart that was able to predict the severity of fetal haemolytic disease and aid in determining the appropriate time for labour induction in affected gestations. Liley’s work decreased the perinatal mortality rate in Rh-sensitised gestations at the National Women’s Hospital in Auckland from 22% in 1958 to 8.7% in 1962.
To improve outcomes for the most severely affected fetuses, Liley further developed the concept of intraperitoneal fetal transfusion. In patients with suspected severe haemolytic disease who were not likely to survive, compatible red blood cells (RBCs) were injected intraperitoneally in the early third trimester. The initial procedures were done by first injecting radiopaque dye into the amniotic cavity of affected pregnancies. X-ray still images were then used to localise the fetal abdomen using the radiopaque dye that had been swallowed by the fetus. Finally, proper placement of the needle in the peritoneal cavity was confirmed by injection of additional radiopaque dye. The first transfusion with fetal survival was reported by Liley and his colleagues in 1962, and by 1965, Liley reported on a further 16 transfused fetuses with a 38% survival rate.
Today, serial intrauterine transfusions (IUTs) to treat severe HDFN in association with maternal RBC alloimmunisation result in neonatal survival in well over 90% of cases. Advancements in ultrasound and IUT technique have certainly played a role in this improvement, but the prevention of Rhesus alloimmunisation by the introduction of Rhesus immunoglobulin (RhIG) has also decreased the disease burden of RhD disease in particular.
Epidemiology
The adoption of antenatal and postpartum RhIG has resulted in a marked reduction in the incidence of disease secondary to alloimmunisation by the Rh(D) antigen. Cases of RhD alloimmunisation still occur, however, either secondary to the failure to administer RhIG or secondary to inadequate dosing of RhIG in the presence of an undetected large fetomaternal haemorrhage. Even with the perfect implementation of RhIG, alloimmunisation resulting from incompatibility to the other Rhesus antigens and the non-Rhesus antigens will continue. For example, in east Asia, there is a lower proportion of Rh(D)-negative individuals, leading to a higher relative frequency of non–Rh(D)-related HDFN.
Pathogenesis
By 30 days of gestation, fetal RBCs express antigens, half of which are paternally derived and may be foreign to the maternal immune system. The transfer of RBCs across the fetal–maternal interface that occurs with spontaneous fetomaternal haemorrhage has been demonstrated to occur in almost all gestations with increasing frequency and volume as the pregnancy progresses. Although fetomaternal haemorrhage before or during birth is thought to be the primary factor in causing maternal alloimmunisation, a complete list of potential precipitating events is listed in Table 40.1 . The exposure of the maternal immune system to the foreign paternal antigen on the fetal RBCs is the impetus for the initiation of the HDFN process.
| Unprovoked | Provoked |
|---|---|
| Idiopathic-spontaneous | Termination of pregnancy |
| Delivery | Amniocentesis |
| Spontaneous abortion | Chorionic villus sampling |
| Ectopic pregnancy | Cordocentesis |
| Abruption | External cephalic version |
| Antepartum haemorrhage | Fetal intervention: fetoscopy, shunt, drainage |
| Trauma | |
| Manual removal of placenta |
Maternal Response
The maternal response to RBC foreign antigens is well documented. Cells of the innate immune system identify and destroy foreign cells and present the antigens to the humoural immune system, where specialised cells, specifically B lymphocytes, can recognise the antigen in future encounters and respond rapidly with the production of IgG antibodies. The initial development of immunoglobulin (Ig) G antibodies is a slow process, and it can take anywhere from 5 to 15 weeks for a human antiglobulin titre to be detected after a sensitising event. With few exceptions, the maternal response to the paternal antigen is not sufficient to have a significant effect on the fetus in the sensitising pregnancy. Exposure in a subsequent gestation when the precipitating antigen is present will trigger the rapid production of IgG antibodies. These IgG antibodies freely cross the placenta and bind to fetal RBCs with the offending antigen. These sensitised cells are then sequestered by the fetal spleen and destroyed by macrophages, resulting in fetal anaemia.
The maternal response to paternal antigens on fetal RBCs that have crossed the fetomaternal barrier is variable. Studies in Rh(D)-negative men have demonstrated that some individuals can be sensitised by an intravenous (IV) injection of as little as 0.1 mL of Rh(D)-positive blood, but 30% of individuals are still not sensitised after serial IV injections of 10 mL and 5 mL of Rh(D)-positive blood over a 6-month period. Volume is not the only factor responsible for initiating a maternal response to the paternal antigen on fetal RBCs. The maximum rate of sensitisation after exposure to a full unit of Rh(D)-positive blood is only 80%. Other factors thought to play a role are the frequency of the exposure, a protective effect of ABO incompatibility between the fetus and the mother and the status of the maternal immune system because immunodeficiency may prevent alloimmunisation.
Fetal Response
The severity of the fetal anaemia is primarily dependent on the concentration of maternal antibody crossing the placenta into the fetal compartment, but other factors also play a significant role. The following factors are all known to affect the development and severity of HDFN: (i) the subclass and glycosylation of the maternal antibody; (ii) the structure, site density, maturational development and tissue distribution of the fetal blood group antigens; (iii) the efficiency of transplacental IgG transport; (iv) the functional maturity of the fetal spleen; (v) polymorphisms affecting the Fc receptor function and (vi) the presence of human leukocyte (HLA)–related inhibitory antibodies. As an example, maternal antibodies cannot cause fetal anaemia if they cannot cross the placenta or if they are directed against an antigen that is poorly expressed or not expressed on the fetal RBCs. All IgG antibodies are freely transported across the placenta by pinocytosis; however, the IgG1 subclass is more efficiently transported and can more easily result in haemolysis of fetal RBCs. In contrast, IgM antibodies, such as antibodies to the Lewis, I, and P blood groups, do not cross the placenta and therefore do not result in HDFN. Similarly, antibodies to the Cromer blood group bind to placental proteins, preventing their access to the fetal compartment and protecting against the development of HDFN. Antibodies to the Lutheran, Vel and Cartwright blood groups are also unlikely to cause HDFN because these antigens are poorly developed on the RBCs during fetal life. Finally, fetal sex may play a role in the severity of HDFN. Ulm and colleagues demonstrated that Rh(D)-positive male fetuses have a 13-fold increased risk for developing hydrops and an odds ratio (OR) for perinatal mortality of 3.4 compared with Rh(D)-positive female fetuses.
As described earlier, the fetus is not an innocent bystander in the development of fetal anaemia. Extravascular haemolysis of antibody-bound fetal RBCs occurs via phagocytosis by reticuloendothelial macrophages in the spleen and liver. In severe forms of HDFN, intravascular haemolysis by direct lysis of antibody bound fetal RBCs also occurs. Severe anaemia resulting in fetal hydrops occurs when the fetal haemoglobin is greater than 7 g/dL below the mean for the estimated gestational age. This is usually consistent with a fetal haematocrit less than 15% and a fetal haemoglobin less than 5g/dL. Hydrops is associated with end-stage disease and an increased likelihood of a poor fetal outcome. Erythropoiesis is usually elevated in a fetus with the exception of cases of Kell alloimmunisation. The Kell antibody destroys RBC progenitor cells in the fetus and results in an earlier onset and more severe anaemia than that found with other alloantibodies. Hydrops is defined as fluid collections detected by ultrasound in two or more of the following fetal compartments: (i) skin oedema, (ii) ascites, (iii) pericardial effusion and (iv) pleural effusion. Placentomegaly and polyhydramnios are also often included in the diagnostic criteria. Ascites is usually the first finding, followed later by the development of pleural effusions and finally scalp and skin oedema. The exact mechanism for the development of fetal hydrops is not understood. Lower serum albumin levels secondary to the decreased production of proteins by the haematopoietically focused liver has been hypothesised to lead to decreased colloid osmotic pressure, third spacing of fetal fluid and finally the development of hydrops. This theory, however, is not supported by animal models in which the fetal plasma proteins have been replaced by saline or in human fetuses with congenital hypoalbuminaemia, neither of which develop hydrops despite low serum colloid osmotic pressure. Proposed theories to explain the pathophysiology of developing hydrops are (i) iron overload from haemolysed RBCs leading to increased free radical formation and the development of endothelial cell dysfunction, (ii) tissue hypoxia from anaemia leading to increased capillary permeability and (iii) elevated central venous pressures leading to the functional blockage of draining lymphatics. The last theory is supported by the fact that intraperitoneal transfusions (IPTs) are not as effective in hydropic fetuses. The development of hydrops is also gestational age dependent. Hydrops in association with HDFN at less than 22 weeks’ gestation is rare despite the presence of severe anaemia. Yinon and colleagues in their series found that 71% of fetuses with haemoglobin less than 5 g/dL did not demonstrate any evidence of hydrops before their first transfusion. The hyperbilirubinaemia resulting from the destruction of fetal RBCs does not pose the same danger to the fetus as the neonate because the placenta transports the bilirubin to the maternal side. Of specific clinical importance, it is imperative for the physician managing any HDFN case to continue to monitor the infant postnatally for haemolysis because the presence of maternal antibodies in the fetal circulation will continue to cause haemolysis after delivery and still poses a risk for poor neonatal outcomes. This is compounded in a neonate who has received multiple antenatal transfusions because her or his haematopoietic system will be suppressed with minimal reticulocytosis at the time of birth.
Pathogenesis
By 30 days of gestation, fetal RBCs express antigens, half of which are paternally derived and may be foreign to the maternal immune system. The transfer of RBCs across the fetal–maternal interface that occurs with spontaneous fetomaternal haemorrhage has been demonstrated to occur in almost all gestations with increasing frequency and volume as the pregnancy progresses. Although fetomaternal haemorrhage before or during birth is thought to be the primary factor in causing maternal alloimmunisation, a complete list of potential precipitating events is listed in Table 40.1 . The exposure of the maternal immune system to the foreign paternal antigen on the fetal RBCs is the impetus for the initiation of the HDFN process.
| Unprovoked | Provoked |
|---|---|
| Idiopathic-spontaneous | Termination of pregnancy |
| Delivery | Amniocentesis |
| Spontaneous abortion | Chorionic villus sampling |
| Ectopic pregnancy | Cordocentesis |
| Abruption | External cephalic version |
| Antepartum haemorrhage | Fetal intervention: fetoscopy, shunt, drainage |
| Trauma | |
| Manual removal of placenta |
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