Immune Hydrops Fetalis

Definition

Immune hydrops is defined as the diagnosis of fetal hydrops in the presence of a maternal immunologic response to a paternally derived red blood cell antigen in the fetus. Fetal hydrops is further defined as the accumulation of fluid in at least two of the following fetal serous compartments: abdomen, pleural cavity, pericardium, and skin. Polyhydramnios and placental thickening are also commonly included in the diagnostic criteria.

Prevalence and Epidemiology

The incidence of Rh alloimmunization in the United States is reported to be 6.8 : 1000 live births. The adoption of prenatal and postpartum RhIG has resulted in a marked reduction in the incidence of disease caused by the presence of the paternal Rh(D) antigen, however, 1%–3% of Rh(D)-negative women will still become alloimmunized despite proper prophylaxis. There has been a corresponding increase in the incidence of other Rh antigens and non-Rh antigens that can cause HDFN, with a reported incidence for these antigens of 0.2% of pregnancies. A recent Canadian study identified 559 cases of alloimmunization among 155,153 pregnancies for an incidence of 0.36%. Only 34 (0.06%) of the affected pregnancies had adverse outcomes defined by the need for prenatal therapy (maternal plasmapheresis or intrauterine transfusions), an intrauterine death attributed to alloimmunization, preterm delivery secondary to HDFN, or neonatal treatment (intravenous immunoglobulin [IVIg] administration, transfusion, or exchange transfusion). A prospective analysis of over 300,000 women in The Netherlands showed that the antibodies most commonly associated with HDFN were anti-E, followed in decreasing frequency by anti-D, anti-Kell, and anti-c antibodies. The decreasing prevalence of anti-D antibodies was also shown in the aforementioned Canadian study with anti-E (43%), anti-c (13%), anti-Jk ^a (9%), and anti-C (5%) antibodies making up a majority of affected women, with anti-D accounting for only 0.4% of women with a single antibody identified. Currently in the United States, HDFN causes approximately 200 perinatal deaths yearly, most from alloimmunization to the Rh(D), Rh(c), and Kell antigens.

Etiology and Pathogenesis

Fetal red blood cells express antigens by 30 days of gestation, half of which are paternally derived. The transfer of fetal antigens across the fetal-maternal interface occurs in almost all gestations with increasing frequency and volume as the pregnancy progresses. Fetomaternal hemorrhage before or during birth is thought to be the primary factor in maternal alloimmunization. A list of potential spontaneous and iatrogenic events associated, with maternal sensitization are listed in Table 123.1 .

The maternal response to foreign antigen is well documented. Cells of the innate immune system identify and destroy foreign cells and present the antigens to the humoral immune system, where specialized B lymphocytes can recognize the antigen in future encounters and respond rapidly with immunoglobulin (Ig) G antibodies. The initial development of IgG antibodies is a slow process taking 5–15 weeks for a human antiglobulin titer to be detected after a sensitizing event. With few exceptions, the maternal response to the paternal antigen is not sufficient to affect the sensitizing pregnancy. Exposure to a subsequent gestation with the precipitating antigen present will trigger the rapid production of IgG antibodies. These IgG antibodies freely cross the placenta and bind to fetal red blood cells with the offending antigen. These marked cells are then sequestered by the fetal spleen and destroyed by macrophages resulting in fetal anemia if the response is significant enough.

The maternal response to paternal antigens on fetal red blood cells that cross the fetomaternal barrier is variable. Studies in Rh(D)-negative men have demonstrated that some individuals can be sensitized by as little as 0.1 mL of Rh(D)-positive blood, whereas 30% of individuals are still not sensitized after subsequent exposure to 10 mL of Rh(D)-positive blood. Other factors thought to play a role in sensitization are the frequency of the exposure, the ABO compatibility between the fetus and the mother, the antibody class, placental transport of the antibody, the maturity of the fetal red blood cell antigen, and the status of the maternal immune system as immunodeficiency may prevent alloimmunization.

Hydrops occurs when the fetal hemoglobin is greater than 7 g/dL below the mean for the estimated gestational age. This is consistent with a fetal hematocrit and hemoglobin of less than 15% and 5 g/dL, respectively. Erythropoiesis is elevated in the fetus with the exception of alloimmunization caused by anti-Kell antibodies that destroy erythroid precursor cells and result in an earlier onset and more severe anemia than that found with other alloantibodies.

The exact mechanism for the development of hydrops is not understood. Lower serum albumin has been hypothesized to lead to decreased colloid osmotic pressure, the third-spacing of fetal fluid, and finally the development of hydrops. This theory, however, is not supported by animal models or in human fetuses with hypoproteinemia. Other proposed theories for hydrops are: (1) iron overload from hemolyzed red blood cells leading to increased free radical formation and endothelial cell dysfunction, (2) tissue hypoxia from anemia leading to increased capillary permeability, and (3) elevated central venous pressure resulting in lymphatic blockage. The development of hydrops is also gestational-age dependent. Hydrops under 22 weeks' gestation is rare despite the presence of severe anemia.