Introduction

The genetic characterization of many blood antigen systems has enabled the development of molecular diagnostic assays capable of providing physicians with information that can greatly improve patient care. This technology, when applied to the field of obstetrics, is useful in identifying those fetuses at risk for immune cytopenic disorders. In these disorders, the mother lacks a genetic marker that the child might inherit from the father. Offspring of such parents, therefore, have at least a 50% chance of inheriting the paternal alloallele to which the mother might be immunologically sensitized. If the mother has been previously sensitized to this paternal antigen, either through a previous pregnancy or blood transfusion, the fetus will be at risk for the immune cytopenic disorder, because maternal antibodies can cross the placenta and mediate destruction of the targeted cell. Fetuses that do not inherit the alloal-lele will not be at risk.

Fetomaternal incompatibilities involving several platelet alloantigens (Table 1) might result in neonatal alloimmune thrombocytopenic purpura (NATP), a condition in which maternal IgG antibodies cross the placenta and destroy fetal platelets, predisposing the fetus to bleeding, possible brain damage, or even death. Incompatibilities within the Fcy III receptor b (CD16) and HNA-2 (CD177) antigen might result in neonatal alloimmune neutropenia (NAN), a condition in which the fetal neutrophils are destroyed as a result of a maternal IgG antibody, leaving the newborn susceptible to infection. Hemolytic disease of the newborn (HDN), the focus of this chapter, can occur when there exists fetomaternal incompatibilities within any number of different erythrocyte antigen systems, including the RhD, RhCc, RhEe, Kell, Kidd, and Duffy antigen systems. HDN results in the destruction of fetal erythrocytes as a result of the presence of a maternal IgG antibody. Permanent neurological damage can be a result of HDN, and in extreme cases, loss of the fetus or death of the neonate could occur. Investigative and therapeutic measures used for alloimmunized pregnant women involve some risk to the fetus. Currently, women who present with alloantibody titers to red cell antigens will be monitored by amniotic fluid spectrophotometric analysis to detect deviation from linearity at 450 nm, the wavelength at which bilirubin absorbs (1). Accurate determination of fetal risk is achieved through serial analysis, generally weekly for several weeks. Although the risk of placental trauma during amniocente-sis has been greatly reduced since the introduction of ultrasound imaging techniques, there still remains a 2% risk of placental trauma (2). Alternatively, percutaneous umbilical blood sampling allows direct measurements of all fetal blood parameters, including blood groups. However, because of the risk of fetomaternal hemorrhage and further sensitization of the mother, its use is limited. Prenatal identification of the relevant genotypes for fetuses potentially at risk for HDN requires fetal DNA isolated from only a single amniocentesis. This can obviate the need for expensive and invasive monitoring throughout the pregnancy when fetuses are shown to be compatible with sensitized mothers and therefore not at risk. Genetic identification of fetuses at risk, on the other hand, allows for appropriate monitoring and early intervention.

This chapter focuses on typing red cell antigen systems involved with the development of HDN and the caveats associated with this area of molecular diagnostics, namely allelic variants and the contamination of fetal samples with maternal (nucleated blood) cells. Many hematologic antigen systems arise through single-nucleotide polymorphisms (SNPs), and in recent years, numerous technologies have been developed that enable rapid and accurate SNP typing that utilize various allelic discrimination biochemistries, reaction formats, and detection methods. These methods include fluorescent bead-based technologies (Luminex, Illumina, Q-dot), automated enzyme-linked immunosorbant (ELISA) assays (Orchid Biocomputer), fluorescent detection of pyrophosphate release (pyrosequencing), fluorescence resonance energy transfer (FRET)-based cleavase assays (Third Wave Technologies) (3,4), and others. These

Table 1

Human Platelet Antigens0

Antigens

Other

Phenotypic

Glycoprotein Location/

Nucleotide

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