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The Lewis and soluble blood group substances A, B, and H, are present in AF as early as 9–24 weeks of gestation.^{225, 257} The best evidence suggests that the AF Lewis substances and secretor types are of fetal origin. Because of their molecular weights (about 300,000), the soluble blood group substrates do not easily cross fetal membranes. Because the fetal ABH secretor and Lewis types can be determined from AF in early gestation, they were useful for their linkage relationships to genetic disease. Examples include the linkage relationships of the ABO locus to the nail–patella syndrome³⁷⁴ now detectable by analysis of the LMX1b gene³⁷⁵ and the linkage of the secretor and myotonic dystrophy loci.³⁷⁶ Milunsky et al.³⁷⁷ reported the prenatal diagnosis of six cases and stressed the risk of neurologic impairment when the mother herself is affected. Myotonic dystrophy is now accurately diagnosed by trinucleotide repeat analysis (see Chapter 14).³⁷⁸

The development of fetoscopy facilitated the measurement of factor VIII coagulant antigen and factor VIII‐related antigen. The ratio of factor VIII coagulant antigen to factor VIII‐related antigen has a fairly constant value, and in three affected fetuses, a very low ratio was pathognomonic of classic hemophilia. This immunologic test does not apply to all families at risk, and has been replaced by molecular analysis (see Chapter 14).

Cell‐free HLA‐A and ‐B maternal and paternal antigens have been detected in AF obtained between 16 and 18 weeks of gestation. HLA antigens can be detected in fetal tissues as early as the sixth week of pregnancy, and defective synthesis is seen in severe combined immunodeficiency syndrome.³⁷⁹ Kleinbauer et al.²⁰⁶ studied blood coagulation and fibrinolytic factor activities in the AF. Prothrombin rose during the last trimester, while factor X activity decreased. Plasminogen, α₁‐antitrypsin, α₂‐antiplasmin, antithrombin III, and α₂‐macroglobulin levels did not change significantly during gestation.