Neonatal disease in neutral endopeptidase alloimmunization:: lessons for immunological monitoring

Neutral endopeptidase (NEP) alloimmunization has recently been determined to cause severe forms of neonatal disease as a result of the transplacental passage of anti-NEP antibodies. However there is a wide spectrum of neonatal disease variability. We present the medical histories of a large family, specifically of two alloimmunized sisters in their second pregnancy in whom we established the basis of immunological surveillance and therapeutic intervention during pregnancy and after delivery. One mother developed dramatically high titers of IgG1 and IgG4, and was treated with IvIg and one plasma exchange, both of which substantially reduced the anti-NEP Ab titer. However, the neonatal syndrome observed in her infant was severe, partly due to treatment delay. Anti-NEP Ab were also found in the mother's milk and the infant's urine. In contrast, the other mother had a normal second pregnancy and delivered a healthy neonate, which was related to the fact that she only produced the non-complement activating IgG4 subclass of anti-NEP antibodies. Thus, anti-NEP Ab (titer and subclass) seem to be highly sensitive biomarkers of neonatal risk. Interventional strategy aimed at reducing anti-NEP titer, should be started early during pregnancy and, possibly, even before pregnancy in those mothers producing anti-NEP IgG1. Careful monitoring of anti-NEP Ab titer and subclass is mandatory in NEP-deficient mothers during their pregnancies.