Diagnostic Yield Of Serologic Evaluation For Neonatal Alloimmune Thrombocytopenia (NAIT) In Cases With Fetal Abnormalities Without Documented Thrombocytopenia

NAIT, in which mothers are sensitized to a paternally derived fetal platelet antigen, is known to be a major cause of fetal in utero intracranial hemorrhage (ICH). The diagnosis can be serologically confirmed by demonstrating a platelet antigen (HPA) incompatibility between the parents (or between mother and fetus or neonate) and detection of maternal antibody with matching specificity.

An increasing number of NAIT serologic evaluations are being referred based on a clinical presentation of a fetal hemorrhage or an abnormality thought to be due to such a hemorrhage, usually without a fetal platelet count. We sought to compare the diagnostic yield of our laboratory’s standard NAIT evaluation in cases referred because of in utero ICH without known fetal platelet counts with the yield in a previously reported series of cases that were referred usually because of documented fetal or neonatal thrombocytopenia.

Between July 2000 and April 2013, we were consulted by referring physicians on 33 cases in which a fetal abnormality had been detected (usually by ultrasound or MRI) that was either a frank hemorrhage or could have been caused by hemorrhage. No fetal platelet counts had been done. In all cases, no previous sibling had been recognized to have had thrombocytopenia. Of the 33 evaluations performed, 18 were done during an affected pregnancy and 15 were performed after an affected pregnancy had occurred. There were 25 frank ICH, 4 porencephalic cysts (PEC), 2 hydrocephalus only, 1 fetal stroke and in 1 case the abnormality was not specified. The abnormalities were detected between 20 weeks and 35 weeks gestation, median 24 weeks. 15 were detected at 24 weeks or earlier, 11 between 25 and 31 weeks and 2 at 32 weeks or later. In 5 cases (all in the previous pregnancy group) the week in gestation when the abnormality was detected was not known.

The standard NAIT evaluation involved testing of maternal serum for antibody to intact platelets, pooled class I HLA, and platelet glycoproteins (GP) including GPIIb/IIIa, GPIa/IIa, GPIb/IX and GPIV derived from blood group O panel platelets of known HPA phenotype. Panel platelets were known to express both alleles (-a and –b) of HPA-1 to 5 and -15. In addition, maternal serum was tested against intact paternal platelets and paternal platelet GPIIb/IIIa. Genotyping was performed on genomic DNA from both parents for HPA -1 to 6, -9 and -15 alleles.

In only 2 of the 33 cases (6.4%) was a diagnosis of NAIT serologically confirmed: 1 due to an HPA-15a antibody detected during a current affected pregnancy complicated by a fetal PEC discovered at 20 weeks; and another due to an HPA-5b antibody detected 4 months after a pregnancy complicated by a fetal ICH discovered at 21 weeks gestation.

In our previously reported series (Transfusion 44:1220, 2004) NAIT was serologically diagnosed in 31% of 1162 suspected cases, almost all of which were referred based on known fetal or neonatal thrombocytopenia. Moreover, the severity of the fetal abnormalities in these cases (PEC and ICH) occurring prior to 21 weeks gestation is unusual in non-HPA-1a related NAIT, leading to some uncertainty as to whether the HPA antibodies detected in these 2 cases were causal.

Although the diagnostic yield of a serologic NAIT evaluation is lower when the clinical indication is either a frank fetal hemorrhage or an abnormality that is likely caused by hemorrhage and no fetal platelet count is available Vs in cases in which fetal or neonatal thrombocytopenia is documented (6.4% Vs 31%), testing may still be reasonable to pursue, given the potential importance for managing subsequent pregnancies in such families.