High frequency of critical and rising titers in alloimmunized pregnancies with antigen-negative fetuses.

Introduction: In this study we performed a retrospective chart review of alloimmunized pregnancies undergoing monitoring for hemolytic disease of the fetus and newborn (HDFN) in a cohort with known fetal antigen (FA) status. The objective was to compare fetal monitoring with titers and middle cerebral artery peak systolic velocity Doppler (MCA-PSV Doppler) in FA-negative and FA-positive pregnancies and to understand downstream impacts of screening with titers in FA-negative pregnancies. Methods: Retrospective chart review of alloimmunized pregnant patients who underwent FA cell-free DNA (cfDNA) analysis and participated in a registry in which neonatal genotyping was performed to confirm FA cfDNA results. Patients were divided into FA-positive or FA-negative cohorts based on the FA genotypes. Medical records were reviewed to characterize monitoring for anemia, titer results, MCA-PSV Doppler results, and whether interventions were performed. Fischer's exact or chi-square tests were performed as appropriate to ascertain differences between the cohorts. Results: Sixty-nine alloimmunized pregnant individuals were included. Forty pregnancies (58%) were FA positive. Of 29 FA-positive pregnancies who had titers more than once, 20 (69%) had titers that rose over two or more time points. There were 29 FA-negative pregnancies (42%). Of 20 FA-negative pregnancies that underwent titers more than once, 10 (50%) had titers that rose over two or more time points. The FA-positive and FA-negative cohorts had similar proportions of pregnancies that reached critical titers-70% (28/40) and 69% (20/29), respectively. In the FA-positive cohort 14 of 34 participants who underwent MCA-PSV Doppler reached greater than 1.5 multiples of the median (MoM), suggestive of fetal anemia. One patient in the FA-negative cohort reached 1.5 MoM. Conclusions: Titers frequently yield elevations that, while reflective of maternal alloimmunization, are not indicative of positive FA status or risk for HDFN in antigen-negative pregnancies. Such results lead to unnecessary monitoring, including MCA-PSV Doppler as well as invasive interventions. These outcomes can be avoided using methods including FA cfDNA, which has been shown to be highly accurate. These results suggest that monitoring for fetal anemia should be discontinued if FA cfDNA has determined the FA status is negative, as this will reduce downstream burdens and risks to alloimmunized patients who are not at risk for HDFN.