Identification of Early Predictors of Fetomaternal Hemorrhage And Development Of An Automated Screening Strategy For At-Risk Pregnancies

1. Introduction:

The objective of this study is to identify candidate clinical predictors of fetomaternal hemorrhage (FMH) and to devise a screening strategy to identify pregnancies affected by the condition before the fetus is compromised by severe anemia.

Fetomaternal hemorrhage is a condition in which the placental barrier fails and the fetus "bleeds" into the maternal circulation. When functioning correctly, the placenta allows transfer of nutrients and waste between the mother and fetus while keeping the cellular components of blood separate. It is not uncommon for small amounts of fetal blood to reach the maternal circulation without adverse effect on the fetus. In fact, mild FMH can be detected in up to 75% of normal pregnancies. In approximately 3 in 1000 pregnancies, however, the volume of fetal blood transferred to the mother causes clinically-significant anemia in the fetus. Fetal anemia can cause significant morbidity and mortality. In fetuses who survive severe anemia, life-long disability is common.

Diagnosis of FMH is most commonly made after an adverse fetal or neonatal outcome has occurred, indicating the need for testing. Early risk factors for FMH are unknown. Clinical predictors of FMH have been suggested, but have not been born out in retrospective study. Current standard of care testing for FMH, the Kleihauer-Betke (KB) acid elution test, is labor-intensive and time-consuming, and therefore expensive. Additionally, the KB test is observer-dependent and can be significantly affected by variations in sample preparation. No screening protocol for FMH with automated laboratory testing appropriate for use in the general pregnant population exists.

Specific Aim: To identify an appropriate laboratory protocol for diagnosis of fetomaternal hemorrhage by prospective study and to pilot a study intended to determine early clinical predictors of mild fetomaternal hemorrhage. 2. Background and Significance Fetomaternal hemorrhage occurs when the normal flow of blood within the placenta is disrupted and the cellular components of fetal blood cross into the maternal circulation. A healthy placenta permits transfer of dissolved substances between the mother and fetus while keeping the cellular components of the two circulations separate. It is common for the placental filter to "leak" during normal pregnancies, resulting in transfer of small volumes of fetal whole blood into the maternal bloodstream. Volumes of fetal blood under 1 mL can be detected in up to 75% of pregnancies. This volume of blood loss is thought to be clinically insignificant to the fetus. Severe FMH with a large volume of blood transfer from the fetus to the mother is less common. Although the exact volume of blood transfer needed to classify FMH as "severe" is debated, it is clear that significant acute or chronic hemorrhage leads to adverse perinatal outcome. Estimates of the incidence of severe FMH vary, primarily because no comprehensive epidemiologic studies of the condition exist. Estimates based on screening for Rh alloimmunization in Rho(d) negative women suggest that severe FMH occurs in 1-3 of 1000 pregnancies, , but accounts for almost 14% of otherwise unexplained fetal deaths. Large volume FMH can result in severe fetal anemia. Although fetal anemia can manifest in utero with recognized hydrops fetalis or intrauterine growth restriction, more commonly there are no outward signs of FMH-related severe anemia before stillbirth, fetal distress at delivery, or neonatal critical illness. The immediate sequelae of severe FMH for neonates that survive delivery include devastating illnesses such as persistence of the fetal circulation, hypovolemic shock, and hypoxic-ischemic encephalopathy. Ultimate detrimental outcomes include high rates of mental retardation, cerebral palsy, neurologic devastation, and death. Despite these consequences, and a suspected recent rise in incidence of severe FMH, early predictors of severe FMH remain unknown and no cause of hemorrhage can be identified in over 80% of cases. Maternal or pregnancy risk factors appropriate for early screening or diagnosis of severe FMH in the general pregnant population have not been elucidated. , If identified prior to delivery, fetal anemia from FMH can be successfully managed by intrauterine fetal transfusion and delivery prior to the onset of labor. , Outcomes following treatment of fetal anemia with fetal transfusion, even repeated fetal transfusion, are encouraging. Thus, empirical predictors of FMH would offer immediate promise for improving clinical outcomes. The social and financial cost of both initial intensive care and long-term chronic care for children with cognitive and motor disability resulting from FMH is substantial. There is considerable need for early risk identification and a practical screening strategy to mitigate the human and economic costs of severe FMH.