This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Neonatal lupus (NL) is the name given to a group of conditions that can affect the babies of mothers who have certain autoantibodies against components of the body's cells that are called SSA/Ro and SSB/La. NL can appear as a temporary rash that usually goes away by the time the baby is 6 months old, or very rarely an abnormal blood or liver condition that also improves with time - or it can cause permanent and often life-threatening damage to the fetal heart, known as congenital heart block (CHB). In women with anti-Ro/La antibodies who are pregnant for the first time, only about 2% of the babies will develop CHB. But for a woman who has already had a child with CHB or NL rash, the risk of CHB in her next pregnancy is nearly 20%. Unfortunately, once complete (third degree) heart block has been unequivocally identified in a fetus, it has never been reversed with any of the therapies that have been tried to date. Our previous studies strongly indicate that scarring of the conduction system (the heart's own natural 'pacemaker'), a consequence of inflammation triggered by the mother's antibodies, damages or even destroys the cells that allow the heart to beat at a normal rhythm. Instead, the damaged heart beats extremely slowly, to an extent that is fatal in about a fifth of the affected babies (with most deaths occurring as fetal demises). Nearly all surviving children with CHB require permanent implantation of a pacemaker device. Because it is so difficult to treat or repair the damaged heart, a high-priority strategy is to try to prevent the inflammatory process before irreversible scarring can occur.
The aim of this translational proposal is to determine whether treating the pregnant mother with intravenous immune globulin (IVIG) will prevent the development of CHB. (It should be noted that IVIG has been established as a safe treatment during pregnancy for other conditions.) Basic research experiments are also planned to identify the mechanism(s) by which this therapy might be preventative. Our group has assembled the largest cohort of families with affected children and their unaffected siblings, through the establishment of the U.S.-based national Research Registry for Neonatal Lupus (RRNL), the PR Interval and Dexamethasone Evaluation (PRIDE) study, and international cooperative efforts. We have focused nearly two decades of research on the study of NL, integrating both basic science ('bench') and clinical ('bedside') discoveries. Based on our previous studies, we consider it feasible that we will be able to enroll women who have previously had a child with NL (rash or CHB) and are currently pregnant, in numbers sufficient to determine the effectiveness of IVIG treatment in preventing CHB. In the first two years of the study, we aim to follow 19 pregnant women who have previously had a child with CHB or NL rash, in whom we would expect to see ~4 cases of CHB develop in their current pregnancies if untreated. If fewer than 3 cases of CHB develop in the 19 pregnancies treated with IVIG, we would consider the treatment worthy of further study, and continue the trial for two additional years in which we would aim to treat 35 additional pregnant women. To be able, at last, to prevent this life-threatening disease in babies would be an enormous benefit to these mothers and their families.
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