Stillbirth Prevention by Combating Placental Rejection

Abstract

As a semi-allogeneic organ, the human placenta must be tolerated by the maternal immune system throughout pregnancy in order to maintain the survival and development of the fetus. Any failure in this process is suspected to underpin several pregnancy complications including miscarriage, stillbirth and perinatal death. Chronic histiocytic intervillositis (CHI) is one such example of a severe inflammatory placental lesion, characterised by maternal macrophage infiltration of the intervillous space. Presently, CHI can only be diagnosed by histopathological examination (usually performed) after poor pregnancy outcome has already occurred, and there is no standardised protocol for its prevention or treatment. CHI’s cause remains largely unknown, though its incidence in women with autoimmune disease, high recurrence rate and similarities shared with rejected allografts has given rise to the theory that it is a disorder of maternal anti-fetal rejection. This study aimed to investigate this hypothesis by characterising the placental inflammatory profile, evaluating the efficacy of immunomodulatory medication in reducing CHI severity, and applying crossmatching techniques commonly used in the prediction of antibody-mediated allograft rejection to affected women. Cases of CHI were identified retrospectively from medical records and clinical data on treatment and pregnancy outcomes collected. In participants who were treated with one or both of prednisolone and hydroxychloroquine in their subsequent pregnancy following diagnosis, CHI severity was reduced in 86.7% of cases compared to 33.3% of those treated without (p=0.02). A reduction in placental lesion severity was also associated with a 62.3% increase in livebirth rate (p=0.003). These data provide preliminary evidence to support the use of immunomodulatory medication in the treatment of CHI. Unbiased computerised quantification of immune cells in untreated (index) cases of CHI showed a 28-fold median increase in intervillous CD68+ macrophages compared to healthy controls (p

Date of Award	1 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Ian Crocker (Supervisor) & Alexander Heazell (Supervisor)