Defining the Mechanism of Complement Pathway Activation during Pregnancy and its Role in Adverse Pregnancy Outcomes in Sickle Cell Disease - PROJECT SUMMARY/ABSTRACT The complement system and its careful regulation play critical dual roles in maintaining healthy pregnancy – combating infection and allowing tolerance of the semi-allogenic fetus. The trigger of complement activation and pathway(s) involved in pregnancy remain elusive. Complement dysregulation or excess activation is implicated in pregnancy loss, preterm birth, and development of pre-eclampsia and the HELLP syndrome. Sickle cell disease (SCD) is a thromboinflammatory disorder with high rates of adverse pregnancy outcomes (APOs), including severe pre-eclampsia, preterm birth, fetal growth restriction, and fetal loss. Complement activation is implicated in SCD-related organ damage, though the role of complement in SCD pregnancies has not been explored. In the US, maternal mortality in women with SCD is ~10 times higher than in black pregnant people without SCD, highlighting the need for translational studies to address these pathobiologic mechanisms. Dr. Gerber has initiated prospective collection of serial blood samples and clinical data during pregnancy in SCD and generated exciting preliminary data suggesting that classical complement is triggered by IgM in pregnancy. This proposal employs the bioluminescent modified Ham (bmHam), a novel, functional assay of membrane- directed complement activation that has the ability to test specific complement pathways using targeted inhibitors. We will prospectively collect serial samples from healthy pregnant women (controls) and women with HbSS disease during pregnancy. We will define the pathway and triggers of increased complement activity in controls and pregnant women with HbSS disease. Using the bmHam, we will compare differences in complement activity by trimesters between pregnant women with HbSS disease and controls. We also will test the association between increased complement activity and the development of APOs in women with HbSS disease. Lastly, we will evaluate the influence of SCD genotype (e.g., HbSS, HbSC) on complement activity in non-pregnant women of reproductive age to determine expansion of our pregnancy cohort. Elucidating the role of complement activation as a mechanism and biomarker for APOs in SCD pregnancies will provide a tool for risk stratification and potentially early intervention strategies to be tested in future clinical trials. This mentored research and career develop award will facilitate Dr. Gerber’s long-term goal of becoming a translational investigator in classical hematology with a focus on thromboinflammatory disorders during pregnancy. Dr. Gerber’s interdisciplinary team of mentors and advisors have extensive expertise in complement- mediated disorders, bioassay development and translational research methods, reproductive health in SCD, maternal fetal medicine, placental biology, and biostatistics. The additional proposed experiential and didactic training in reproductive research methods, longitudinal cohort analysis, prospective cohort study design and biomarker testing, and clinical trial design will enable her to transition to an independent investigator at the intersection of hematology and women’s health bridging clinical and laboratory researchers.
