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Activated protein C in normal human pregnancy and pregnancies complicated by severe preeclampsia: A therapeutic opportunity?*

von Dadelszen, Peter MBChB, DPhil; Magee, Laura A. MD, MSc; Lee, Shoo K. MBBS, PhD; Stewart, Shawn D. BA; Simone, Carmine MD; Koren, Gideon MD; Walley, Keith R. MD; Russell, James A. MD

Review Article

Objectives: Given the efficacy and safety of recombinant human activated protein C (rhAPC) in the systemic inflammatory response syndrome, this study was designed to review the evidence for a role for APC in the pathogenesis of preeclampsia. Preeclampsia is a proinflammatory and procoagulant state, and it is a pregnancy-specific condition that mimics the systemic inflammatory response syndrome. rhAPC reduces mortality in patients with systemic inflammatory response syndrome and could potentially have a role as disease-modifying therapy in preeclampsia. To determine which patients would be offered rhAPC, the literature pertaining to fetal/neonatal outcomes for preeclampsia remote from term, transplacental transport of protein C, and pregnancy experience with the compound were reviewed.

Data Sources: MEDLINE, review papers, hand searches of relevant nonindexed journals, and the bibliographies of relevant textbooks and articles reviewed.

Study Selection: Randomized controlled trials were considered to provide the best quality of clinical data. Case-control series were considered over uncontrolled data. Some data were not available in the published literature (e.g., neonatal outcomes at various gestational ages and birthweights after a hypertensive pregnancy; and transplacental transfer of protein C), and these data were determined by us.

Data Extraction: Data were extracted by systematic review onto data collection sheets. Because of the quality of the data, this review is primarily qualitative.

Data Synthesis: APC levels fall during normal gestation, returning to normal values by 6 wks postpartum. Limited data suggest that early onset preeclampsia is a state of further, and inappropriate, reduction in APC. Preeclampsia resembles systemic inflammatory response syndrome in this regard. After hypertensive pregnancies, neonates have a 50% chance of intact survival if delivered after 27 + 0 wks of gestation with a birthweight of >600 g. It would seem ethical to offer women with preeclampsia with <50% chance of intact perinatal survival novel and potentially disease-modifying therapy such as rhAPC, especially as there is no transplacental transfer of protein C. Limited evidence would support the use of rhAPC in women with severe postpartum preeclampsia.

Conclusions: Sufficient data exist to support the use of rhAPC in phase II clinical studies for women with either early onset preeclampsia or severe or deteriorating postpartum disease.

From the Departments of Obstetrics and Gynaecology (Division of Maternal-Fetal Medicine) (PvD), Medicine (Divisions of General Medicine [LAM] and Intensive Care [KRW, JAR]), and Paediatrics (Centre for Community Health and Health Evaluation Research) (SKL, SDS), University of British Columbia, Vancouver, British Columbia, Canada; and the Motherisk Program (LAM, CS, GK), Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.

Address requests for reprints to: Peter von Dadelszen, MBChB, DPhil, 2H30-4500 Oak Street, Vancouver, BC, Canada V6H 3N1. E-mail: pvd@cw.bc.ca

Supported, in part, by the BC Research Institute for Children’s and Women’s Health (PvD), the BC Women’s Hospital and Health Centre Foundation (LAM), and grants 1520 and CAAA-40503 from the Medical Research Council of Canada (SKL, SDS).

Dr. Russell was a site investigator in the phase II and phase III trials of recombinant human activated protein C in sepsis and has been a consultant to Eli Lilly Inc. of Canada.

Sufficient data exist to support the use of recombinant human activated protein C in phase II clinical studies for women with either early onset preeclampsia or severe or deteriorating postpartum disease.

© 2002 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins