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Stillbirth Associated With Infection in a Diverse U.S. Cohort

Page, Jessica M. MD; Bardsley, Tyler MS; Thorsten, Vanessa MPH; Allshouse, Amanda A. MS; Varner, Michael W. MD; Debbink, Michelle P. MD, PhD; Dudley, Donald J. MD; Saade, George R. MD; Goldenberg, Robert L. MD; Stoll, Barbara MD; Hogue, Carol J. PhD; Bukowski, Radek MD, PhD; Conway, Deborah MD; Reddy, Uma M. MD, MPH; Silver, Robert M. MD

doi: 10.1097/AOG.0000000000003515
Contents: Infectious Disease: Original Research

OBJECTIVE: To better characterize infection-related stillbirth in terms of pathogenesis and microbiology.

METHODS: We conducted a secondary analysis of 512 stillbirths in a prospective, multisite, geographically, racially and ethnically diverse, population-based study of stillbirth in the United States. Cases underwent evaluation that included maternal interview, chart abstraction, biospecimen collection, fetal autopsy, and placental pathology. Recommended evaluations included syphilis and parvovirus serology. Each case was assigned probable and possible causes of death using the INCODE Stillbirth Classification System. Cases where infection was assigned as a probable or possible cause of death were reviewed. For these cases, clinical scenario, autopsy, maternal serology, culture results, and placental pathology were evaluated.

RESULTS: For 66 (12.9%) cases of stillbirth, infection was identified as a probable or possible cause of death. Of these, 36% (95% CI 35–38%) were categorized as a probable and 64% (95% CI 62–65%) as a possible cause of death. Infection-related stillbirth occurred earlier than non–infection-related stillbirth (median gestational age 22 vs 28 weeks, P=.001). Fetal bacterial culture results were available in 47 cases (71%), of which 35 (53%) grew identifiable organisms. The predominant species were Escherichia coli (19, 29%), group B streptococcus (GBS) (8, 12%), and enterococcus species (8, 12%). Placental pathology revealed chorioamnionitis in 50 (76%), funisitis in 27 (41%), villitis in 11 (17%), deciduitis in 35 (53%), necrosis in 27 (41%), and viral staining in seven (11%) cases. Placental pathology found inflammation or evidence of infection in 65 (99%) cases and fetal autopsy in 26 (39%) cases. In infection-related stillbirth cases, the likely causative nonbacterial organisms identified were parvovirus in two (3%) cases, syphilis in one (2%) case, cytomegalovirus (CMV) in five (8%) cases, and herpes in one (2%) case.

CONCLUSION: Of infection-related stillbirth cases in a large U.S. cohort, E coli, GBS, and enterococcus species were the most common bacterial pathogens and CMV the most common viral pathogen.

Most cases of infection-related stillbirth are due to bacterial pathogens, of which Escherichia coli, group B streptococcus, and enterococcus species are the most common.

University of Utah Health Sciences, Salt Lake City, and Intermountain Health Care, Murray, Utah; RTI International, Research Triangle Park, North Carolina; the University of Virginia Healthcare, Charlottesville, Virginia; the University of Texas Medical Branch at Galveston, Galveston, Texas; Columbia University, New York, New York; the University of Texas Health Science Center at Houston, Houston, Texas; Rollins School of Public Health, Emory University, Atlanta, Georgia; the University of Texas at Austin, Austin, and the University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Yale School of Medicine, New Haven, Connecticut.

Corresponding author: Robert M. Silver, MD, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, UT; email:

This investigation was supported by the University of Utah Study Design and Biostatistics Center, with funding in part from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant 8UL1TR000105 (formerly UL1RR025764). This work, including the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review and approval of the manuscript, was supported by grant funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development: U10-HD045953 Brown University, Rhode Island; U10-HD045925 Emory University, Georgia; U10-HD045952 University of Texas Medical Branch at Galveston, Texas; U10-HDO45955 University of Texas Health Sciences Center at San Antonio, Texas; U10-HD045944 University of Utah Health Sciences Center, Utah; and U01-HD045954 RTI International, RTP.

Financial Disclosure Donald J. Dudley received funds for serving on the British Journal of Obstetrics and Gynecology Editorial Board. Radek Bukowski is an advisor and holds stock in Savran Technologies Inc., a company that developed technology to isolate ultra-rare cells from blood for noninvasive diagnostics. The other authors did not report any potential conflicts of interest.

Presented in part at the Society for Maternal-Fetal Medicine's 37th Annual Pregnancy Meeting, January 29–February 2, 2018, Dallas, Texas.

Comments and views of the author(s) do not necessarily represent the views of the NICHD.

Each author has confirmed compliance with the journal's requirements for authorship.

Peer reviews and author correspondence are available at

© 2019 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.