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Infection and Immunity, April 2004, p. 2272-2279, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.2272-2279.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Fusobacterium nucleatum Induces Premature and Term Stillbirths in Pregnant Mice: Implication of Oral Bacteria in Preterm Birth

Yiping W. Han,1,2* Raymond W. Redline,2 Mei Li,1 Lihong Yin,1 Gale B. Hill,3 and Thomas S. McCormick4

Department of Periodontics, School of Dental Medicine,1 Departments of Pathology and,2 Dermatology, School of Medicine, Case Western Reserve University, Cleveland, Ohio,4 Departments of Obstetrics and Gynecology and Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina3

Received 11 September 2003/ Returned for modification 7 November 2003/ Accepted 2 January 2004

Fusobacterium nucleatum is a gram-negative anaerobe ubiquitous to the oral cavity. It is associated with periodontal disease. It is also associated with preterm birth and has been isolated from the amniotic fluid, placenta, and chorioamnionic membranes of women delivering prematurely. Periodontal disease is a newly recognized risk factor for preterm birth. This study examined the possible mechanism underlying the link between these two diseases. F. nucleatum strains isolated from amniotic fluids and placentas along with those isolated from orally related sources invaded both epithelial and endothelial cells. The invasive ability may enable F. nucleatum to colonize and infect the pregnant uterus. Transient bacteremia caused by periodontal infection may facilitate bacterial transmission from the oral cavity to the uterus. To test this hypothesis, we intravenously injected F. nucleatum into pregnant CF-1 mice. The injection resulted in premature delivery, stillbirths, and nonsustained live births. The bacterial infection was restricted inside the uterus, without spreading systemically. F. nucleatum was first detected in the blood vessels in murine placentas. Invasion of the endothelial cells lining the blood vessels was observed. The bacteria then crossed the endothelium, proliferated in surrounding tissues, and finally spread to the amniotic fluid. The pattern of infection paralleled that in humans. This study represents the first evidence that F. nucleatum may be transmitted hematogenously to the placenta and cause adverse pregnancy outcomes. The results strengthen the link between periodontal disease and preterm birth. Our study also indicates that invasion may be an important virulence mechanism for F. nucleatum to infect the placenta.

* Corresponding author. Mailing address: Department of Periodontics, Case Western Reserve University School of Dental Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-4905. Phone: (216) 368-1995. Fax: (216) 368-0145. E-mail: ywh2{at}case.edu.

Editor: A. D. O'Brien

Infection and Immunity, April 2004, p. 2272-2279, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.2272-2279.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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