Abstract
Lyme disease is an inflammatory syndrome caused by infection with Borrelia burgdorferi. Although this syndrome has important implications for human pregnancy, little is known about gestational infection with B. burgdorferi. Fetal death occurred in 33 of 280 gestational sacs (12%) in 39 C3H/HeN female mice infected by intradermal injection of B. burgdorferi 4 days after mating (acute infection), compared with 0 of 191 sacs in 25 control mice (P = 0.0001). Forty-six percent of acutely infected mice suffered at least one fetal death, compared with none of the control animals (P = 0.0002). There were no fetal deaths in 18 C3H/HeN mice infected 3 weeks prior to mating (chronic infection). A sensitive PCR technique detected B. burgdorferi DNA in the uteri of acutely infected mice but did not detect DNA in the uteri of controls or chronically infected mice. Spirochete DNA was only rarely detected in fetal tissues, and its presence was not required for fetal death. The inclusion of an internal competitive PCR target indicated that the lack of B. burgdorferi sequences in fetal DNA was not due to the presence of a PCR inhibitor. Histologic analysis of gestational tissues from infected animals demonstrated nonspecific pathology consistent with fetal death. These findings indicate an association between murine fetal death and acute infection with B. burgdorferi early in gestation but not with chronic infection. Our data suggest that fetal death is due to a maternal response to infection rather than fetal infection. These findings could provide an explanation for observations in humans in which sporadic cases of fetal death in women infected with B. burgdorferi during pregnancy have been reported, while previous infection has not been associated with fetal death.
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- Barbour A. G. Isolation and cultivation of Lyme disease spirochetes. Yale J Biol Med. 1984 Jul-Aug;57(4):521–525. [PMC free article] [PubMed] [Google Scholar]
- Barthold S. W., Beck D. S., Hansen G. M., Terwilliger G. A., Moody K. D. Lyme borreliosis in selected strains and ages of laboratory mice. J Infect Dis. 1990 Jul;162(1):133–138. doi: 10.1093/infdis/162.1.133. [DOI] [PubMed] [Google Scholar]
- Barthold S. W., Persing D. H., Armstrong A. L., Peeples R. A. Kinetics of Borrelia burgdorferi dissemination and evolution of disease after intradermal inoculation of mice. Am J Pathol. 1991 Aug;139(2):263–273. [PMC free article] [PubMed] [Google Scholar]
- Beck G., Benach J. L., Habicht G. S. Isolation of interleukin 1 from joint fluids of patients with Lyme disease. J Rheumatol. 1989 Jun;16(6):800–806. [PubMed] [Google Scholar]
- Burkman R. T., Friedlander R. L. Ruptured appendix in pregnancy. Am J Obstet Gynecol. 1975 May;122(2):265–265. doi: 10.1016/s0002-9378(16)33502-5. [DOI] [PubMed] [Google Scholar]
- Defosse D. L., Johnson R. C. In vitro and in vivo induction of tumor necrosis factor alpha by Borrelia burgdorferi. Infect Immun. 1992 Mar;60(3):1109–1113. doi: 10.1128/iai.60.3.1109-1113.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Duff P. Pyelonephritis in pregnancy. Clin Obstet Gynecol. 1984 Mar;27(1):17–31. doi: 10.1097/00003081-198403000-00006. [DOI] [PubMed] [Google Scholar]
- Gustafson J. M., Burgess E. C., Wachal M. D., Steinberg H. Intrauterine transmission of Borrelia burgdorferi in dogs. Am J Vet Res. 1993 Jun;54(6):882–890. [PubMed] [Google Scholar]
- Kenefick K. B., Lederer J. A., Schell R. F., Czuprynski C. J. Borrelia burgdorferi stimulates release of interleukin-1 activity from bovine peripheral blood monocytes. Infect Immun. 1992 Sep;60(9):3630–3634. doi: 10.1128/iai.60.9.3630-3634.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lebech A. M., Hindersson P., Vuust J., Hansen K. Comparison of in vitro culture and polymerase chain reaction for detection of Borrelia burgdorferi in tissue from experimentally infected animals. J Clin Microbiol. 1991 Apr;29(4):731–737. doi: 10.1128/jcm.29.4.731-737.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ma Y., Seiler K. P., Tai K. F., Yang L., Woods M., Weis J. J. Outer surface lipoproteins of Borrelia burgdorferi stimulate nitric oxide production by the cytokine-inducible pathway. Infect Immun. 1994 Sep;62(9):3663–3671. doi: 10.1128/iai.62.9.3663-3671.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- MacDonald A. B., Benach J. L., Burgdorfer W. Stillbirth following maternal Lyme disease. N Y State J Med. 1987 Nov;87(11):615–616. [PubMed] [Google Scholar]
- MacDonald A. B. Gestational Lyme borreliosis. Implications for the fetus. Rheum Dis Clin North Am. 1989 Nov;15(4):657–677. [PubMed] [Google Scholar]
- Magid D., Schwartz B., Craft J., Schwartz J. S. Prevention of Lyme disease after tick bites. A cost-effectiveness analysis. N Engl J Med. 1992 Aug 20;327(8):534–541. doi: 10.1056/NEJM199208203270806. [DOI] [PubMed] [Google Scholar]
- Markowitz L. E., Steere A. C., Benach J. L., Slade J. D., Broome C. V. Lyme disease during pregnancy. JAMA. 1986 Jun 27;255(24):3394–3396. [PubMed] [Google Scholar]
- Mather T. N., Telford S. R., 3rd, Adler G. H. Absence of transplacental transmission of Lyme disease spirochetes from reservoir mice (Peromyscus leucopus) to their offspring. J Infect Dis. 1991 Sep;164(3):564–567. doi: 10.1093/infdis/164.3.564. [DOI] [PubMed] [Google Scholar]
- Miller L. C., Isa S., Vannier E., Georgilis K., Steere A. C., Dinarello C. A. Live Borrelia burgdorferi preferentially activate interleukin-1 beta gene expression and protein synthesis over the interleukin-1 receptor antagonist. J Clin Invest. 1992 Sep;90(3):906–912. doi: 10.1172/JCI115966. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miller L. C., Lynch E. A., Isa S., Logan J. W., Dinarello C. A., Steere A. C. Balance of synovial fluid IL-1 beta and IL-1 receptor antagonist and recovery from Lyme arthritis. Lancet. 1993 Jan 16;341(8838):146–148. doi: 10.1016/0140-6736(93)90006-3. [DOI] [PubMed] [Google Scholar]
- Moody K. D., Barthold S. W. Relative infectivity of Borrelia burgdorferi in Lewis rats by various routes of inoculation. Am J Trop Med Hyg. 1991 Feb;44(2):135–139. doi: 10.4269/ajtmh.1991.44.135. [DOI] [PubMed] [Google Scholar]
- Nocton J. J., Dressler F., Rutledge B. J., Rys P. N., Persing D. H., Steere A. C. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid from patients with Lyme arthritis. N Engl J Med. 1994 Jan 27;330(4):229–234. doi: 10.1056/NEJM199401273300401. [DOI] [PubMed] [Google Scholar]
- Pachner A. R., Delaney E., Ricalton N. S. Murine Lyme borreliosis: route of inoculation determines immune response and infectivity. Reg Immunol. 1992 Nov-Dec;4(6):345–351. [PubMed] [Google Scholar]
- Piatak M., Jr, Luk K. C., Williams B., Lifson J. D. Quantitative competitive polymerase chain reaction for accurate quantitation of HIV DNA and RNA species. Biotechniques. 1993 Jan;14(1):70–81. [PubMed] [Google Scholar]
- Radolf J. D., Norgard M. V., Brandt M. E., Isaacs R. D., Thompson P. A., Beutler B. Lipoproteins of Borrelia burgdorferi and Treponema pallidum activate cachectin/tumor necrosis factor synthesis. Analysis using a CAT reporter construct. J Immunol. 1991 Sep 15;147(6):1968–1974. [PubMed] [Google Scholar]
- Schlesinger P. A., Duray P. H., Burke B. A., Steere A. C., Stillman M. T. Maternal-fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi. Ann Intern Med. 1985 Jul;103(1):67–68. doi: 10.7326/0003-4819-103-1-67. [DOI] [PubMed] [Google Scholar]
- Silen M. L., Firpo A., Morgello S., Lowry S. F., Francus T. Interleukin-1 alpha and tumor necrosis factor alpha cause placental injury in the rat. Am J Pathol. 1989 Aug;135(2):239–244. [PMC free article] [PubMed] [Google Scholar]
- Silver R. M., Lohner W. S., Daynes R. A., Mitchell M. D., Branch D. W. Lipopolysaccharide-induced fetal death: the role of tumor-necrosis factor alpha. Biol Reprod. 1994 May;50(5):1108–1112. doi: 10.1095/biolreprod50.5.1108. [DOI] [PubMed] [Google Scholar]
- Steere A. C. Lyme disease. N Engl J Med. 1989 Aug 31;321(9):586–596. doi: 10.1056/NEJM198908313210906. [DOI] [PubMed] [Google Scholar]
- Strobino B. A., Williams C. L., Abid S., Chalson R., Spierling P. Lyme disease and pregnancy outcome: a prospective study of two thousand prenatal patients. Am J Obstet Gynecol. 1993 Aug;169(2 Pt 1):367–374. doi: 10.1016/0002-9378(93)90088-z. [DOI] [PubMed] [Google Scholar]
- Tan S. S., Weis J. H. Development of a sensitive reverse transcriptase PCR assay, RT-RPCR, utilizing rapid cycle times. PCR Methods Appl. 1992 Nov;2(2):137–143. doi: 10.1101/gr.2.2.137. [DOI] [PubMed] [Google Scholar]
- Weber K., Bratzke H. J., Neubert U., Wilske B., Duray P. H. Borrelia burgdorferi in a newborn despite oral penicillin for Lyme borreliosis during pregnancy. Pediatr Infect Dis J. 1988 Apr;7(4):286–289. doi: 10.1097/00006454-198804000-00010. [DOI] [PubMed] [Google Scholar]
- Wendel G. D. Gestational and congenital syphilis. Clin Perinatol. 1988 Jun;15(2):287–303. [PubMed] [Google Scholar]
- Yang L., Ma Y., Schoenfeld R., Griffiths M., Eichwald E., Araneo B., Weis J. J. Evidence for B-lymphocyte mitogen activity in Borrelia burgdorferi-infected mice. Infect Immun. 1992 Aug;60(8):3033–3041. doi: 10.1128/iai.60.8.3033-3041.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
