The Infectious Disease Review - for the medical, veterinary & environmental professions Vol 1 No 3 200 The Infectious Disease Review 1999;1(3):200-207 The role of Ureaplasma urealyticum in human reproductive and neonatal diseases Jerry K Davis (1)*, Dennis T Crouse (2), Janet A Robertson (3), Maureen K Davidson (1), Mary B Brown (1), Leticia Reyes (1). (1) Division of Comparative Medicine, Department of Pathobiology, College of Veterinary Medicine, University of Florida, Gainesville, Florida USA 32610 (2)Department of Pediatrics and Obstetrics and Gynecology, and Perinatal Infectious Disease Laboratory, University of Tennessee, Memphis Tennessee, USA, 38163 (3) Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7 *Corresponding author Key words: Review, ureaplasma, neonatal disease, genital disease, infertility, Abstract The role of Ureaplasma urealyticum in reproductive and neonatal diseases remains controversial, primarily because of the high incidence of colonization of normal individuals. In the absence of good animal models, clarification of the role these organisms play in reproductive disease depends upon epidemiological studies with all of their attendant problems. Although the role for U. urealyticum remains controversial, there is compelling evidence to believe that this organism is involved in chorioamnionitis and in utero fetal infection. In utero infection may lead to abortion or premature birth, and appears to be a factor in congenital pneumonia, especially in low birth weight infants. Although the mechanisms are unclear, very low birth weight infants colonized with U. urealyticum are more apt to develop broncho-pulmonary dysplasia and chronic lung disease. Additional understanding of the role of U. urealyticum in disease is not likely to come from strictly epidemiological studies, but will require understanding of the relationships between the organism and the host as defined either by in vitro studies or in vivo studies in animal models. Introduction Ureaplasma urealyticum was first isolated from men with primary and recurrent nongonococcal urethritis (NGU) in 1954 (1). Controversy over the significance of cultural isolation continued for more than twenty years while the epidemiology of the infection was delineated (2). Because of the frequency with which the organism could be isolated from healthy adult men and women, U. urealyticum was not accepted as the cause of human disease until Koch’s postulates were fulfilled in 1977 by urethral self-inoculation studies in humans (3). The induced urethritis mimicked natural NGU cases in which chlamydia could not be isolated. Currently, U. urealyticum is accepted as one of the causes of NGU. U. urealyticum also has been strongly associated with renal disease due to urinary calculi (4-6). Although isolations from the upper urinary tract were quite low, there is evidence to support that an association may exist between U. urealyticum and reflux nephropathy (7,8). U. urealyticum can be found in the cervix or vagina of 40- 80% of sexually mature, asymptomatic women (2,9) with the prevalence being altered by age, socioeconomic status, sexual activity, race, and oral contraceptive use (4). The organism has been implicated as a cause of several reproductive disorders including infertility, spontaneous abortion, stillbirth, premature birth, low birth weight, and perinatal morbidity and mortality (10). However, Koch’s postulates remain unfulfilled, and epidemiologic evidence remains a source of controversy. Recent reviews of the biological, molecular biology, and pathogenic properties of mycoplasmas and ureaplasmas have been published (11-14). The purpose of this review is to evaluate the role of U. urealyticum in reproductive and neonatal diseases of humans, to suggest possible pathogenic mechanisms, and to identify areas where conclusive evidence is lacking. In the absence of good animal models, it is unlikely that Koch’s postulates can be fulfilled; instead other “rules of evidence” proposed for epidemiological studies must be the standard (15). In brief, the study’s design should be the strongest possible and avoid biases in determination of exposure and outcome; the strength of the association (relative risk) should be both clinically and statistically significant; the association should be consistent across studies; the temporal sequence should be correct; a dose response gradient should be present; and the association should make sense. Infertility Perhaps no area in the study of reproductive diseases has been as controversial as the possible role of U. urealyticum in involuntary infertility. The most common approaches have been to compare isolation rates of ureaplasmas, often from the lower genital tract, from fertile and infertile couples, and to determine the incidence of conception in infertile couples following antibiotic therapy. Both approaches yield inconsistent results. As reviewed previously (4), there are a number of reasons that past studies remain inconclusive. The most common defects include failure to exclude other infectious agents including chlamydia, failure to include appropriate controls in antibiotic treatment trials, inadequate numbers of either patients or controls, failure to appropriately match controls and patients for factors known to influence ureaplasmal colonization, and either inappropriate samples or inadequate diagnostic evaluations. Colonization of the lower male or female genital tract with U. urealyticum per se does not seem to