Corresponding author: Tae-Jung Sung, M.D. Department of Pediatrics, Kangnam Sacred Heart Hospital, Hallym University Medical Center, 948-1 Daerim 1-Dong, Yungdungpo-ku, Seoul 150-950, Korea. Introduction
Ureaplasma species are the most common bacteria detected in urogenital infections, including nongonococcal urethritis in men and multiple obstetrical complications in women1, 2). Since Ureaplasma spp. can be found in vaginal flora in 40% of sexually inactive and 67% sexually active women, it is known as a commensal in the female genital tract3).
Although numerous clinical observational studies were conducted over a period of over 30 years, the clinical significance of these bacteria is still under debate4). These bacteria are considered to be of low virulence; however, Ureaplasma colonization has been associated with infertility5), stillbirth6), preterm delivery7, 8), histologic chorioamnionitis9), and perinatal death in neonates10).
This article summarizes recent information on the role of Ureaplasma infection in diseases in preterm infants and future considerations.
Ureaplasma spp.
1. Classification and characteristics
Ureaplasma spp. is a member of the Mollicutes class, which is comprised of 4 orders, 5 families, 8 genes, and nearly 200 known species, 17 of which are known to use humans as their primary host4). Another well-known member of the Mollicutes class is Mycoplasma spp., in which there are 3 species, Mycoplasma hominis, Mycoplasma genitalium, and Mycoplasma fermentans, which are known to occur in the female urogenital tract. Ureaplasma was first described by Shepard in the 1950s and were detected in the male urethritis11). Recently, Ureaplasma was subdivided into 2 separate species and 14 serovars that have been grouped according to 16S dRNA sequencing results into 2 genetically related biovars3, 4).
U. parvum, known as biovar 1, contains serovars 1, 3, 6, and 14, and U. urealyticum (biovar 2) contains the remaining serovars (2, 4, 5, and 7-13)12). Characteristics of all serovars include lack of cell walls, limited biosynthetic abilities, small genome size, and mucosal association in the human host3). The unique characteristic of Ureaplasma is their ability to hydrolyze urea to generate metabolic energy1, 4). Some debates still occur regarding whether there is a difference in pathogenicity exists among these 14 serovars and 2 biovars.
2. Virulence factors
Ureaplasma can directly activate the first component of complements and attach to host erythrocytes, neutrophils, spermatozoa, and urethral epithelial cells1). This can induce inflammation in humans and produces multiple manifestations of clinical diseases4). Since Ureaplasma spp. metabolizes urea to generate energy, it also produces secretory products such as ammonia, which may induce a local cytotoxic effect.
Previously reported ureaplasmal virulence factors include IgA protease, urease, phospholipases A and C, and production of hydrogen peroxide13). These factors may allow the organism to evade mucosal immune defenses by degrading IgA and injuring mucosal cells through the local generation of ammonia, membrane phospholipid degradation, prostaglandin synthesis, and membrane peroxidation3). Although phenotypic production of IgA protease and phopholipases was described several years ago, genome examination of multiple serovars has failed to reveal genes encoding these enzymes4).
The multiple-banded antigen (MBA) of Ureaplasma spp. is the predominant antigen recognized during the infection process and may be involved in host inflammatory response stimulation. It undergoes a high rate of variation in vitro and exhibits variable sizes in vitro on invasive isolates, suggesting that antigen size variation may be another mechanism through which the organism evades host defenses3, 4). Ureaplasma serovars have multiple MBA genes, and some contain multiple copies of the same type of MBA gene.
3. Vertical transmission and intrauterine infection
Ureaplasmas can be isolated from endotracheal aspirations in up to 40% of newborn infants within 30 minutes to 24 hours after delivery14, 15), and from maternal and umbilical cord blood at these delivery times16). This provided evidence that vertical Ureaplasma transmission and neonatal infection may occur in newborn infants. Additionally, recovery of Ureaplasma from the chorion increased with the duration of membrane rupture, suggesting an ascending route of infection17). Those born weighing less than 1,000 g are at higher risk of infection when the mother is colonized at up to 90% of the infection rate18). The possible pathogenesis involves fetal exposure to ascending ureaplasmal intrauterine infection, passage through an infected birth canal, hematogenous dissemination through the placenta into umbilical vessels, and colonization of the skin, mucosal membranes, respiratory tract, and dissemination into the blood and central nervous system19, 20).
Intrauterine infection is now believed to be a major cause of preterm birth, particularly in gestations of less than 30 weeks21). Ureaplasma spp. is the most common isolate identified in amniotic fluid. Isolated Ureaplasma spp. from the chorioamnion has been consistently associated with histologic chorioamnionitis, which is inversely related to birth weight22). Several experimental studies with intra-amniotic inoculation of U. parvum showed that it did not stimulate premature labor in mice23) or sheep24), but did stimulate progressive uterine contractions and preterm delivery in rhesus macaques25). The Rhesus macaque experimental result suggests that species differences result in differences in host response or serovar differences in virulence.
Ureaplasma spp. infection in neonatal pathogens
1. Congenital pneumonia in preterm infants
In the mid-1970s, some investigators suggested a potential role for Ureaplasma in neonatal respiratory disease after isolation of these organisms from lungs of stillborn infants with peumonitis26). Evidence that Ureaplasma spp. cause congenital pneumonia includes isolation of bacteria in pure culture from amniotic fluid, affected lungs of neonates less than 14 hours after birth in the midst of an acute inflammatory response, and chorioamnion1, 20). Other evidence includes demonstration of a specific IgM response in the neonate27), radiographic changes indicative of pneumonia in culture-positive infants28), demonstration of the bacteria in lung tissue using immunofluorescence29), and electron microscopy27).
2. Bacteremia and systemic infections
Ureaplasma isolation from cord blood was first described in 196930) and in a recent prospective study it was shown that 23% of infants had a positive cord blood culture for this organism31). Cassell et al.32) reported that 26% of neonates culture-positive for Ureaplasma spp. in the lower respiratory tract were bacteremia with these organisms. Ureaplasma has been isolated from gastric aspirates, blood, cerebrospinal fluid (CSF), lung, and brain tissue, although this organism is most commonly isolated from respiratory secretions3). In 2 recent large prospective cohorts, Ureaplasma was detected in 17% of cord blood cultures and 23.6% of serum or CSF polymerase chain reaction (PCR) samples, with U. parvum as the predominant species detected in serum and CSF10, 31).
3. Meningitis and neonatal brain injury
The largest recent prospective survey of invasive infections analyzed samples from 313 very low-birth-weight (VLBW) infants with suspected sepsis/meningitis or hydrocephalus reported that the risk of severe intraventricular hemorrhage (IVH) (≥grade 3) was 2.5-fold higher in serum PCR-positive than PCR-negative infants after adjustment for gestational age, but there was no association of cranial ultrasound abnormalities with detection of Ureaplasma in CSF10).
A role for Ureaplasma in neonatal brain injury is supported by recent studies in experimental animal models23). In the murine intrauterine U. parvum infection model, the brains of fetal and newborn mice showed evidence of microglial activation, deleted myelination, and disturbed neuronal development. Future studies are needed to provide additional information regarding mechanisms of Ureaplasma-mediated brain injury.
4. Role of Ureaplasma infection in lung injury and inflammation
Some investigators found that Ureaplasma isolated from lower respiratory tract colonization is associated with peripheral blood leukocytosis, particularly the neutrophil component29, 33). Crouse et al.28) evaluated chest radiographs of 44 preterm infants with Ureaplasma colonization the lower respiratory tract in comparison with those who were culture-negative. They found that pneumonia was twice as common in the Ureaplasma-positive group and early radiographic emphysematous changes within 2 weeks of birth were significantly more common in the Ureaplasma-positive group. In a recent cohort study of infants less than 33 weeks gestation, Ureaplasma spp. were detected during the first week of life in tracheal aspirates or nasopharyngeal aspirates in 35% of infants10). These findings suggest an in utero onset of inflammatory responses and lung injury3).
Ureaplasma infection in neonate promotes a proinflammatory cytokine cascade in the lower respiratory tract; this infection is associated with an increase in tumor necrosis factors (TNF)-α, interleukin (IL)-1β, and IL-820) and blocks expression of the regulatory cytokines IL-6 and/or IL-104). Viscardi et al.33) examined pathological specimens from Ureaplasma-infected infants and reported that Transforming growth factor (TGF)-β1 expression increased in infants with pneumonia compared with control specimens. Li and coworkers34) demonstrated that human macrophages exposed to the Ureaplasma antigen produce TNF-α and IL-6, and Ureaplasma-exposed macrophages release vascular endothelial growth factor and intracellular adhesion molecule-1.
5. Association of Ureaplasma infection with development of bronchopulmonary dysplasia
The classic definition of bronchopulmonary dysplasia (BPD), a supplemental oxygen requirement at 28 days of age, has been criticized since widespread antenatal corticosteroid treatment, postnatal exogenous surfactant therapy, and gentler ventilator strategies in VLBW infants, a "new" BPD, emerged. Recently, Bancalari et al.37) defined BPD as an oxygen requirement and the presence of radiographic abnormalities at 36 weeks postmenstrual age.
Since BPD etiology is multifactorial and complex, the relationship of Ureaplasma respiratory tract colonization with the development of BPD has been debated. In 1988, 3 independent groups published results of cohort studies linking BPD development with airway colonization with Ureaplasma18, 32, 38). A meta-analysis of 17 clinical studies published before 1995 supported a significant association between Ureaplasma respiratory tract colonization and BPD development. Another recent meta-analysis conducted by Schelonka et al.39), who analyzed 36 cohort studies published between 1988 and 2004 involving approximately 3000 preterm infants, showed a significant association between Ureaplasma respiratory colonization and BPD development whether it was defined as oxygen dependence at 28 days (P<0.001) or at 36 weeks postmenstrual age (P<0.001). Other studies support the Ureaplasma respiratory colonization-BPD association, particularly in the subset of Ureaplasma-colonized infants exposed to chorioamnionitis and leukocytosis at birth3).
Castro-Alcaraz et al.40) observed that persistent, but not transient, Ureaplasma respiratory complications are significantly higher in colonized infants. Mortality due to respiratory complications is significantly higher in colonized infants and the risk of a combined outcome measure of BPD or death due to lung disease was 4.2-fold higher in colonized Ureaplasma rather than in noncolonized VLBW infants14, 32).
Infants with BPD have elevated proinflammatory cytokines such as IL-1, IL-6, and IL-8, with IL-8 acting as a potent neutrophil chemoattractant and, as a result, theses infants have elevated neutrophils in the lungs20). Perinatal Ureaplasma infection may promote the inflammatory cascade in the lung and impair alveolar development directly or in conjunction with oxidant and ventilator-induced lung injury3, 20). Hence, postnatal application of high oxygen concentrations and mechanical ventilation and duration of exposure may potentiate the effect of Ureaplasma-associated injury to the lungs.
Treatment of Ureaplasma infection in preterm infants
Although it is known that macrolides are the only antimicrobial agents currently available for use in the treatment of neonatal ureaplasmal infections, in the clinical field it is difficult to make decisions regarding which antibiotics should be used. Due to its toxicity, doxycycline is not an alternative unless U. urealyticum is isolated from CSF. Clindamycin has also been used to successfully treat systemic M. homin is infections in infants1). As such, making specific recommendations for treating neonatal ureaplasma infections is difficult because the spectrum of ureaplasmal disease has not been fully described and there are very few clinical studies indicating the in vivo efficacy of antibiotics1). Therefore, not only are choices between limited drug options controversial, but also the actual indications concerning conditions under which treatment should be offered, dosage, and duration of therapy is debated.
Antibiotic therapy is a standard treatment modality for premature rupture of membranes (PROM). However, standard regimens failed to eradicate organisms including Ureaplasma or diminish inflammation in the amniotic cavity with PROM41). In an experimental Ureaplasma intraamniotic infection (IAI) in Rhesus monkeys, azitromycin alone or in combination with dexamethasone and indomethacin prevented fetal lung damage42).
Despite the in vitro susceptibility of Ureaplasma to erythromycin, trials of erythromycin therapy in the first few weeks of life in Ureaplasma-colonized preterm infants have failed to demonstrate efficacy in preventing BPD3). Recently, Walls and colleagues43) demonstrated that azithromycin prophylaxis, but not erythromycin, improved outcomes and reduced inflammation in a murine neonatal Ureaplasma infection model. This finding suggests that azithromycin is effective if administered immediately after birth. However, there have been no published investigations of azithromycin in neonates regarding low birth weight infants. Hence, until appropriate pharmacokinetics and efficacy trials are conducted, a dosing regimen for azithromycin in neonates cannot be recommended41).
Conclusions and future perspectives
Recent clinical and experimental studies have shown significant evidence that Ureaplasma infection may induce inflammatory processes early in utero and, as a result it can cause intrauterine chorioamnionitis, postnatal systemic infection, and lung injury, including BPD. However, more studies are needed to determine the relationship of Ureaplasma virulence factors, host immune factors affecting pathogen susceptibility, and inflammatory variability, and interactions with environmental factors such as oxygen exposure and mechanical ventilation3). Furthermore, a study analyzing antimicrobial therapy of Ureaplasma-colonized infants should be conducted in a large, multicenter, randomized clinical trial to determine whether these antibiotics are effective in reducing BPD rate and improving neonatal outcomes.
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