Pediatric Annals

Special Issue Article 

Neonatal Mycoplasma and Ureaplasma Infections

Alison Chu, MD; Annabelle de St. Maurice, MD, MPH; Myung S. Sim, DrPH; Suhas G. Kallapur, MD


Mycoplasma species (spp.) can be commensals or opportunistic pathogens of the urogenital tract, and they can be commonly isolated from amniotic fluid, placenta, and fetal/neonatal tissue or blood in mothers delivering prematurely or their preterm infants. Although the presence of Mycoplasma spp. has been associated with adverse maternal-fetal outcomes such as preterm birth and maternal chorioamnionitis, it is less clear whether vertical transmission to the neonate results in colonization or active infection/inflammation. Moreover, the presence of Mycoplasma spp. in neonatal blood, cerebrospinal fluid, or tissue has been variably associated with increased risk of neonatal comorbidities, especially bronchopulmonary dysplasia (BPD). Although the treatment of the mother or neonate with antibiotics is effective in eradicating Ureaplasma, it is not clear that the treatment is effective in reducing the incidence of major morbidities of the preterm neonate (eg, BPD). In this article, we review the animal and clinical data for ureaplasma-related complications and treatment strategies. [Pediatr Ann. 2020;49(7):e305–e312.]


Mycoplasma species (spp.) can be commensals or opportunistic pathogens of the urogenital tract, and they can be commonly isolated from amniotic fluid, placenta, and fetal/neonatal tissue or blood in mothers delivering prematurely or their preterm infants. Although the presence of Mycoplasma spp. has been associated with adverse maternal-fetal outcomes such as preterm birth and maternal chorioamnionitis, it is less clear whether vertical transmission to the neonate results in colonization or active infection/inflammation. Moreover, the presence of Mycoplasma spp. in neonatal blood, cerebrospinal fluid, or tissue has been variably associated with increased risk of neonatal comorbidities, especially bronchopulmonary dysplasia (BPD). Although the treatment of the mother or neonate with antibiotics is effective in eradicating Ureaplasma, it is not clear that the treatment is effective in reducing the incidence of major morbidities of the preterm neonate (eg, BPD). In this article, we review the animal and clinical data for ureaplasma-related complications and treatment strategies. [Pediatr Ann. 2020;49(7):e305–e312.]

Mycoplasma species (spp.), including M. hominis and M. genitalium, are commensals of the urogenital tract and can lead to congenital infection or colonization of the neonatal respiratory tract. Ureaplasma parvum,U. urealyticum, and other Ureaplasma spp. resemble Mycoplasma spp. and can cause similar infections. Ureaplasma spp. that infect humans were first discovered in agar cultures of urethral exudate from men with nongonococcal urethritis in 1954.1 Initially, Ureaplasma spp. were referred to as T-mycoplasmas because of their resemblance to Mycoplasma spp., but were later reclassified in 1974 into their own genus within the Mycoplasmataceae family based on their distinctive urease activity.2 There are 14 Ureaplasma serovars, which can be grouped into two species—U. parvum and U. urealyticum. The organisms characteristically hydrolyze urea to generate adenosine triphosphate, lack cell walls, and adhere to mucosal surfaces in humans, such as the genitourinary tract in adults and respiratory tract of neonates.3 Among the smallest self-replicating microorganisms, Ureaplasma spp. are pleomorphic because they are surrounded by a cell membrane only and range in size from 100 nm to 1 mcm. Of the serovars, U. parvum represents the most common respiratory isolate in premature neonates, with serovars 3 and 6 accounting for the vast majority of this group.4

The purported burden of disease from these agents in the neonatal population remains controversial. U. parvum and U. urealyticum are common species colonizing the genitourinary tract of adults, but have been associated with adverse pregnancy outcomes5 such as preterm birth or chorioamnionitis.6 Horizontal or vertical transmission7 to the neonate is documented, given that these organisms are commonly isolated from infected amniotic fluid8 and placental tissue,2 and can also be detected in cord blood,9 and neonatal respiratory secretions,4 gastric aspirates,10 cerebrospinal fluid, as well as postmortem tissue. However, what remains less clear is whether the presence of Ureaplasma spp. in the individual neonate represents active infection versus colonization. Furthermore, whether the presence of mycoplasma/ureaplasma causatively contributes to comorbidities of prematurity, such as bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), or intraventricular hemorrhage (IVH), has not been definitively proven.

The purpose of this article is to describe the infectious characteristics of these bacteria, to review the available evidence on how these organisms affect neonatal outcomes, and to provide guidelines on the clinical presentation, diagnosis, and management of infection with mycoplasma/ureaplasma in the neonatal population.


Virulence Factors and Host Response

It is generally believed that the major virulence factor for ureaplasma is the multiple banded antigen (MBA) size,11–13 which is the surface lipoprotein that serves as the pathogen-associated molecular pattern recognized by the host innate immune system. Because ureaplasma can alter the size of MBA, ureaplasma may be able to escape eradication. Other proposed virulence factors include urease production of ammonia, immunoglobulin A (IgA) protease, (which leads to degradation of mucosal IgA),14 hydrogen peroxide, phospholipases A and C (leading to host cell membrane breakdown),15 inhibition of host cell antimicrobial peptide expression,16 and serine/threonine kinase and protein phosphatase-mediated cytotoxicity.17

As Ureaplasma spp. lack the lipopolysaccharides or peptidoglycans found in bacterial cell walls, these microbes do not activate the innate immune system's testicular receptor 4, toll like receptor 2 (TLR2) or nucleotide-binding oligomerization domain-like receptor 1 and 2 pathways.18 However, in vivo and in vitro studies suggest that lipoprotein-mediated macrophage stimulation induces inflammatory cytokine release,19–22 including tumor necrosis factor alpha, interleukin-1 beta, monocyte chemoattractant-1, and transforming growth factor alpha-1, by various cell types. An important host defense against ureaplasma in the lung is local surfactant protein A, which enhances phagocytosis and death in vitro,23 which may explain why preterm neonates are relatively immunocompromised against ureaplasma. Interestingly, one study on single nucleotide polymorphisms suggests that variation in innate immune response genes such as TLR2 and TLR6 have been associated with increased or decreased susceptibility to ureaplasma respiratory tract colonization and risk for BPD.24 Therefore, the interplay between microbial factors and host response variabilities remains poorly understood, especially in its relevance to clinical infection.

Consequences of Ureaplasma spp. as a Perinatal Pathogen

Intrauterine infection most commonly results from an ascending infection.25 Recent studies on the vaginal microbiome demonstrated that an increased prevalence of Gardnerella or Ureaplasma spp. (vaginal dysbiosis) predisposes to prematurity.26–28 Given that intrauterine infection is a known cause of preterm birth, and that urea-plasma is one of the most commonly isolated organisms in amniotic fluid, multiple studies have demonstrated that the presence of ureaplasma in amniotic fluid in human females at the time of amniocentesis shortened the time to eventual delivery.29,30 These findings are further supported by animal models that demonstrate that intraamniotic inoculation of primates with U. parvum leads to histologic chorioamnionitis, fetal inflammation, and clinical preterm labor.31

Neonates, especially those born preterm secondary to intra-amniotic infection, are at risk for prolonged in utero exposure to microbial pathogens. In fact, prospective studies have found that infants with respiratory tract colonization by ureaplasma were more likely to be born extremely preterm by vaginal delivery to women with chorioamnionitis or preterm premature rupture of membranes.32,33 Vertical transmission rate was positively correlated with duration of membrane rupture. Infants delivered for maternal indications (mother not in labor) had the lowest rates of respiratory tract ureaplasma colonization. Transmission to the infant can occur during both vaginal and cesarean deliveries at equal rates when chorioamnionitis is present.34

When examining postmortem tissue, infants colonized with ureaplasma had early lung fibrosis, increased myofibroblasts, disordered elastin patterning, and increased inflammatory cell populations.35,36 Moreover, three meta-analyses spanning from 1995 to 2014 suggest that ureaplasma respiratory tract colonization in human neonates is associated with an outcome of BPD.37–39 Animal studies in sheep support this association, with ureaplasma colonization via intra-amniotic injection in early gestation leading to recruitment and activation of inflammatory cells and dysmaturation of the lung.40 In nonhuman primates, intra-amniotic injection of ureaplasma led to preterm labor, and neonatal baboons with persistent colonization demonstrated histologic lung inflammation and fibrosis and worse lung function.41,42 In Rhesus macaques, intra-amniotic injection of U. parvum induced chorioamnionitis with preterm labor in some studies,31,43 but not in another study.44 However, all nonhuman primate studies thus far demonstrated varying degrees of fetal lung inflammation in response to intra-amniotic exposure to ureaplasma regardless of the presence of chorioamnionitis. In a study of mostly term infants, those infants exposed to ureaplasma in the perinatal period may be at an increased risk for reactive airway disease and asthma.45

Although the association of ureaplasma and BPD seems to be well supported by both animal and human studies, the other prematurity-related complications that may be associated with perinatal ureaplasma exposure are less studied. Limited studies that exist suggest that perinatally acquired ureaplasma may also increase risk for necrotizing enterocolitis,46,47 high-grade intraventricular hemorrhage,48,49 and neurodevelopmental impairment50 and may lead to more severe retinopathy of prematurity.51

Clinically, concerns for ureaplasma active infection in the neonate are often difficult to distinguish from other comorbidities commonly seen in the preterm population. For example, in a preterm neonate with worsening respiratory status and positive ureaplasma growth from a tracheal aspirate, it is unclear whether this culture represents colonization or true pneumonia.

It also remains unclear whether Ureaplasma spp. detected in blood, cerebrospinal fluid (CSF), and brain tissue represent invasive disease and active neonatal infection. Estimates from the United States and one Brazilian cohort suggest that ureaplasma can be detected in approximately 13% to 24% of cord blood, venous blood, or CSF cultures9,48,52 taken from preterm or low birthweight neonates. In particular, in studies on whether ureaplasma detection in CSF indicates meningitis, neonates with ureaplasma detected in CSF are variably symptomatic and cell counts from the CSF can be normal.53 Limited studies in both human cohorts and animal models suggest that urea-plasma in CSF may be associated with severe IVH and potentially inflammatory-mediated brain injury.48,54,55


Ureaplasma spp. can be cultured in urea containing broth and agar. However, proper sample collection via direct inoculation of tracheal or nasopharyngeal (NP) aspirate/NP swab into 10BB broth or appropriate transport media (such as Copan's Universal transport media, or routine Bacteriology Transport media) on ice is essential to minimize false-negative results, as these organisms lacking a cell wall are susceptible to drying and heat. Organism growth is signaled by a color change (yellow to pink) resulting from the pH change due to urease activity.56Ureaplasma colonies have a characteristic brown appearance with CaCl2 indicator in A8 agar. Colorimetric assays are commercially available, require less skilled personnel, and allow for decreased detection times, with similar reported sensitivities and specificities as culture and polymerase chain reaction (PCR) methods. However, these kits do not differentiate between species.57,58 Molecular diagnostic methods (real-time PCR) allow for differentiation of serovars and increased sensitivity (<100 genome copies), but do not distinguish between viable and nonviable organisms.59 Additionally, urea-plasma PCR testing may not be widely available. Serologic testing has limited value in the diagnosis of acute infection and is not available commercially.

Management and Therapeutic Considerations

Prenatal Management

Although Mycoplasma spp. are ubiquitous in the urogenital tract, but not always pathologic,60 it is less clear when to screen or when to treat Mycoplasma infections in pregnancy. Moreover, genital Mycoplasma spp. are frequently part of polymicrobial infections, which makes it difficult to discern the true relationship between Mycoplasma organisms and adverse pregnancy and neonatal outcomes. That said, U. parvum, U. Urealyticum, M. hominis, and M. genitalium are variably associated with increased risk of preterm birth and BPD in the neonate, as well as early miscarriage.60–64M. genitalium is generally considered pathogenic, causing a sexually transmitted infection,65 with some groups advocating for testing and treating symptomatic women for M. genitalium. However, with the advent of molecular diagnostics, other Mycoplasma spp. are being detected in the context of lacking evidence-based guidelines regarding whether to treat other species. To date, studies evaluating efficacy and improved pregnancy or neonatal outcomes with treatment are largely inconclusive.66,67 Importantly, current antibiotic regimens recommended for the indication of premature rupture of membranes fail to eradicate ureaplasmas.

Evaluation of the risks and benefits of antimicrobial treatment of Mycoplasma spp. infections is key as there is insufficient data to support treating pregnant women.68 Overuse of antibiotics during pregnancy can contribute to antibiotic resistance, alterations in the microbiome, and reactive airway disease in the neonate.45

Postnatal Management

Therapeutic agents against urea-plasma include azithromycin and clarithromycin, which not only enhance ureaplasma clearance in patients who are infected, but may also inhibit the inflammatory response thought to contribute to increased risk for BPD.43 Both antibiotics have immunomodulatory properties, preferential concentration in the lung epithelial-lining fluid and alveolar macrophages, and antimicrobial activity against ureaplasma. However, clinical studies on eradication of ureaplasma from the respiratory tract using erythromycin have collectively suggested that BPD rates were not altered.69,70 Azithromycin and clarithromycin may have slightly improved efficacy to prevent BPD, but published studies were conducted at single centers67,71,72 without establishing optimal dosing regimens or safety of use in the neonatal population. When compiling data from four studies published on the use of azithromycin to prevent BPD, the unadjusted odds ratio of developing BPD (or of developing BPD or dying) was approximately 0.4 for infants treated with azithromycin (Figure 1).71–74 To obtain the overall odds ratio (OR), the analysis under the assumption of homogeneity of variance among studies was performed using a fixed effect model. The analysis under heterogeneity was also carried out by using a random effect model. The test of homogeneity of between-study variance was performed through likelihood ratio test between the two models and there was evidence of non-homogeneity between-study variance (P < .001). Hence, the random effect model was used to obtain overall OR and its confidence interval. However, there is significant variability in these studies in sample size, location of study, definitions of BPD, duration of azithromycin treatment, and rates of BPD in the study population. Moreover, these studies range from 2007 to 2020, which is a time period during which significant changes in respiratory management occurred in the field of neonatology.

Forest plot and meta-analysis of unadjusted odds ratios from studies on azithromycin use to decrease bronchopulmonary dysplasia (BPD) and death. Relative size of OR symbol reflects study weight, which was determined by study sample sizes. Forest plot depicts unadjusted odds ratio and 95% confidence intervals. (A) Unadjusted odds ratios for an outcome of BPD. (B) Unadjusted odds ratios for an outcome of BPD or death. (C) Compares the included studies in terms of year of publication, study country, study weight for each outcome, and BPD rates calculated from the control population.

Figure 1.

Forest plot and meta-analysis of unadjusted odds ratios from studies on azithromycin use to decrease bronchopulmonary dysplasia (BPD) and death. Relative size of OR symbol reflects study weight, which was determined by study sample sizes. Forest plot depicts unadjusted odds ratio and 95% confidence intervals. (A) Unadjusted odds ratios for an outcome of BPD. (B) Unadjusted odds ratios for an outcome of BPD or death. (C) Compares the included studies in terms of year of publication, study country, study weight for each outcome, and BPD rates calculated from the control population.

The most recent study was a multi-center randomized controlled trial informed by a pharmacokinetic study of azithromycin conducted in preterm infants at risk for BPD (NCT01778634).73 A 3-day course of 20 mg/kg/day of intravenous azithromycin within the first 72 hours of life eradicated ureaplasma from respiratory samples but failed to have a significant impact on BPD.73,75 Long-term follow-up of this cohort is in progress and was recently reported in an abstract; at age 1 year, early post-natal azithromycin treatment appeared to decrease the incidence of death or severe post-neonatal intensive care unit discharge morbidity compared to the placebo group.76 Although azithromycin was an effective antimicrobial for ureaplasma, the trial by Viscardi failed to show a beneficial effect of azithromycin treatment during an era of practice that reflects current respiratory management strategies.73 Newer macrolides (eg, solithromycin), with improved pharmacokinetic and antimicrobial properties, are being tested in clinical trials but are not yet available for clinical use.77 Overall, there was significant variability in study design, treatment regimen, subject inclusion/exclusion criteria, and baseline subject population characteristics, making it difficult to draw conclusions on the efficacy of ureaplasma clearance by antibiotic use in the preterm population to reduce BPD.

Although our meta-analysis suggests a benefit of using azithromycin, given the heterogenous nature of studies, we do not recommend routine azithromycin antibiotic use for preterm infants at risk for BPD. The presence of ureaplasma in the respiratory tract may be a marker of respiratory distress syndrome (RDS) severity in neonates. Additionally, treatment with azithromycin in the first 2 weeks of life has been associated with an increased risk of hypertrophic pyloric stenosis.78 When weighing the risks and benefits of treatment, we support selective treatment of preterm ureaplasma culture or PCR-positive infants within the first week of life.

The efficacy of treating older preterm infants who have detectable ureaplasma at other sites is not well understood. It is unclear whether detectable ureaplasma in the respiratory tract of older preterm infants represents true infection. However, symptomatic meningitis with ureaplasma has been reported in a limited number of cases,79 and there is little evidence on the optimal treatment for central nervous system (CNS) infections. Macrolides and quinolones have been used as monotherapy or in combination, with quinolones having the advantage of better CSF penetration but contra-indicated in patients with epileptic seizures. Although reports on the compassionate use of fluoroquinolones in neonates have not demonstrated serious adverse effects, concerns about the effect of fluoroquinolones on the musculoskeletal system remain.80 The duration of antibiotic treatment for CNS infections is also unclear.


Mycoplasma spp. are commonly isolated from maternal-fetal tissues, especially in the preterm population, and have been linked to adverse pregnancy outcomes. After birth, the presence of Mycoplasma spp. in the neonate may predispose to comorbidities of prematurity, such as BPD, NEC, and IVH. However, routine antibiotic administration to the neonate to eradicate ureaplasma has not shown convincing efficacy in reducing BPD rates. Active mycoplasma infection causing pneumonia in the first week of life can also be difficult to distinguish from evolving RDS, given the high prevalence of RDS in the preterm population at risk for mycoplasma colonization. Therefore, a selective treatment approach is warranted.


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Alison Chu, MD, is an Assistant Professor-in-Residence, Division of Neonatology, Department of Pediatrics. Annabelle de St. Maurice, MD, MPH, is an Assistant Professor, Division of Infectious Diseases. Myung S. Sim, DrPH, is an Associate Professor, Department of Medicine Statistics Core. Suhas G. Kallapur, MD, is a Professor, Division of Neonatology, Department of Pediatrics. All authors are affiliated with the David Geffen School of Medicine at the University of California Los Angeles (UCLA).

Address correspondence to Alison Chu, MD, Division of Neonatology, Department of Pediatrics, David Geffen School of Medicine at UCLA, 10833 LeConte Avenue, MDCC B2-411, Los Angeles, CA 90095; email:

Grant: This research is supported by grant UL1TR001881 from the National Institutes of Health (NIH) National Center for Advancing Translational Science. S. G. K. is supported by grant R01HD98389 from the NIH.

Disclosure: The authors have no relevant financial relationships to disclose.


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