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

Abstract

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.]

Abstract

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.

Review

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

Diagnosis

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.

ConclusIon

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.

References

  1. Shepard MC. The recovery of pleuropneumonia-like organisms from Negro men with and without nongonococcal urethritis. Am J Syph Gonorrhea Vener Dis. 1954;38(2):113–124. PMID:13138817
  2. Sweeney EL, Dando SJ, Kallapur SG, Knox CL. The human ureaplasma species as causative agents of chorioamnionitis. Clin Microbiol Rev. 2016;30(1):349–379. doi:10.1128/CMR.00091-16 [CrossRef] PMID:27974410
  3. Viscardi RM, Kallapur SG. Role of urea-plasma respiratory tract colonization in bronchopulmonary dysplasia pathogenesis: current concepts and update. Clin Perinatol. 2015;42(4):719–738. doi:10.1016/j.clp.2015.08.003 [CrossRef] PMID:26593075
  4. Sung TJ, Xiao L, Duffy L, Waites KB, Chesko KL, Viscardi RM. Frequency of ureaplasma serovars in respiratory secretions of preterm infants at risk for broncho-pulmonary dysplasia. Pediatr Infect Dis J. 2011;30(5):379–383. doi:10.1097/INF.0b013e318202ac3a [CrossRef] PMID:21099445
  5. Murtha AP, Edwards JM. The role of Mycoplasma and Ureaplasma in adverse pregnancy outcomes. Obstet Gynecol Clin North Am. 2014;41(4):615–627. doi:10.1016/j.ogc.2014.08.010 [CrossRef] PMID:25454994
  6. Suzuki Y, Horie K, Yada Y, et al. Vaginal Ureaplasma species increase chorioamnionitis in very preterm infants with pre-term premature rupture of the membranes at <28 weeks of gestation. Eur J Clin Microbiol Infect Dis. 2018;37(12):2371–2380. doi:10.1007/s10096-018-3385-5 [CrossRef] PMID:30244363
  7. Huber BM, Meyer Sauteur PM, Unger WWJ, et al. Vertical transmission of mycoplasma pneumoniae Infection. Neonatology. 2018;114(4):332–336. doi:10.1159/000490610 [CrossRef] PMID:30089291
  8. Romero R, Miranda J, Chaemsaithong P, et al. Sterile and microbial-associated intra-amniotic inflammation in preterm prelabor rupture of membranes. J Matern Fetal Neonatal Med. 2015;28(12):1394–1409. doi:10.3109/14767058.2014.958463 [CrossRef] PMID:25190175
  9. Goldenberg RL, Andrews WW, Goepfert AR, et al. The Alabama Preterm Birth Study: umbilical cord blood Ureaplasma urealyticum and Mycoplasma hominis cultures in very preterm newborn infants. Am J Obstet Gynecol. 2008;198(1):43.e1–43.e5. doi:10.1016/j.ajog.2007.07.033 [CrossRef] PMID:18166302
  10. Payne MS, Goss KC, Connett GJ, et al. Molecular microbiological characterization of preterm neonates at risk of bronchopulmonary dysplasia. Pediatr Res. 2010;67(4):412–418. doi:10.1203/PDR.0b013e3181d026c3 [CrossRef] PMID:20035248
  11. Dando SJ, Nitsos I, Kallapur SG, et al. The role of the multiple banded antigen of Urea-plasma parvum in intra-amniotic infection: major virulence factor or decoy?PLoS One. 2012;7(1):e29856. doi:10.1371/journal.pone.0029856 [CrossRef] PMID:22253806
  12. Knox CL, Dando SJ, Nitsos I, et al. The severity of chorioamnionitis in pregnant sheep is associated with in vivo variation of the surface-exposed multiple-banded antigen/gene of Ureaplasma parvum. Biol Reprod. 2010;83(3):415–426. doi:10.1095/biolreprod.109.083121 [CrossRef] PMID:20519696
  13. Uchida K, Nakahira K, Mimura K, et al. Effects of Ureaplasma parvum lipoprotein multiple-banded antigen on pregnancy outcome in mice. J Reprod Immunol. 2013;100(2):118–127. doi:10.1016/j.jri.2013.10.001 [CrossRef] PMID:24238827
  14. Kilian M, Brown MB, Brown TA, Freundt EA, Cassell GH. Immunoglobulin A1 protease activity in strains of Ureaplasma urealyticum. Acta Pathol Microbiol Immunol Scand [B]. 1984;92(1):61–64. doi:10.1111/j.1699-0463.1984.tb02794.x [CrossRef] PMID:6369873
  15. DeSilva NS, Quinn PA. Characterization of phospholipase A1, A2, C activity in Ureaplasma urealyticum membranes. Mol Cell Biochem. 1999;201(1–2):159–167. doi:10.1023/A:1007082507407 [CrossRef] PMID:10630635
  16. Xiao L, Crabb DM, Dai Y, Chen Y, Waites KB, Atkinson TP. Suppression of antimicrobial peptide expression by ureaplasma species. Infect Immun. 2014;82(4):1657–1665. doi:10.1128/IAI.01231-13 [CrossRef] PMID:24491573
  17. Martinez MA, Das K, Saikolappan S, Materon LA, Dhandayuthapani S. A serine/threonine phosphatase encoded by MG_207 of Mycoplasma genitalium is critical for its virulence. BMC Microbiol. 2013;13(1):44. doi:10.1186/1471-2180-13-44 [CrossRef] PMID:23432936
  18. Kumar H, Kawai T, Akira S. Pathogen recognition by the innate immune system. Int Rev Immunol. 2011;30(1):16–34. doi:10.3109/08830185.2010.529976 [CrossRef] PMID:21235323
  19. Estrada-Gutierrez G, Gomez-Lopez N, Zaga-Clavellina V, et al. Interaction between pathogenic bacteria and intrauterine leukocytes triggers alternative molecular signaling cascades leading to labor in women. Infect Immun. 2010;78(11):4792–4799. doi:10.1128/IAI.00522-10 [CrossRef] PMID:20805331
  20. Manimtim WM, Hasday JD, Hester L, Fairchild KD, Lovchik JC, Viscardi RM. Urea-plasma urealyticum modulates endotoxin-induced cytokine release by human monocytes derived from preterm and term newborns and adults. Infect Immun. 2001;69(6):3906–3915. doi:10.1128/IAI.69.6.3906-3915.2001 [CrossRef] PMID:11349058
  21. Shimizu T, Kida Y, Kuwano K. Ureaplasma parvum lipoproteins, including MB antigen, activate NF-{kappa}B through TLR1, TLR2 and TLR6. Microbiology. 2008;154(Pt 5):1318–1325. doi:10.1099/mic.0.2007/016212-0 [CrossRef] PMID:18451040
  22. Peltier MR, Freeman AJ, Mu HH, Cole BC. Characterization of the macrophage-stimulating activity from Ureaplasma urealyticum. Am J Reprod Immunol. 2007;57(3):186–192. doi:10.1111/j.1600-0897.2006.00460.x [CrossRef] PMID:17295897
  23. Okogbule-Wonodi AC, Chesko KL, Famuyide ME, Viscardi RM. Surfactant protein-A enhances ureaplasmacidal activity in vitro. Innate Immun. 2011;17(2):145–151. doi:10.1177/1753425909360552 [CrossRef] PMID:20197455
  24. Winters AH, Levan TD, Vogel SN, Chesko KL, Pollin TI, Viscardi RM. Single nucleotide polymorphism in toll-like receptor 6 is associated with a decreased risk for ureaplasma respiratory tract colonization and broncho-pulmonary dysplasia in preterm infants. Pediatr Infect Dis J. 2013;32(8):898–904. doi:10.1097/INF.0b013e31828fc693 [CrossRef] PMID:23518821
  25. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75–84. doi:10.1016/S0140-6736(08)60074-4 [CrossRef] PMID:18177778
  26. DiGiulio DB, Callahan BJ, McMurdie PJ, et al. Temporal and spatial variation of the human microbiota during pregnancy. Proc Natl Acad Sci USA. 2015;112(35):11060–11065. doi:10.1073/pnas.1502875112 [CrossRef] PMID:26283357
  27. Brown RG, Marchesi JR, Lee YS, et al. Vaginal dysbiosis increases risk of preterm fetal membrane rupture, neonatal sepsis and is exacerbated by erythromycin. BMC Med. 2018;16(1):9. doi:10.1186/s12916-017-0999-x [CrossRef] PMID:29361936
  28. Payne MS, Ireland DJ, Watts R, et al. Urea-plasma parvum genotype, combined vaginal colonisation with Candida albicans, and spontaneous preterm birth in an Australian cohort of pregnant women. BMC Pregnancy Childbirth. 2016;16(1):312. doi:10.1186/s12884-016-1110-x [CrossRef] PMID:27756249
  29. Yoon BH, Romero R, Lim JH, et al. The clinical significance of detecting Ureaplasma urealyticum by the polymerase chain reaction in the amniotic fluid of patients with preterm labor. Am J Obstet Gynecol. 2003;189(4):919–924. doi:10.1067/S0002-9378(03)00839-1 [CrossRef] PMID:14586326
  30. Gerber S, Vial Y, Hohlfeld P, Witkin SS. Detection of Ureaplasma urealyticum in second-trimester amniotic fluid by polymerase chain reaction correlates with subsequent preterm labor and delivery. J Infect Dis. 2003;187(3):518–521. doi:10.1086/368205 [CrossRef] PMID:12552439
  31. Novy MJ, Duffy L, Axthelm MK, et al. Urea-plasma parvum or Mycoplasma hominis as sole pathogens cause chorioamnionitis, pre-term delivery, and fetal pneumonia in rhesus macaques. Reprod Sci. 2009;16(1):56–70. doi:10.1177/1933719108325508 [CrossRef] PMID:19122105
  32. Olomu IN, Hecht JL, Onderdonk AO, Allred EN, Leviton AInvestigators ELGANSExtremely Low Gestational Age Newborn Study Investigators. Perinatal correlates of Ureaplasma urealyticum in placenta parenchyma of singleton pregnancies that end before 28 weeks of gestation. Pediatrics. 2009;123(5):1329–1336. doi:10.1542/peds.2008-1113 [CrossRef] PMID:19403499
  33. Namba F, Hasegawa T, Nakayama M, et al. Placental features of chorioamnionitis colonized with Ureaplasma species in preterm delivery. Pediatr Res. 2010;67(2):166–172. doi:10.1203/PDR.0b013e3181c6e58e [CrossRef] PMID:19858776
  34. Sánchez PJ. Perinatal transmission of Urea-plasma urealyticum: current concepts based on review of the literature. Clin Infect Dis. 1993;17(suppl 1):S107–S111. doi:10.1093/clinids/17.Supplement_1.S107 [CrossRef] PMID:8399899
  35. Viscardi RM, Manimtim WM, Sun CC, Duffy L, Cassell GH. Lung pathology in premature infants with Ureaplasma urealyticum infection. Pediatr Dev Pathol. 2002;5(2):141–150. doi:10.1007/s10024-001-0134-y [CrossRef] PMID:11910508
  36. Viscardi R, Manimtim W, He JR, et al. Disordered pulmonary myofibroblast distribution and elastin expression in preterm infants with Ureaplasma urealyticum pneumonitis. Pediatr Dev Pathol. 2006;9(2):143–151. doi:10.2350/10-05-0112.1 [CrossRef] PMID:16822087
  37. Lowe J, Watkins WJ, Edwards MO, et al. Association between pulmonary ureaplasma colonization and bronchopulmonary dysplasia in preterm infants: updated systematic review and meta-analysis. Pediatr Infect Dis J. 2014;33(7):697–702. doi:10.1097/INF.0000000000000239 [CrossRef] PMID:24445836
  38. Wang EE, Ohlsson A, Kellner JD. Association of Ureaplasma urealyticum colonization with chronic lung disease of prematurity: results of a metaanalysis. J Pediatr. 1995;127(4):640–644. doi:10.1016/S0022-3476(95)70130-3 [CrossRef] PMID:7562292
  39. Schelonka RL, Katz B, Waites KB, Benjamin DK Jr, . Critical appraisal of the role of Ureaplasma in the development of bronchopulmonary dysplasia with metaanalytic techniques.Pediatr Infect Dis J. 2005;24(12):1033–1039. doi:10.1097/01.inf.0000190632.31565.83 [CrossRef] PMID:16371861
  40. Collins JJ, Kallapur SG, Knox CL, et al. Inflammation in fetal sheep from intra-amniotic injection of Ureaplasma parvum. Am J Physiol Lung Cell Mol Physiol. 2010;299(6):L852–L860. doi:10.1152/ajplung.00183.2010 [CrossRef] PMID:20935228
  41. Viscardi RM, Atamas SP, Luzina IG, et al. Antenatal Ureaplasma urealyticum respiratory tract infection stimulates proinflammatory, profibrotic responses in the preterm baboon lung. Pediatr Res. 2006;60(2):141–146. doi:10.1203/01.pdr.0000228322.73777.05 [CrossRef] PMID:16864693
  42. Yoder BA, Coalson JJ, Winter VT, Siler-Khodr T, Duffy LB, Cassell GH. Effects of antenatal colonization with ureaplasma urealyticum on pulmonary disease in the immature baboon. Pediatr Res. 2003;54(6):797–807. doi:10.1203/01.PDR.0000091284.84322.16 [CrossRef] PMID:12930907
  43. Grigsby PL, Novy MJ, Sadowsky DW, et al. Maternal azithromycin therapy for Ureaplasma intraamniotic infection delays preterm delivery and reduces fetal lung injury in a primate model. Am J Obstet Gynecol. 2012;207(6):475.e1–475.e14. doi:10.1016/j.ajog.2012.10.871 [CrossRef] PMID:23111115
  44. Senthamaraikannan P, Presicce P, Rueda CM, et al. Intra-amniotic ureaplasma parvum-induced maternal and fetal inflammation and immune responses in rhesus macaques. J Infect Dis. 2016;214(10):1597–1604. doi:10.1093/infdis/jiw408 [CrossRef] PMID:27601620
  45. Benn CS, Thorsen P, Jensen JS, et al. Maternal vaginal microflora during pregnancy and the risk of asthma hospitalization and use of antiasthma medication in early childhood. J Allergy Clin Immunol. 2002;110(1):72–77. doi:10.1067/mai.2002.125833 [CrossRef] PMID:12110824
  46. Okogbule-Wonodi AC, Gross GW, Sun CC, et al. Necrotizing enterocolitis is associated with ureaplasma colonization in preterm infants. Pediatr Res. 2011;69(5 Pt 1):442–447. doi:10.1203/PDR.0b013e3182111827 [CrossRef] PMID:21258263
  47. Wolfs TG, Kallapur SG, Knox CL, et al. Antenatal ureaplasma infection impairs development of the fetal ovine gut in an IL-1-dependent manner. Mucosal Immunol. 2013;6(3):547–556. doi:10.1038/mi.2012.97 [CrossRef] PMID:23149664
  48. Viscardi RM, Hashmi N, Gross GW, Sun CC, Rodriguez A, Fairchild KD. Incidence of invasive ureaplasma in VLBW infants: relationship to severe intraventricular hemorrhage. J Perinatol. 2008;28(11):759–765. doi:10.1038/jp.2008.98 [CrossRef] PMID:18596706
  49. Kasper DC, Mechtler TP, Böhm J, et al. In utero exposure to Ureaplasma spp. is associated with increased rate of bronchopulmonary dysplasia and intraventricular hemorrhage in preterm infants. J Perinat Med. 2011;39(3):331–336. doi:10.1515/jpm.2011.022 [CrossRef] PMID:21526978
  50. Berger A, Witt A, Haiden N, et al. Intrauterine infection with Ureaplasma species is associated with adverse neuromotor outcome at 1 and 2 years adjusted age in preterm infants. J Perinat Med. 2009;37(1):72–78. doi:10.1515/JPM.2009.016 [CrossRef] PMID:18976044
  51. Ozdemır R, Sarı FN, Tunay ZO, et al. The association between respiratory tract Urea-plasma urealyticum colonization and severe retinopathy of prematurity in preterm infants ≤1250 g. Eye (Lond). 2012;26(7):992–996. doi:10.1038/eye.2012.77 [CrossRef] PMID:22562187
  52. Fonseca LT, Silveira RC, Procianoy RS. Ureaplasma bacteremia in very low birth weight infants in Brazil. Pediatr Infect Dis J. 2011;30(12):1052–1055. doi:10.1097/INF.0b013e31822a8662 [CrossRef] PMID:21747320
  53. Clifford V, Tebruegge M, Everest N, Curtis N. Ureaplasma: pathogen or passenger in neonatal meningitis?Pediatr Infect Dis J. 2010;29(1):60–64. doi:10.1097/INF.0b013e3181b21016 [CrossRef] PMID:19910840
  54. Viscardi RM. Ureaplasma species: role in diseases of prematurity. Clin Perinatol. 2010;37(2):393–409. doi:10.1016/j.clp.2009.12.003 [CrossRef] PMID:20569814
  55. Normann E, Lacaze-Masmonteil T, Eaton F, Schwendimann L, Gressens P, Thébaud B. A novel mouse model of Ureaplasma-induced perinatal inflammation: effects on lung and brain injury. Pediatr Res. 2009;65(4):430–436. doi:10.1203/PDR.0b013e31819984ce [CrossRef] PMID:19127208
  56. Waites KB, Duffy LB, Bébéar CM, et al. Standardized methods and quality control limits for agar and broth microdilution susceptibility testing of Mycoplasma pneumoniae, Mycoplasma hominis, and Ureaplasma urealyticum. J Clin Microbiol. 2012;50(11):3542–3547. doi:10.1128/JCM.01439-12 [CrossRef] PMID:22915608
  57. Cheah FC, Anderson TP, Darlow BA, Murdoch DR. Comparison of the mycoplasma duo test with PCR for detection of urea-plasma species in endotracheal aspirates from premature infants. J Clin Microbiol. 2005;43(1):509–510. doi:10.1128/JCM.43.1.509-510.2005 [CrossRef] PMID:15635030
  58. Redelinghuys MJ, Ehlers MM, Dreyer AW, Lombaard HA, Kock MM. Comparison of the new Mycofast Revolution assay with a molecular assay for the detection of genital mycoplasmas from clinical specimens. BMC Infect Dis. 2013;13(1):453. doi:10.1186/1471-2334-13-453 [CrossRef] PMID:24079603
  59. Xiao L, Glass JI, Paralanov V, et al. Detection and characterization of human Ureaplasma species and serovars by real-time PCR. J Clin Microbiol. 2010;48(8):2715–2723. doi:10.1128/JCM.01877-09 [CrossRef] PMID:20554828
  60. Bayraktar MR, Ozerol IH, Gucluer N, Celik O. Prevalence and antibiotic susceptibility of Mycoplasma hominis and Urea-plasma urealyticum in pregnant women. Int J Infect Dis. 2010;14(2):e90–e95. doi:10.1016/j.ijid.2009.03.020 [CrossRef] PMID:19515594
  61. Donders GGG, Ruban K, Bellen G, Petricevic L. Mycoplasma/Ureaplasma infection in pregnancy: to screen or not to screen. J Perinat Med. 2017;45(5):505–515. doi:10.1515/jpm-2016-0111 [CrossRef] PMID:28099135
  62. Harada K, Tanaka H, Komori S, et al. Vaginal infection with Ureaplasma urealyticum accounts for preterm delivery via induction of inflammatory responses. Microbiol Immunol. 2008;52(6):297–304. doi:10.1111/j.1348-0421.2008.00039.x [CrossRef] PMID:18577163
  63. Kataoka S, Yamada T, Chou K, et al. Association between preterm birth and vaginal colonization by mycoplasmas in early pregnancy. J Clin Microbiol. 2006;44(1):51–55. doi:10.1128/JCM.44.1.51-55.2006 [CrossRef] PMID:16390947
  64. Witt A, Berger A, Gruber CJ, et al. Increased intrauterine frequency of Ureaplasma urealyticum in women with preterm labor and preterm premature rupture of the membranes and subsequent cesarean delivery. Am J Obstet Gynecol. 2005;193(5):1663–1669. doi:10.1016/j.ajog.2005.03.067 [CrossRef] PMID:16260207
  65. Lis R, Rowhani-Rahbar A, Manhart LE. Mycoplasma genitalium infection and female reproductive tract disease: a meta-analysis. Clin Infect Dis. 2015;61(3):418–426. doi:10.1093/cid/civ312 [CrossRef] PMID:25900174
  66. Eschenbach DA, Nugent RP, Rao AV, et al. The Vaginal Infections and Prematurity Study Group. A randomized placebo-controlled trial of erythromycin for the treatment of Ureaplasma urealyticum to prevent premature delivery. Am J Obstet Gynecol. 1991;164(3):734–742. doi:10.1016/0002-9378(91)90506-M [CrossRef] PMID:2003533
  67. Ozdemir R, Erdeve O, Dizdar EA, et al. Clarithromycin in preventing broncho-pulmonary dysplasia in Ureaplasma urealyticum-positive preterm infants. Pediatrics. 2011;128(6):e1496–e1501. doi:10.1542/peds.2011-1350 [CrossRef] PMID:22123897
  68. Raynes Greenow CH, Roberts CL, Bell JC, Peat B, Gilbert GL, Parker S. Antibiotics for ureaplasma in the vagina in pregnancy. Cochrane Database Syst Rev. 2011;(9):CD003767. doi:10.1002/14651858.CD003767.pub3 [CrossRef] PMID:21901685
  69. Bowman ED, Dharmalingam A, Fan WQ, Brown F, Garland SM. Impact of erythromycin on respiratory colonization of Ureaplasma urealyticum and the development of chronic lung disease in extremely low birth weight infants. Pediatr Infect Dis J. 1998;17(7):615–620. doi:10.1097/00006454-199807000-00008 [CrossRef] PMID:9686728
  70. Jónsson B, Rylander M, Faxelius G. Ureaplasma urealyticum, erythromycin and respiratory morbidity in high-risk preterm neonates. Acta Paediatr. 1998;87(10):1079–1084. doi:10.1111/j.1651-2227.1998.tb01418.x [CrossRef] PMID:9825977
  71. Ballard HO, Shook LA, Bernard P, et al. Use of azithromycin for the prevention of bronchopulmonary dysplasia in pre-term infants: a randomized, double-blind, placebo controlled trial. Pediatr Pulmonol. 2011;46(2):111–118. doi:10.1002/ppul.21352 [CrossRef] PMID:20963840
  72. Ballard HO, Anstead MI, Shook LA. Azithromycin in the extremely low birth weight infant for the prevention of bronchopulmonary dysplasia: a pilot study. Respir Res. 2007;8(1):41. doi:10.1186/1465-9921-8-41 [CrossRef] PMID:17550598
  73. Viscardi RM, Terrin ML, Magder LS, et al. Randomised trial of azithromycin to eradicate Ureaplasma in preterm infants [published online ahead of print March 13, 2020]. Arch Dis Child Fetal Neonatal Ed. doi:10.1136/archdischild-2019-318122 [CrossRef] PMID:32170033
  74. Nair V, Loganathan P, Soraisham AS. Azithromycin and other macrolides for prevention of bronchopulmonary dysplasia: a systematic review and meta-analysis. Neonatology. 2014;106(4):337–347. doi:10.1159/000363493 [CrossRef] PMID:25278176
  75. Merchan LM, Hassan HE, Terrin ML, et al. Pharmacokinetics, microbial response, and pulmonary outcomes of multidose intravenous azithromycin in preterm infants at risk for Ureaplasma respiratory colonization. Antimicrob Agents Chemother. 2015;59(1):570–578. doi:10.1128/AAC.03951-14 [CrossRef] PMID:25385115
  76. Viscardi R, Terrin M, Magder L, et al. Azithromycin (AZM) reduces death or severe respiratory morbidity at 12 month adjusted age (AA) in Ureaplasma-positive intubated preterms. Euro Resp J. 2018;52:OA301. doi:10.1183/13993003.congress-2018.OA301 [CrossRef]
  77. Keelan JA, Payne MS, Kemp MW, Ireland DJ, Newnham JP. A new, potent, and placenta-permeable macrolide antibiotic, solithromycin, for the prevention and treatment of bacterial infections in pregnancy. Front Immunol. 2016;7:111. doi:10.3389/fimmu.2016.00111 [CrossRef] PMID:27066004
  78. Eberly MD, Eide MB, Thompson JL, Nylund CM. Azithromycin in early infancy and pyloric stenosis. Pediatrics. 2015;135(3):483–488. doi:10.1542/peds.2014-2026 [CrossRef] PMID:25687145
  79. Keus AMJMH, Peeters DD, Bekker VV, et al. Neonatal meningitis and subdural empyema caused by an unusual pathogen. Pediatr Infect Dis J. 2019;38(12):e329–e331. doi:10.1097/INF.0000000000002482 [CrossRef] PMID:31738340
  80. Patel K, Goldman JL. Safety concerns surrounding quinolone use in children. J Clin Pharmacol. 2016;56(9):1060–1075. doi:10.1002/jcph.715 [CrossRef] PMID:26865283
Authors

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: alisonchu@mednet.ucla.edu.

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.

10.3928/19382359-20200625-01

Sign up to receive

Journal E-contents