Infecţia cu Mycoplasma în determinismul naşterii premature – review din literatură

 Association between preterm birth and genital colonization with Mycoplasma – literature review

First published: 21 mai 2019

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/Gine.24.2.2019.2375


Preterm labor is responsible for most cases of neonatal death. In most of these cases, the causes have not been established, although several risk factors have been incriminated. My­co­plas­ma hominis is a common vaginal organism that is associated with bacterial vaginosis. The bacterium is con­si­dered inoffensive for the most part in nonpregnant wo­men, but it can cause intraamniotic infections which are associated with inflammation, preterm premature rup­ture of membranes, and preterm birth. The role of these genital tract habitants in their infection during preg­nan­cy and their capacity to invade placental and fe­tal tissue are discussed. In particular, the role of some of these or­ga­nisms in prematurity may be mechanistically as­so­cia­ted to their ability to induce inflammatory cytokines, thus trig­gering pathways causing to premature labor. A re­view of this intensifying research of mycoplasmas in re­la­tion to pregnancy lead to several questions and findings that will be important to examine in future research.

preterm birth, genital mycoplasmas, microbial invasion of the amniotic cavity


Naşterea prematură este responsabilă pentru majoritatea cazurilor de deces neonatal. În cele mai multe dintre aceste cazuri, cauzele nu au fost stabilite, deşi mai mulţi factori de risc sunt incriminaţi. Mycoplasma hominis este un organism asociat vaginozei bacteriene. Infecţia cu Mycoplasma este considerată inofensivă în cea mai mare parte la femeile care nu sunt gravide, dar poate provoca infecţii intraamniotice, care sunt asociate cu inflamaţia, ruptura prematură a mem­branelor şi naşterea prematură. Rolul acestor bac­te­rii ale tractului genital în infecţia din timpul sarcinii şi ca­pa­ci­ta­tea lor de a invada ţesutul placentar şi fetal sunt încă discutate. Rolul unora dintre aceste organisme în pre­ma­tu­ri­tate poate fi mecanic şi asociat cu capacitatea lor de a produce citokine inflamatorii, iniţiind astfel evenimente fi­na­li­zate cu travaliul prematur. O analiză critică a literaturii pri­vind implicarea micoplasmelor în naşterea prematură con­du­ce la câteva constatări importante şi la necesitatea ela­bo­rării unor cercetări viitoare.


Preterm birth is a major public health issue worldwide and a main cause of infant mortality, as well as a serious neonatal morbidity.

Approximately 15 million babies (1 in 10) are born prematurely each year around the world. Prematurity is the leading cause of death among newborns, accounting for 1 million deaths per year, and it is the second leading cause of death in children under the age of 5 years old(1). Lower genital tract colonization of the cervix and vagina by microorganisms is common and found in 70% of women(2). Mycoplasma hominis is a common vaginal inhabitant which is associated with bacterial vaginosis(3,4). The bacterium is considered harmless for the most part in nonpregnant women, but can cause intraamniotic infections, which are associated with inflammation, preterm premature rupture of membranes, and preterm birth(5,6). Genital mycoplasmas are the most frequently isolated organisms from placental membranes and amniotic fluid in chorioamnionitis. Mycoplasmas belong to the class Mollicutes, the smallest free-living organisms. Mycoplasmas are distinguished phenotypically from other bacteria by their minute size and total lack of a cell wall (they are limited by a plasma membrane only), rendering them resistant to -lactam antibiotics(7,8).

Mycoplasma hominis and Ureaplasma urealyticum have been isolated from placental membranes in 47% and 30% of causes of confirmed chorioamnionitis, respectively(9). The mechanism by which lower genital tract colonization leads to adverse pregnancy outcomes is poorly understood. The inflammatory process associated with genital mycoplasmas colonization would be evidenced by placental histologic chorioamnionitis in the absence of bacterial infection, meaning that genital mycoplasmas colonization is associated with histologic chorioamnionitis independent of placental infection with other bacteria(10).

Materials and method

The objective of this study is to analyze the literature related to the implication of Mycoplasma infection in premature birth. The following databases have been reviewed: Pubmed, Medline and Cochrane, using as keywords: preterm birth, genital mycoplasmas, microbial invasion of the amniotic cavity.


A cohort study that implicated >10,000 pregnant women established that women with bacterial vaginosis had an increased risk for preterm birth; among women with bacterial vaginosis, those who were colonized with Mycoplasma hominis had a considerable risk increase(11). Intraamniotic infections can cause inflammation, which triggers spontaneous preterm birth(12). One of three preterm births is associated with microbial invasion of the amniotic cavity(13,14,15). It has been reported that women exposed to microbial invasion of the amniotic cavity have a significantly earlier gestational age at admission and delivery, a shorter latency to delivery, and a worse neonatal outcome compared with women who weren’t exposed to microbial invasion(16,17). Intraamniotic infection is common in births that occur at <32 weeks of gestation. This conclusion is significant because morbidity and death increase with decreasing gestational age at delivery. Mycoplasma hominis is frequently isolated from infected fetal membranes and amniotic fluid, and Ureaplasma is isolated from umbilical cord blood in approximately 20% of very preterm newborn infants (<32 weeks of gestation)(18).

Under normal conditions, the amniotic cavity is sterile for microorganisms, using cultivation and molecular microbiologic techniques, based on the detection of the 16S rRNAgene(19).

The pathogenesis and the cause of preterm birth infectious are poorly understood. Ascending microbial invasion from the lower genital tract appears to be the most frequent pathway for intraamniotic infection(20).

The rupture of membranes is not obligatory for bacteria to reach the amniotic cavity; there is experimental evidence that bacteria can traverse intact membranes(21). Most of these infections are subclinical and occur in the absence of clinical chorioamnionitis(22,23). Therefore, most of these infections are undetected unless the amniotic fluid is analyzed. The most frequent microorganisms detect in the amniotic cavity are genital mycoplasmas(24,25).

Although some studies consider that there is a stage in which the bacteria are diffusely located in the choriodecidual layer, other studies, using FISH with a bacterial 16S rRNA probe, indicate that there is no extensive implication of the chorion-decidua in cases with microbial invasion of the amniotic cavity(26,27).

Microbial invasion of the amniotic cavity induces a strong local inflammatory response, and this is accompanied by a considerable increase in the concentrations of proinflammatory cytokines such as IL-1(28,29), IL-6(30), IL-8(31,32) and TNF-(33).

The primary cells and tissues responsible for the intraamniotic inflammatory response include fetal skin, cells comprising the chorioamniotic membranes, and the umbilical cord. The amnion and chorion-decidua respond to bacterial products by increasing the expression of IL-1(34) and TNF-(35). Amnion cells also synthesize IL-8(36).

In another study, the detection of M. hominis was associated with elevated intraamniotic concentrations of IL-4(37).

The most accurate evidence that intraamniotic infection is associated with acute chorioamnionitis is obtained from studies in which a transabdominal amniocentesis was performed in patients with preterm labor and intact membranes, and the placenta was examined within 48 hours of the procedure. Placentas with acute chorioamnionitis and acute funisitis were from mothers who had intraamniotic infection proven by culture in 71.1% and 78.7% of cases, respectively. The prevalence of microbial invasion of the amniotic cavity was 38%. The negative predictive values of acute chorioamnionitis and funisitis for intraamniotic infection were 87% and 82%, respectively(38).

Recently, it was reported a new type of intraamniotic inflammation termed “sterile inflammation”. Interestingly, sterile intraamniotic inflammation is associated with acute histological chorioamnionitis (40-60% of cases)(39).

Roberts et el. reported, using cultivation and molecular microbiologic techniques, that only 4% of patients with acute histologic chorioamnionitis at term had microorganisms in the placenta(40).

The frequency with which microorganisms invade the human fetus is difficult to establish. Studies in which amniocentesis and cordocentesis have been performed in patients with preterm premature rupture of membranes indicate that 30% of patients with microbial invasion of the amniotic cavity have positive fetal blood cultures for microorganisms(41,42). Similar conclusions have been reported when cultures for genital mycoplasmas have been performed in umbilical cord blood at the time of birth(43,44).

A study conducted in 2015 sequenced genomes of two amniotic fluid isolates and a placental isolate of Mycoplasma hominis from pregnancies that resulted in preterm births and compared them with the previously sequenced genome of the type strain PG21. Genes that were isolated from amniotic fluid and placenta were identified, then the microbial load and the presence of these genes were determined in another set of subjects from which amniotic fluid samples were collected and were positive for Mycoplasma hominis. There were identified two genes that encode surface-located membrane proteins (Lmp1 and Lmp-like) in the sequenced amniotic fluid/placental isolates that were truncated severely in PG21. It has been identified a gene in M. hominis that was significantly associated with colonization or infection of the upper reproductive tract during pregnancy and with premature birth. The pre­sence of the gene was associated with bacterial burden in the amniotic fluid, suggesting that it could play a role in survival. This observation is clinically relevant because the mycoplasmal bacterial burden in amniotic fluid correlates with histological corioamnionitis(45). At present, little information exists about the pathogene­sis of microbial invasion of the amniotic cavity, but in order for a bacterium in the vagina to invade the amniotic cavity, it would probably must colonize the vagina, ascend through the cervix to the uterine cavity, colonize the uterine cavity, and evade immune defenses and potentially other antagonistic bacterial species. In order to cause amnionitis, it would also need to pass the fetal membranes or placenta, and survive and grow in a nutrient-poor, iron-limited amniotic fluid. Probably, this induces premature labor, and it would then have to elicit a maternal or fetal inflammatory response. Randis et al. investigated recently the role of group B Streptococcus -hemolysin/cytolysin in the pathogenesis of ascending group B streptococcal infection using a mouse model(46). It was found that the toxins had a role in vaginal colonization and in inducing inflammation, host tissue injure and preterm birth or fetal death, but they were not required for ascending infection. They found a gene that was associated with bacterial burden in amniotic fluid and with preterm birth, but it was not required for amnionitis. It was not significantly associated with the presence of bacterial load of M. hominis in the vagina, suggesting that it does not play a role in survival in the vagina. Therefore, it may be more likely that the product of this gene is involved in bacterial survival or growth on placenta and in the amniotic cavity rather than being required for ascension or invasion. Of note, they also found that the two isolates from amniotic fluid are more similar to each other than they are to the placental isolate, suggesting that these two strains may have a higher genetic potential for traversing fetal membranes or surviving in amniotic fluid. There were detected differences in genes encoding surface-associated lipoproteins that have been previously implicated in adherence to host cells and colonization. They noted that upon liquid culture, the amniotic fluid/placental strains appeared dispersed, whereas PG21 appeared flocculated and adhered to the plastic culture vessel, suggesting a variation on the bacterial surface. The variation in the sequence and structure of surface lipoproteins likely concur to the avidity of the bacteria for host cells and tissues, and therefore it may be associated with disease outcome. There are found considerable variation bet­ween genes. The genes encoding an Lmp-like protein and Lmp1 are more similar among the amniotic fluid/placental strains than they are to homologs in PG21. These lipoproteins could contribute to adherence to host cells in some way that promotes ascension from the lower to the upper genitourinary tract or colonization of the uterine cavity(47).


The evidence regarding genital mycoplasmas in initiating preterm labor and delivery is becoming more convincing.

It was identified a gene in Mycoplasma hominis which was significantly associated with colonization and infection of the upper reproductive tract during pregnancy and with preterm birth.

Acute chorioamnionitis and acute funisitis are acute inflammatory lesions with important short- and long-term clinical significance. Substantial progress has been made in the understanding of the mechanisms responsible for maternal and fetal inflammation in the context of infection.

The causes of sterile intraamniotic inflammation are unknown, and there are important clinical and scientific challenges. 


Conflict of interests: The authors declare no conflict of interests.


  1. Nawal MN. Premature delivery and the millennium development goal. Rev Obstet Gynecol. 2012; 5(2):100–5.
  2. Cassell GH, Waites KB, Watson HL, Crouse DT, Harasawa R. Ureaplasma Urealyticum intrauterine infection: role in prematurity and disease in newborns. Clin Microbiol Rev. 1993; 6:69-87.
  3. Pereyre S, Sirand-Pugnet P, Beven L, et al. Life on arginine for Mycoplasma hominis: clues from its minimal genome and comparison with other human urogenital. PLoS Genet. 2009 Oct; 5(10):e1000677.
  4. Thorsen P, Jensen IP, Jeune B, et al. Few microorganisms associated with bacterial vaginosis may constitute the pathologic core: a population-based microbiologic study among 3596 pregnant women. Am J Obstet Gynecol. 1998; 178:580-7.
  5. Kwak DW, Hwang HS, Kwon JY, Park YW, Kim YH. Co-infection with vaginal Ureaplasma urealyticum and Mycoplasma hominis increases adverse pregnancy outcomes in patients with preterm labor or preterm premature rupture of membranes. J Matern Fetal Neonatal Med. 2014; 27:333-7.
  6. Wen A, Srinivasan U, Goldberg D, et al. Selected vaginal bacteria and risk of preterm birth: an ecological perspective. J Infect Dis. 2014; 209:1087-94.
  7. Ekiel AM, Friedek DA, Romanik MK, Jóźwiak J, Martirosian G. Occurrence of Ureaplasma parvum and Ureaplasma urealyticum in women with cervical dysplasia in Katowice, Poland. J Korean Med Sci. 2009; 24: 1177-81.
  8. Taylor-Robinson D, Lamont RF. Mycoplasmas in pregnancy. BJOG. 2011; 118(2):164-74.
  9. Hillier SL, Martius J, Krohn M, Kiviat N, Holmes KK, Eschenbach DA. A case-control study of chorioamnionic infection and histologic chorioamnionitis in prematurity. N Engl J Med. 1988; 319:972-8.
  10. Namba F, Hasegawa T, Nakayama M. Placental features of chorioamnionitis colonized with Ureaplasma species in preterm delivery. Pediatr Res. 2010; 67:166-72.
  11. Hillier SL, Nugent RP, Eschenbach DA, et al. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant: the Vaginal Infections and Prematurity Study Group. N Engl J Med. 1995; 333:1737-42.
  12. Combs CA, Gravett M, Garite TJ, et al. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol. 2014; 210:125. e1-15.
  13. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med. 2000; 342:1500-7.
  14. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008; 371:75-84.
  15. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014; 345:760-5.
  16. Cobo T, Palacio M, Navarro-Sastre A, Ribes A, Bosch J, Filella X, et al. Predictive value of combined amniotic fluid proteomic biomarkers and interleukin-6 in preterm labor with intact membranes. Am J Obstet Gynecol. 2009; 200:499.e1–6.
  17. Waites KB, Katz B, Schelonka RL. Mycoplasmas and ureaplasmas as neonatal pathogens. Clin Microbiol Rev. 2005; 18:757–89.
  18. Romero R, Garite TJ. Twenty percent of very preterm neonates (23-32 weeks of gestation) are born with bacteremia caused by genital Mycoplasmas. Am J Obstet Gynecol. 2008;198: 1-3.
  19. Harris JW, Brown H. Bacterial content of the uterus at cesarean section. Am J Obstet Gynecol. 1927; (13):133.
  20. Romero R, Mazor M. Infection and preterm labor. Clin Obstet Gynecol. 1988; 31(3):553–84.
  21. Galask RP, Varner MW, Petzold CR, Wilbur SL. Bacterial attachment to the chorioamniotic membranes. Am J Obstet Gynecol. 1984; 148(7):915–28.
  22. Gravett MG, Hummel D, Eschenbach DA, Holmes KK. Preterm labor associated with subclinical amniotic fluid infection and with bacterial vaginosis. Obstet Gynecol. 1986; 67(2):229–37.
  23. Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel L, Hassan S. The role of inflammation and infection in preterm birth. Semin Reprod Med. 2007; 25(1):21–39.
  24. Romero R, Sirtori M, Oyarzun E, Avila C, Mazor M, Callahan R, et al. Infection and labor. V. Prevalence, microbiology, and clinical significance of intraamniotic infection in women with preterm labor and intact membranes. Am J Obstet Gynecol. 1989; 161(3):817–24.
  25. Allen-Daniels MJ, Serrano MG, Pflugner LP, Fettweis JM, Prestosa MA, Koparde VN, et al. Identification of a gene in Mycoplasma hominis associated with preterm birth and microbial burden in intraamniotic infection. Am J Obstet Gynecol. 2015; 212(6):779.e1-779.e13.
  26. Kim MJ, Romero R, Gervasi MT, Kim JS, Yoo W, Lee DC, et al. Widespread microbial invasion of the chorioamniotic membranes is a consequence and not a cause of intra-amniotic infection. Lab Invest. 2009; 89(8):924–36.
  27. Kim CJ. Acute Chorioamnionitis and Funisitis: Definition, Pathologic Features, and Clinical Significance. Am J Obstet Gynecol. 2015; 213(4 0):S29–S52.
  28. Marconi C, De Andrade Ramos BR, Peracoli JC, Donders GG, Da Silva MG. Amniotic fluid interleukin-1 beta and interleukin-6, but not interleukin-8 correlate with microbial invasion of the amniotic cavity in preterm labor. Am J Reprod Immunol. 2011; 65(6):549–56.
  29. Puchner K, Iavazzo C, Gourgiotis D, Boutsikou M, Baka S, Hassiakos D, et al. Mid-trimester amniotic fluid interleukins (IL-1beta, IL-10 and IL-18) as possible predictors of preterm delivery. In Vivo. 2011; 25(1):141–8.
  30. Kacerovsky M, Musilova I, Andrys C, Hornychova H, Pliskova L, Kostal M, et al. Prelabor rupture of membranes between 34 and 37 weeks: the intraamniotic  inflammatory response and neonatal outcomes. Am J Obstet Gynecol. 2014; 210(4):325, e1–e10.
  31. Figueroa R, Garry D, Elimian A, Patel K, Sehgal PB, Tejani N. Evaluation of amniotic fluid cytokines in preterm labor and intact membranes. J Matern Fetal Neonatal Med. 2005; 18(4):241–7.
  32. Romero R, Chaemsaithong P, Korzeniewski SJ, Tarca AL, Bhatti G, Xu Z, et al. Clinical chorioamnionitis at term II: the intra-amniotic inflammatory response. 
  33. J Perinat Med. 2015; 44(1): 5–22.
  34. Sadowsky DW, Adams KM, Gravett MG, Witkin SS, Novy MJ. Preterm labor is induced by intraamniotic infusions of interleukin-1beta and tumor necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model. Am J Obstet Gynecol. 2006; 195(6):1578–89.
  35. Fidel PL Jr., Romero R, Ramirez M, Cutright J, Edwin SS, Lamarche S, et al. Interleukin-1 receptor antagonist (IL-1ra) production by human amnion, chorion, and decidua. Am J Reprod Immunol. 1994; 32(1):1–7.
  36. Vince G, Shorter S, Starkey P, Humphreys J, Clover L, Wilkins T, et al. Localization of tumour necrosis factor production in cells at the materno/fetal interface in human pregnancy. Clin Exp Immunol. 1992;88(1):174–80.
  37. Laham N, Brennecke SP, Rice GE. Interleukin-8 release from human gestational tissue explants: the effects of lipopolysaccharide and cytokines. Biol Reprod. 1997; 57(3):616–20.
  38. Perni SC, Vardhana S, Korneeva I, Tuttle SL, Paraskevas LR, Chasen ST et al. Mycoplasma hominis and Ureaplasma urealyticum in midtrimester amniotic fluid: association with amniotic fluid cytokine levels and pregnancy outcome. Am J Obstet Gynecol. 2004; 191:1382-6.
  39. Romero R, Salafia CM, Athanassiadis AP, Hanaoka S, Mazor M, Sepulveda W, et al. The relationship between acute inflammatory lesions of the preterm placenta and amniotic fluid microbiology. Am J Obstet Gynecol. 1992; 166(5):1382–8.
  40. Romero R, Miranda J, Chaiworapongsa T, Korzeniewski SJ, Chaemsaithong P, Gotsch F, et al. Prevalence and clinical significance of sterile intra-amniotic inflammation in patients with preterm labor and intact membranes. Am J Reprod Immunol. 2014; 72(5):458–74.
  41. Roberts DJ, Celi AC, Riley LE, Onderdonk AB, Boyd TK, Johnson LC, et al. Acute histologic chorioamnionitis at term: nearly always noninfectious. PLoS One. 2012; 7(3):e31819.
  42. Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM. The fetal inflammatory response syndrome. Am J Obstet Gynecol. 1998; 179(1):194–202.
  43. Romero R, Gomez R, Ghezzi F, Yoon BH, Mazor M, Edwin SS, et al. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol. 1998; 179(1):186–93.
  44. Romero R, Garite TJ. Twenty percent of very preterm neonates (23-32 weeks of gestation) are born with bacteremia caused by genital Mycoplasmas. Am J Obstet Gynecol. 2008; 198(1):1–3.
  45. Goldenberg RL, Andrews WW, Goepfert AR, Faye-Petersen O, Cliver SP, Carlo WA, 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, e1–5.
  46. Allen-Daniels MJ, et al. Identification of a gene in Mycoplasma hominis associated with preterm birth and microbial burden in intra-amniotic infection. Am J Obstet Gynecol. 2015; 212(6):779.e1–779.e13.
  47. Randis TM, Gelber SE, Hooven TA, et al. Group B Streptococcus beta-hemolysin/Cytolysin breaches maternal-fetal barriers to cause preterm birth and intrauterine fetal demise in vivo. J Infect Dis. 2014; 210:265–73.
  48. Razin S, Yogev D, Naot Y. Molecular biology and pathogenicity of mycoplasmas. Microbiol Mol Biol Rev. 1998; 62:1094–156.

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