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• Mollicutes and adverse pregnancy outcomes: A challenging research area to navigate
  Axel Skafte-Holm, Thomas Roland Pedersen and Jørgen Skov Jensen
  Published on: 13 March 2023

• Published on: 13 March 2023

  Mollicutes and adverse pregnancy outcomes: A challenging research area to navigate

  • Axel Skafte-Holm, MD Statens Serum Institut, Copenhagen, Denmark
  • Other Contributors:
    • Thomas Roland Pedersen, Cand. Scient. Biology
    • Jørgen Skov Jensen, Consultant physician, MD, PhD, DMedSci.

  Axel Skafte-Holm 1, Thomas Roland Pedersen 1 and Jørgen Skov Jensen 1*
  1 Department of Bacteria, Parasites and Fungi, Research Unit for Reproductive Microbiology, Statens Serum Institut, Copenhagen, Denmark

  *Corresponding author
  Jørgen Skov Jensen
  Consultant physician, MD, PhD, DMedSci.
  Statens Serum Institute
  5 Artillerivej
  DK-2300 Copenhagen S
  Denmark
  Research Unit for Reproductive Microbiology.
  Division of Diagnostic Infectious Disease Preparedness
  Telephone +45 3268 3636
  jsj@ssi.dk

  To the Editor,

  We read with interest the systematic review and meta-analysis by Jonduo et al. [1], investigating the association between Mycoplasma (M.) hominis, Ureaplasma (U.) urealyticum and U. parvum colonisation of the genital tract of pregnant women and adverse pregnancy outcomes. This is a highly relevant analysis, as this subject is a matter of ongoing debate, due to the complex interactions with other microbial and non-microbial factors. It is also a subject where enormous taxonomic confusion exists due to the re-classification of the ureaplasmas. We were, consequently, interested in the comprehensive analysis on the relative importance of the two Ureaplasma spp. Unfortunately, we detected some shortcomings, which need to be discussed.
  (I) Culture-based studies. The review excluded articles published before the year 2000 if unspeciated U. urealyticum were re...

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  Axel Skafte-Holm 1, Thomas Roland Pedersen 1 and Jørgen Skov Jensen 1*
  1 Department of Bacteria, Parasites and Fungi, Research Unit for Reproductive Microbiology, Statens Serum Institut, Copenhagen, Denmark

  *Corresponding author
  Jørgen Skov Jensen
  Consultant physician, MD, PhD, DMedSci.
  Statens Serum Institute
  5 Artillerivej
  DK-2300 Copenhagen S
  Denmark
  Research Unit for Reproductive Microbiology.
  Division of Diagnostic Infectious Disease Preparedness
  Telephone +45 3268 3636
  jsj@ssi.dk

  To the Editor,

  We read with interest the systematic review and meta-analysis by Jonduo et al. [1], investigating the association between Mycoplasma (M.) hominis, Ureaplasma (U.) urealyticum and U. parvum colonisation of the genital tract of pregnant women and adverse pregnancy outcomes. This is a highly relevant analysis, as this subject is a matter of ongoing debate, due to the complex interactions with other microbial and non-microbial factors. It is also a subject where enormous taxonomic confusion exists due to the re-classification of the ureaplasmas. We were, consequently, interested in the comprehensive analysis on the relative importance of the two Ureaplasma spp. Unfortunately, we detected some shortcomings, which need to be discussed.
  (I) Culture-based studies. The review excluded articles published before the year 2000 if unspeciated U. urealyticum were reported alone, as Ureaplasma spp. detected by culture previously were reported as U. urealyticum. In this matter, it is surprising that seven of the included articles [2-8] on U. urealyticum were culture-based. Although bacteriological culture is considered the gold standard it only identifies bacteria at the genus level, preventing differentiation between U. urealyticum (formerly biovar 2, T980, T960T or A) and U. parvum (formerly biovar 1, parvo or B). In the review, all results from culture-based articles were reported as U. urealyticum, probably because primary authors wrongly reported cultured ureaplasmas as U. urealyticum. Unless additional typing of isolates is performed, cultures should always be reported as Ureaplasma spp.
  (II) Confusion on nomenclature. Harada et al. determined the biovar of colonies using PCR-based typing where they reported all U. urealyticum (i.e. Ureaplasma spp.) colonies as biovar type 1 i.e. U. parvum among 23 women experiencing preterm birth, but the systematic review reported findings as U. urealyticum [9]. Two other articles [10, 11] reported on biovar 1 and biovar 2, but were cited only as U. urealyticum and the review failed to include these results in the U. parvum analysis.
  (III) Shortcomings in methodology. Most articles were based on real-time PCR and two articles [12, 13] used multiplex PCR to identify sexually transmitted infections. Some articles used conventional PCR, but one [14] failed to report information on PCR method and consequently evaluation of the species differentiation was not possible. In order to evaluate primers and probes in the studies included in the meta-analysis, we aligned sequences and queried them using the Basic Local Alignment Search Tool (BLAST) [15] against U. urealyticum serovar 8 (NCBI Reference Sequence: NZ_AAYN02000002.1) and U. parvum serovar 3 (NCBI Reference Sequence: NC_002162.1). Most studies correctly distinguished ureaplasmas at the species level. Unfortunately, we found methodological shortcomings in one paper [16], as primer/probe design did not allow discrimination of Ureaplasma spp. Two studies [17, 18] reported U. urealyticum, but alignment results indicated that the primers were 100% specific for U. parvum and contained several mismatches with the U. urealyticum sequence, thus, at best detecting Ureaplasma spp.
  In general, Mollicutes are complicated pathogens and our assessment of the literature demonstrates a laissez-faire approach to nomenclature and methods applied. The diagnostic methodologies applied should be carefully evaluated when assessing studies to allow conclusions about the relation between Ureaplasma spp. and clinical outcomes. The taxonomic and methodological confusion in the literature is concerning, so an in-depth analysis of the area is warranted and we suggest that the review authors update their analysis of associations between the two Ureaplasma spp. and adverse pregnancy outcomes. The review conclusions may not change because the majority of the studies suffered from lack of control for major confounding factors, but at least the combined effect estimates will be more correct.

  References

  1. Jonduo ME, Vallely LM, Wand H, Sweeney EL, Egli-Gany D, Kaldor J, et al. Adverse pregnancy and birth outcomes associated with Mycoplasma hominis, Ureaplasma urealyticum and Ureaplasma parvum: a systematic review and meta-analysis. BMJ Open. 2022;12(8):e062990. DOI: 10.1136/bmjopen-2022-062990.
  2. Lee MY, Kim MH, Lee WI, Kang SY, Jeon YL. Prevalence and Antibiotic Susceptibility of Mycoplasma hominis and Ureaplasma urealyticum in Pregnant Women. Yonsei Med J. 2016;57(5):1271-5. DOI: 10.3349/ymj.2016.57.5.1271.
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  7. Abele-Horn M, Scholz M, Wolff C, Kolben M. High-density vaginal Ureaplasma urealyticum colonization as a risk factor for chorioamnionitis and preterm delivery. Acta Obstet Gynecol Scand. 2000;79(11):973-8. DOI.
  8. Kacerovský M, Pavlovský M, Tosner J. Preterm premature rupture of the membranes and genital mycoplasmas. Acta Medica (Hradec Kralove). 2009;52(3):117-20. DOI: 10.14712/18059694.2016.115.
  9. Harada K, Tanaka H, Komori S, Tsuji Y, Nagata K, Tsutsui H, 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.
  10. Mitsunari M, Yoshida S, Deura I, Horie S, Tsukihara S, Harada T, et al. Cervical Ureaplasma urealyticum colonization might be associated with increased incidence of preterm delivery in pregnant women without prophlogistic microorganisms on routine examination. J Obstet Gynaecol Res. 2005;31(1):16-21. DOI: 10.1111/j.1447-0756.2005.00246.x.
  11. Povlsen K, Thorsen P, Lind I. Relationship of Ureaplasma urealyticum biovars to the presence or absence of bacterial vaginosis in pregnant women and to the time of delivery. Eur J Clin Microbiol Infect Dis. 2001;20(1):65-7. DOI: 10.1007/pl00011237.
  12. Koucký M, Malíčková K, Cindrová-Davies T, Smíšek J, Vráblíková H, Černý A, et al. Prolonged progesterone administration is associated with less frequent cervicovaginal colonization by Ureaplasma urealyticum during pregnancy - Results of a pilot study. J Reprod Immunol. 2016;116:35-41. DOI: 10.1016/j.jri.2016.04.285.
  13. Peretz A, Tameri O, Azrad M, Barak S, Perlitz Y, Dahoud WA, et al. Mycoplasma and Ureaplasma carriage in pregnant women: the prevalence of transmission from mother to newborn. BMC Pregnancy Childbirth. 2020;20(1):456. DOI: 10.1186/s12884-020-03147-9.
  14. Schwab FD, Zettler EK, Moh A, Schötzau A, Gross U, Günthert AR. Predictive factors for preterm delivery under rural conditions in post-tsunami Banda Aceh. J Perinat Med. 2016;44(5):511-5. DOI: 10.1515/jpm-2015-0004.
  15. Zhang Z, Schwartz S, Wagner L, Miller W. A greedy algorithm for aligning DNA sequences. J Comput Biol. 2000;7(1-2):203-14. DOI: 10.1089/10665270050081478.
  16. Aaltone R, Jalava J, Laurikainen E, Kärkkäinen U, Alanen A. Cervical ureaplasma urealyticum colonization: comparison of PCR and culture for its detection and association with preterm birth. Scand J Infect Dis. 2002;34(1):35-40. DOI: 10.1080/00365540110077074.
  17. Montenegro DA, Borda LF, Neuta Y, Gómez LA, Castillo DM, Loyo D, et al. Oral and uro-vaginal intra-amniotic infection in women with preterm delivery: A case-control study. J Investig Clin Dent. 2019;10(2):e12396. DOI: 10.1111/jicd.12396.
  18. Nasution TA, Cheong SF, Lim CT, Leong EW, Ngeow YF. Multiplex PCR for the detection of urogenital pathogens in mothers and newborns. Malays J Pathol. 2007;29(1):19-24. DOI.

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  Conflict of Interest:
  Jørgen Skov Jensen reports grants, personal fees, and non-financial support from Hologic, personal fees from Roche, grants and personal fees from SpeeDx, grants and personal fees from Nabriva, grants and personal fees from Cepheid, grants and personal fees from Abbott, and grants and personal fees from GSK all outside the submitted work.
  The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
  

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