ISSN: 0973-7510

E-ISSN: 2581-690X

Mini Review | Open Access
Tatyana Bodurska1, Emiliana Konova2, Svetlana Pachkova1and Angel Yordanov3
1Medical Center, Clinical Institute for Reproductive Medicine, Bul Skobelev 20, 5800 Pleven, Bulgaria.
2Center for Reproductive Health, Medical University Pleven, Sv. Kliment Ohridski Str. 5800 Pleven, Bulgaria.
3Department of Gynecologic Oncology, Medical University Pleven, Bul. Georgi Kochev 8A, Pleven, Bulgaria.
J Pure Appl Microbiol. 2021;15(4):1727-1734 | Article Number: 7220
https://doi.org/10.22207/JPAM.15.4.03 | © The Author(s). 2021
Received: 05/08/2021 | Accepted: 16/09/2021 | Published: 07/10/2021
Abstract

Currently, unlike in the past, the endometrial cavity is not considered to be sterile. The endometrium is supposed to be dominated by Lactobacilli, but also their deficiency can be found in the reproductive tract of asymptomatic healthy women. Sometimes the endometrial microbiome is dominated by various pathological microorganisms, and this can lead to various conditions as chronic endometritis, chorioamnionitis and preterm birth. Their presence causes uterine inflammation and infection, release of pro-inflammatory molecules, uterine contractions, disruption of cervical barrier, premature rupture of membranes. Uterine dysbiosis is associated with recurrent implantation failure and recurrent miscarriages. As the microbiome is important for maintaining immunological homeostasis  at the level of gastrointestinal tract  Lactobacilli may play a similar function at the level of uterus. The lactobacillus-dominated uterine microbiome is of great importance for maintaining a hostile uterine microenvironment, embryo implantation, early pregnancy development and normal pregnancy outcome.

Keywords

Lactobacillus, assisted reproductive techniques, pregnancy, endometritis, preeclapsia, chorioamnionits

Introduction

Studies have established the presence of a functioning microbiome in the endometrium under defined physiological conditions.1,2 Pathogens isolation obtained from samples of endometria was initially considered contamination from vaginal contents or attributed to various gynecological diseases.3,4 Like the vaginal microbiota in healthy and asymptomatic women, Lactobacilli dominate the endometrium.2 Non-Lactobacillus-dominated microbiome can be found in the reproductive tract of asymptomatic physically healthy women, which suggests it may be assumed as a norm.5

The colonization of the uterine cavity is mainly due to the transfer of bacteria from the vagina. This presumption is supported by the involvement of a biofilm containing Gardnerella vaginalis affixed to the endometrium and the fallopian tubes in women diagnosed with bacterial vaginosis.6 Nevertheless, in some women, other uterine conditions with different physicochemical or biological properties may cause colonization by bacteria distinct from those in the vagina.

Since the vagina is home to billions of bacteria, the cervix should be a perfect barrier to their ascension to the uterine cavity and tubes. The physical barrier provided by the cervical mucus, the high levels of antimicrobial peptides, inflammatory cytokines, immunoglobulins, and matrix-degrading enzymes are considered to act as protection from bacterial ascension.7-13 However, the composition and pH of cervical mucus change during monthly menstruation, which can lead to its overcoming as a barrier under certain conditions. The uterine peristaltic pump assists in the transmission of sperm from the cervical canal up to the fallopian tubes. It may be involved in the spread of bacteria in the uterus.14 During the follicular phase of the menstrual cycle, uterine contractions are at their highest frequency. Additionally, different uterine conditions can increase the spread of bacteria through hyper- and dysregulation of uterine contractions.15 In addition, assisted reproductive technology (ART) procedures can lead to dissipation of the uterine microbiota and negative reproductive and gynecological results by disrupting the local microenvironment.16

A 2017 study of the microbiome from the vagina to the peritoneal cavity confirmed the presence of an active bacterial microbiota in the urogenital tract of reproductive women, showing that human fetal development is not a sterile event.17 Following the dynamics and composition of the microbiome in different regions of the reproductive tract, the authors found that most types of Lactobacilli dominating the vagina continue to dominate in the uterine cavity. The only difference was that their amount in the vagina was 4 times higher than in the endometrium. According to other authors, this difference is between 100 and 10,000 times.1 This difference in amount means that either the cervix helps as an incomplete filter block for ascending microorganisms, or the immune response in the endometrium washes bacteria that have been able to ascend, or both. Mitchell et al. compare the vaginal and endometrial microbiome composition in healthy, non-pregnant women.1 Prevotella species (76%), Lactobacillus iners (61%), and Lactobacillus crispatus [56%] were found in the vaginal microbiome, and the same basic species were found in the upper genital tract (endometrium and upper endocervix), but in different proportions – Lactobacillus iners (45%), Prevotella species (33%) and Lactobacillus crispatus (33%). According to the same authors, microorganisms in the upper endocervix and the endometrium can remain there even after they have disappeared from the vagina or have better development than in the vagina. The low presence of Lactobacilli in the uterine cavity may indicate that the vaginal microbiota might not be a constant source of Lactobacilli for the endometrium. Walther-Antonio et al. believe that bacterial satiation in the vagina cannot prognosticate bacterial satiation in the cervix and endometrium.18 Bacterial satiation in the cervix is related to that in the endometrium; their bacterial profiles are very similar but different from that of the vagina.19

Despite the many similarities in the cervical and endometrial profiles, there are still differences between them. Most notably, there are more Lactobacilli in the cervix than in the endometrium.

Microbiome in assisted reproduction
The vaginal microbiome is primarily assessed in the Human Microbiome Project. Some of the data emerging from this analysis are about diversity. The vaginal tract shows the smallest diversity compared to other body areas, such as the mouth and skin. The most significant variety is found in the oral cavity. Regardless of the vaginal sample level – vaginal introitus, middle or posterior fornix, the species variation is not considerable, and Lactobacilli dominate at all levels. Vaginal communities in healthy people show low diversity and it is easier to identify a pathological condition.20 The highest diversity in the vaginal microbiome is found in BV (bacterial vaginosis).21 The vaginal microbime may serve as a predictor for outcome in Assisted reproductive techniques.22,23 Concerning the endometrial microbiome, until recently, upper genital tract colonization was considered nothing other than pathological.7-9,12,24

The endometrial microbiome is of major interest in reproductive health studies regarding its effect on the onset and development of pregnancy. Good knowledge of what a healthy endometrial environment is and how to obtain it would favor women conducting ART (Assisted reproductive techniques) and any woman who would like to get pregnant.25

The role of uterine infection is well known in infertility – the microorganisms cause inflammation and activate the immune system in the endometrium which can lead to the problems with the implantation and the beginning of a successful conception. A 2016 survey26 of patients with recurrent implantation failure and recurrent miscarriages or both found dysbiosis with a shift in the ratio of Lactobacilli-dominant environment towards missing or reduced Lactobacilli environment. Other studies of patients with subfertility confirm the above.27 In these patients, the dominant bacteria in the endometrium were the Firmicutes, Bacteroides, and Proteobacteria types.

The endometrial microbiome can be classified as Lactobacillus-dominant or non-Lactobacillus-dominant according to the structure and relative predominance of bacteria in the endometrial fluids, with a cut-off value of more than 90% Lactobacilli as the only significant predictors of reproductive effectiveness. Hence, the non-Lactobacillus-dominant (less than 90%) endometrial microbiome is associated with poor achievement of fertility intentions measured by implantation, pregnancy, current pregnancy, and miscarriage, compared to the Lactobacillus-dominant endometrial microbiome.28 It all comes together to show the importance of Lactobacilli for reproductive health.29-32

At the gastrointestinal tract level, the microbiome is essential for maintaining immunological homeostasis, stimulating mucosal immunity, and averting excessive inflammation.33,34 Mucosal T-regulatory cells maintain a tolerance environment and are selected by interactions with the commensal intestinal microbiome.35 T-regulatory cells are essential for embryo implantation and early placental development.36,37 Moore et al. established a higher percentage of live births in cases of Lactobacilli present at the tip of the embryo transfer catheter,38 which suggests that intrauterine commensal bacteria have a similar role in the selection of intrauterine T-regulatory cells.

Microbiome and pregnancy
The high consistency of the vaginal microbiota during pregnancy is due to high estrogen concentrations, lack of menstruation, changes in the cervical and vaginal environment.18 Lactobacilli may have a preventive effect against the ascension of pathological microorganisms from the vagina to the maternal-fetal interface, preventing pregnancy damage.39 Numerous studies have shown that bacteria and viruses can colonize the maternal-fetal interface and amniotic fluid even in healthy pregnancies in women at term.40-43 Three different mechanisms responsible for the colonization of the fetus by microorganisms have been suggested. The first two mechanisms are distinctly described: advancement from the vagina to the uterus or hematogenous spread from the oral cavity to the placenta. The third hypothesis originates in recent studies connecting bacterial populations present in the endometrial and gastrointestinal microbiome.44

Irrespective of the pathway of colonization, bacterial transmission from mother to fetus may play a substantive role in maintaining pregnancy, fetal development, preparing the fetal microbiota for optimal postnatal health.

Placental microbiome
Bacterial isolation from normal pregnancy at term was first successful in 1988 using culture-dependent techniques.45 The morphological evidence of sterile placenta harvested from preterm and at-term pregnancies demonstrated the representation of intracellular bacteria with diverse morphology in the placenta’s basal part.46 These data have been recently confirmed by low biomass sequencing of the placental microbiome, which is established to be unique and composed of Proteobacteria, Actinobacteria, Firmicutes, Bacteroides, Tenericutes, and phylum Fusobacteria.47 As bacterial colonization of the placenta happens in physiological conditions, microorganisms may play a favorable role in pregnancy and fetus development. Commensal colonization of the fetus by commensal bacteria may be involved in the induction of endotoxin tolerance in future bacterial exposure, prevent subsequent pathogenic access to host cells, and prepare the neonatal gastrointestinal tract for feeding.34

Preterm birth
Premature birth is a primary cause of fetal and neonatal morbidity and mortality worldwide.48 Intrauterine microbial infection, which affects the choriodecidual space, amnion, chorion, placenta, amniotic fluid, umbilical cord, or fetus, causes 25 – 40% of preterm births.49,50 The change in the normal endometrial microbiome with an increase in Ureaplasma urealyticum, Ureaplasma parvum, Mycoplasma hominis, Escherichia coli, Bacteroides species, Gardnerella vaginalis, Sneathia sanguinegens, Streptococcus species, Fusobacterium nucleatum, accompanied by a decrease in Lactobacillus crispatus, is associated with preterm birth.51-54 Underlying causes of infection-induced preterm birth include the release of pro-inflammatory molecules like IL-1b, IL-6, IL-8, MCP-1, TNF-α, and prostaglandins, which induce uterine contractions with simultaneous bacterial activation of matrix metalloproteinases and hyaluronidases disrupting the cervical epithelial barrier and causing preterm birth.55-58 For the reasons listed above and to prevent premature birth, attempts have been made to use antibiotics during the second and third trimesters of pregnancy. The only result has been a reduction in maternal infection but not premature birth itself. A possible explanation for this result is the negative effect of antibiotics on pathogenic microorganisms and beneficial bacteria in the genital tract.59

Chorioamnionitis
Chorioamnionitis is a complication generated by inflammed fetal membranes due to bacterial infection. This intraamniotic infection is polymicrobial, most often including Streptococcus agalactiae, Fusobacterium nucleatum and Ureaplasma parvum. Severe chorioamnionitis is found on the fetal side of the placenta with colonization by Corynebacterium species, Escherichia coli, Peptostreptococcus magnus, Prevotella bivia, Streptococcus species and genital mycoplasmas.41,54,60-62 These bacteria may result from the ascension of microorganisms from the vagina and uterine colonization.63 Their development on chorion and amnion induces immunological and inflammatory changes which can cause an early rupture of the membranes. However, in this case, antibiotic therapy is highly recommended because it reduces chorioamnionitis, prolongs the time to birth at full term, and reduces neonatal infections.64

Preeclampsia
Despite decades of research, the modes by which pregnancy causes or exacerbates hypertension remain unclear, and hypertensive conditions persist to be an essential factor in maternal morbidity and mortality worldwide. Preeclampsia is more probable to develop in women who first come in contact with chorionic villi (nulliparous); who are genetically predisposed to the development of hypertensive conditions during pregnancy; who have pre-existing conditions correlated with endothelial cells induction or inflammation such as diabetes, cardiovascular or kidney disease, or immunological disorders; or females who are susceptible to an increased amount of chorionic villi (multiple pregnancies, molar pregnancy). Currently, four main assumptions for the development of preeclampsia have been accepted: immunological intolerance of either maternal, paternal, or fetal tissues; defective trophoblastic invasion; oxidative stress, leading to endothelial cell disruption; genetic predisposition, and epigenetic factors.65

An association between preeclampsia and bacterial infection, premised on microbial cultures and targeted PCR for the bacterial 16S rRNA gene in patients with preeclampsia, has recently been proposed.66,67 The authors examined the placenta of patients with preeclampsia and found bacterial species typically found in the oral cavity – Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythensis and Treponema denticola. Another study found Lactobacillus iners and bacteria of the genera Leptotrichia, Sneathia, Streptococcus and Ureaplasma in the amniotic fluid of patients with preeclampsia.66 A correlation between the quantitative increase of bacteria in the placenta of women with preeclampsia and normotensive women has been established. The 16S rRNA metagenomics analysis of placentas from women with preeclampsia found bacteria routinely related to gastrointestinal infections (Bacillus, Escherichia, Listeria and Salmonella), respiratory tract infections (Anoxybacillus) and periodontal infections (Dialister, Porphyromonas, Prevotella and Variovorax).68 The variety of bacterial species present in preeclampsia conditions suggests more likely the presence of more infectious agents than a specific pathogen. The association of polymicrobial communities and preeclampsia is based on the triggering inflammatory and antiangiogenic activity with subsequent impaired trophoblastic and endothelial function and increased blood pressure.

CONCLUSION

Pregnancy is a complex process of fertilization, implantation of fertilized ovum, embryonic and fetal tissue growth and differentiation. A lot of changes in maternal organism are developed in order to promote this process and also a lot of factors, internal and external, may complicate it. With rapidly developing new technologies more information is added but more data is still needed to fully understand these complex relationships. Although some authors cannot confirm presence of endometrial microbiome or its impact on pregnancy a lot of data is almost available acknowledging its influence both in normal and pathologic conditions.

Declarations

ACKNOWLEDGMENTS
None.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.

AUTHORS’ CONTRIBUTION
TB conceptualize, investigate and visualize the study and drafted the manuscript. EK, SP designed the methodology. SP performed formal analysis.TB, EK collected the resources. AY,  EK wrote, review and edited the manuscript. AY did the supervision.

FUNDING
None.

ETHICS STATEMENT
This article does not contain any studies with human participants or animals performed by any of the authors.

AVAILABILITY OF DATA
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References
  1. Mitchell CM, Haick A, Nkwopara E, et al. Colonization of the upper genital tract by vaginal bacterial species in nonpregnant women. Am J Obstet Gynecol. 2015;212(5):611.e1-611.e9.
    Crossref
  2. Moreno I, Codoner FM, Vilella F, et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol. 2016;215(6):684-703.
    Crossref
  3. Moller BR, Kristiansen FV, Thorsen P, Frost L, Mogensen SC. Sterility of the uterine cavity. Acta Obstet Gynecol Scand. 1995;74(3):216-219.
    Crossref
  4. Hemsell DL, Obregon VL, Heard MC, Nobles BJ. Endometrial bacteria in asymptomatic, nonpregnant women. J Reprod Med. 1989;34(11):872-874. PMID: 2585386.
  5. Ravel J, Gajer P, Abdo Z, et al. Vaginal microbiome of reproductive-age women. Proc Natl Acad Sci USA. 2011;108(Suppl 1):4680-4687.
    Crossref
  6. Swidsinski A, Verstraelen H, Loening-Baucke V, Swidsinski S, Mendling W, Halwani Z. Presence of a polymicrobial endometrial biofilm in patients with bacterial vaginosis. PLoS One. 2013;8(1):e53997.
    Crossref
  7. Ulcova-Gallova Z. Immunological and physicochemical properties of cervical ovulatory mucus. J Reprod Immunol. 2010;86(2):115-121.
    Crossref
  8. Lieberman JA, Moscicki AB, Sumerel JL, Ma Y, Scott ME. Determination of cytokine protein levels in cervical mucus samples from young women by a multiplex immunoassay method and assessment of correlates. Clin Vaccine Immunol. 2008;15(1):49-54.
    Crossref
  9. Ming L, Xiaoling P, Yan L, et al. Purification of antimicrobial factors from human cervical mucus. Hum Reprod. 2007;22(7):1810-1815.
    Crossref
  10. Hein M, Helmig RB, Schonheyder HC, Ganz T, Uldbjerg N. An in vitro study of antibacterial properties of the cervical mucus plug in pregnancy. Am J Obstet Gynecol. 2001;185(3):586-592.
    Crossref
  11. Hein M, Valore EV, Helmig RB, Uldbjerg N, Ganz T. Antimicrobial factors in the cervical mucus plug. Am J Obstet Gynecol. 2002;187(1):137-144.
    Crossref
  12. Hein M, Petersen AC, Helmig RB, Uldbjerg N, Reinholdt J. Immunoglobulin levels and phagocytes in the cervical mucus plug at term of pregnancy. Acta Obstet Gynecol Scand. 2005;84(8):734-742.
    Crossref
  13. Becher N, Hein M, Danielsen CC, Uldbjerg N. Matrix metalloproteinases in the cervical mucus plug in relation to gestational age, plug compartment, and preterm labor. Reprod Biol Endocrinol. 2010;8:113.
    Crossref
  14. Kunz G, Beil D, Deiniger H, Einspanier A, Mall G, Leyendecker G. The uterine peristaltic pump. Normal and impeded sperm transport within the female genital tract. Adv Exp Med Biol. 1997;424:267-277.
    Crossref
  15. Kunz G, Leyendecker G. Uterine peristaltic activity during the menstrual cycle: characterization, regulation, function and dysfunction. Reprod Biomed Online. 2002;4(Suppl 3):5-9.
    Crossref
  16. Pereira N, Hutchinson AP, Lekovich JP, Hobeika E, Elias RT. Antibiotic Prophylaxis for Gynecologic Procedures prior to and during the Utilization of Assisted Reproductive Technologies: A Systematic Review. J Pathog. 2016;2016:4698314.
    Crossref
  17. Chen C, Song X, Wei W, et al. The microbiota continuum along the female reproductive tract and its relation to uterine-related diseases. Nat Commun. 2017;8(1):875.
    Crossref
  18. Walther-Antonio MR, Jeraldo P, Miller MEB, et al. Pregnancy’s stronghold on the vaginal microbiome. PLoS One. 2014;9(6):e98514.
    Crossref
  19. Pelzer ES, Willner D, Buttini M, Huygens F. A role for the endometrial microbiome in dysfunctional menstrual bleeding. Antonie Van Leeuwenhoek. 2018;111(6):933-943.
    Crossref
  20. Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature. 2012;486(7402):207-214.
    Crossref
  21. Fredricks DN, Fiedler TL, Marrazzo JM. Molecular identification of bacteria associated with bacterial vaginosis. N Engl J Med. 2005;353(18):1899-1911.
    Crossref
  22. Haahr T, Humaidan P, Elbaek HO, et al. Vaginal Microbiota and In Vitro Fertilization Outcomes: Development of a Simple Diagnostic Tool to Predict Patients at Risk of a Poor Reproductive Outcome. J Infect Dis. 2019;219(11):1809-1817.
    Crossref
  23. Koedooder R, Singer M, Schoenmakers S, et al. The vaginal microbiome as a predictor for outcome of in vitro fertilization with or without intracytoplasmic sperm injection: a prospective study. Hum Reprod. 2019;34(6):1042-1054.
    Crossref
  24. Ansbacher R, Boyson WA, Morris JA. Sterility of the uterine cavity. Am J Obstet Gynecol. 1967;99(3):394-396.
    Crossref
  25. Graspeuntner S, Bohlmann MK, Gillmann K, et al. Microbiota-based analysis reveals specific bacterial traits and a novel strategy for the diagnosis of infectious infertility. PLoS One. 2018;13(1):e0191047.
    Crossref
  26. Verstraelen H, Vilchez-Vargas R, Desimpel F, et al. Characterisation of the human uterine microbiome in non-pregnant women through deep sequencing of the V1-2 region of the 16S rRNA gene. PeerJ. 2016;4:e1602.
    Crossref
  27. Van Oostrum N, De Sutter P, Meys J, Verstraelen H. Risks associated with bacterial vaginosis in infertility patients: a systematic review and meta-analysis. Hum Reprod. 2013;28(7):1809-1815.
    Crossref
  28. Moreno I, Garcia-Grau I, Perez-Villaroya D, et al. Endometrial microbiota composition is associated with reproductive outcome in infertile patients. medRxiv. 2021.
    Crossref
  29. Kitaya K, Nagai Y, Arai W, Sakuraba Y, Ishikawa T. Characterization of Microbiota in Endometrial Fluid and Vaginal Secretions in Infertile Women with Repeated Implantation Failure. Mediators Inflamm. 2019;2019:4893437.
    Crossref
  30. Kitaya K, Matsubayashi H, Takaya Y, et al. Live birth rate following oral antibiotic treatment for chronic endometritis in infertile women with repeated implantation failure. Am J Reprod Immunol. 2017;78(5):e12719.
    Crossref
  31. Kyono K, Hashimoto T, Kikuchi S, Nagai Y, Sakuraba Y. A pilot study and case reports on endometrial microbiota and pregnancy outcome: An analysis using 16S rRNA gene sequencing among IVF patients, and trial therapeutic intervention for dysbiotic endometrium. Reprod Med Biol. 2018;18(1):72-82.
    Crossref
  32. Hashimoto T, Kyono K. Does dysbiotic endometrium affect blastocyst implantation in IVF patients? J Assist Reprod Genet. 2019;36(12):2471-2479.
    Crossref
  33. Kristensen NB, Bryrup T, Allin KH, Nielsen T, Hansen TH, Pedersen O. Alterations in fecal microbiota composition by probiotic supplementation in healthy adults: a systematic review of randomized controlled trials. Genome Med. 2016;8(1):52.
    Crossref
  34. Sisti G, Kanninen TT, Witkin SS. Maternal immunity and pregnancy outcome: Focus on preconception and autophagy. Genes Immun. 2016;17(1):1-7.
    Crossref
  35. Lathrop SK, Bloom SM, Rao SM, et al. Peripheral education of the immune system by colonic commensal microbiota. Nature. 2011;478(7368):250-254.
    Crossref
  36. Shima T, Sasaki Y, Itoh M, et al. Regulatory T cells are necessary for implantation and maintenance of early pregnancy but not late pregnancy in allogeneic mice. J Reprod Immunol. 2010;85(2):121-129.
    Crossref
  37. Zhou J, Wang Z, Zhao X, Wang J, Sun H, Hu Y. An increase of Treg cells in the peripheral blood is associated with a better in vitro fertilization treatment outcome. Am J Reprod Immunol. 2012;68(2):100-106.
    Crossref
  38. Moore DE, Soules MR, Klein NA, Fujimoto VY, Agnew KJ, Eschenbach DA. Bacteria in the transfer catheter tip influence the live-birth rate after in vitro fertilization. Fertil Steril. 2000;74(6):1118-1124.
    Crossref
  39. Romero R, Hassan SS, Gajer P, et al. Correction: The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women. Microbiome. 2014;2(1):10.
    Crossref
  40. Steel JH, Malatos S, Kennea N, et al. Bacteria and inflammatory cells in fetal membranes do not always cause preterm labor. Pediatr Res. 2005;57(3):404-411.
    Crossref
  41. Onderdonk AB, Hecht JL, McElrath TF, Delaney ML, Allred EN, Leviton A. Colonization of second-trimester placenta parenchyma. Am J Obstet Gynecol. 2008;199(1):52.e1-52.e10.
    Crossref
  42. Gervasi MT, Romero R, Bracalente G, et al. Viral invasion of the amniotic cavity (VIAC) in the midtrimester of pregnancy. J Matern Fetal Neonatal Med. 2012;25(10):2002-2013.
    Crossref
  43. Romero R, Miranda J, Chaiworapongsa T, et al. A novel molecular microbiologic technique for the rapid diagnosis of microbial invasion of the amniotic cavity and intra-amniotic infection in preterm labor with intact membranes. Am J Reprod Immunol. 2014;71(4):330-358.
    Crossref
  44. Solt I. The human microbiome and the great obstetrical syndromes: a new frontier in maternal-fetal medicine. Best Pract Res Clin Obstet Gynaecol. 2015;29(2):165-175.
    Crossref
  45. 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(15):972-978.
    Crossref
  46. Stout MJ, Conlon B, Landeau M, et al. Identification of intracellular bacteria in the basal plate of the human placenta in term and preterm gestations. Am J Obstet Gynecol. 2013;208(3):226.e1-7.
    Crossref
  47. Aagaard K, Ma J, Antony KM, Ganu R, Petrosino J, Versalovic J. The placenta harbors a unique microbiome. Sci Transl Med. 2014;6(237):237ra65.
    Crossref
  48. Lawn JE, Cousens S, Zupan J; Lancet Neonatal Survival Steering Team. 4 million neonatal deaths: when? Where? Why? Lancet. 2005;365(9462):891-900.
    Crossref
  49. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75-84.
    Crossref
  50. Hyman RW, Fukushima M, Jiang H, et al. Diversity of the vaginal microbiome correlates with preterm birth. Reprod Sci. 2014;21(1):32-40.
    Crossref
  51. DiGiulio DB, Callahan BJ, McMurdie PJ, et al. Temporal and spatial variation of the human microbiota during pregnancy. Proc Natl Acad Sci U S A. 2015;112(35):11060-11065.
    Crossref
  52. Jefferson KK. The bacterial etiology of preterm birth. Adv Appl Microbiol. 2012;80:1-22.
    Crossref
  53. Combs CA, Gravett M, Garite TJ, et al. ProteoGenix/Obstetrix Collaborative Research Network. Amniotic fluid infection, inflammation, and colonization in preterm labor with intact membranes. Am J Obstet Gynecol. 2014;210(2):125.e1-125.e15.
    Crossref
  54. Prince AL, Ma J, Kannan PS, et al. The placental membrane microbiome is altered among subjects with spontaneous preterm birth with and without chorioamnionitis. Am J Obstet Gynecol. 2016;214(5):627.e1-627.e16.
    Crossref
  55. Lyon D, Cheng CY, Howland L, et al. Integrated review of cytokines in maternal, cord, and newborn blood: part I-associations with preterm birth. Biol Res Nurs. 2010;11(4):371-376.
    Crossref
  56. Lannon SM, Vanderhoeven JP, Eschenbach DA, Gravett MG, Adams Waldorf KM. Synergy and interactions among biological pathways leading to preterm premature rupture of membranes. Reprod Sci. 2014;21(10):1215-1227.
    Crossref
  57. Romero R, Gotsch F, Pineles B, Kusanovic JP. Inflammation in pregnancy: its roles in reproductive physiology, obstetrical complications, and fetal injury. Nutr Rev. 2007;65(Suppl_3):S194-S202.
    Crossref
  58. Hagberg H, Mallard C, Jacobsson B. Role of cytokines in preterm labour and brain injury. BJOG. 2005;112(Suppl 1):16-18.
    Crossref
  59. Thinkhamrop J, Hofmeyr GJ, Adetoro O, Lumbiganon P, Ota E. Antibiotic prophylaxis during the second and third trimester to reduce adverse pregnancy outcomes and morbidity. Cochrane Database Syst Rev. 2015. 2015(6):CD002250.
    Crossref
  60. DiGiulio DB, Romero R, Kusanovic JP, et al. Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol. 2010;64(1):38-57.
    Crossref
  61. DiGiulio DB, Gervasi MT, Romero R, et al. Microbial invasion of the amniotic cavity in pregnancies with small-for-gestational-age fetuses. J Perinat Med. 2010;38(5):495-502.
    Crossref
  62. Hecht JL, Onderdonk A, Delaney M, et al. Characterization of chorioamnionitis in 2nd-trimester C-section placentas and correlation with microorganism recovery from subamniotic tissues. Pediatr Dev Pathol. 2008;11(1):15-22.
    Crossref
  63. Silver HM, Sperling RS, St Clair PJ, Gibbs RS. Evidence relating bacterial vaginosis to intraamniotic infection. Am J Obstet Gynecol. 1989;161(3):808-812.
    Crossref
  64. Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of membranes. Cochrane Database Syst Rev. 2013;(12):CD001058.
    Crossref
  65. Bardos J, Fiorentino D, Longman RE, Paidas M. Immunological Role of the Maternal Uterine Microbiome in Pregnancy: Pregnancies Pathologies and Alterated Microbiota. Front Immunol. 2020;10:2823.
    Crossref
  66. DiGiulio DB, Gervasi M, Romero R, et al. Microbial invasion of the amniotic cavity in preeclampsia as assessed by cultivation and sequence-based methods. J Perinat Med. 2010;38(5):503-513.
    Crossref
  67. Barak S, Oettinger-Barak O, Machtei EE, Sprecher H, Ohel G. Evidence of periopathogenic microorganisms in placentas of women with preeclampsia. J Periodontol. 2007;78(4):670-676.
    Crossref
  68. Amarasekara R, Jayasekara RW, Senanayake H, Dissanayake VH. Microbiome of the placenta in pre-eclampsia supports the role of bacteria in the multifactorial cause of pre-eclampsia. J Obstet Gynaecol Res. 2015;41(5):662-669.
    Crossref

Article Metrics

Article View: 304

Share This Article

© The Author(s) 2021. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License which permits unrestricted use, sharing, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.