Initiation of labor activity as a multifactor mechanism of communication between maternal and fetal compartments

Gaidarova A.R., Gusar V.A., Baev O.R.

1) Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, Moscow, Russia; 2) I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia
The timely spontaneous onset of labor is a coordinated process of interaction between the maternal and fetal organisms. The initiation of this process is contributed by various mechanisms, including the secretion of proinflammatory cytokines and chemokines with subsequent activation of the nuclear transcription factor NF-kB, the decreased progesterone receptor function, mechanical uterine distension that promotes the expression of monocyte chemotactic protein-1. The participation of the fetus itself that secretes signaling molecules (SP-A and PAF, corticotropin-releasing hormone, and endothelin-1) from the maturing organs and systems into the amniotic fluid is unquestionable in the induction of labor. The physiological aging of fetal membranes is also one of the triggering stimuli for normal labor, as a result of which there is sterile inflammation that triggers a cascade of events that promote the initiation of labor. The role of small noncoding RNA molecules, microRNAs (miR-200, miR-199a-3p, miR-214, miR-181, miR-143, miR-34b/c, and miR-338) in the control of myometrial relaxation and contractility during pregnancy and childbirth through the regulation of the expression of certain genes and the function of the progesterone receptor has been discussed recently.
Conclusion: Thus, a complex multifactorial process that is finely tuned and coordinated by a multitude of signaling molecules secreted by the maternal and fetal organisms leads to the increased contractility of the myometrium and to the initiation of labor activity.


labor induction
fetal membrane aging


  1. Shynlova O., Nadeem L., Zhang J., Dunk C., Lye S. Myometrial activation: Novel concepts underlying labor. Placenta. 2020; 92: 28-36.
  2. Mendelson C.R. Minireview: fetal-maternal hormonal signaling in pregnancy and labor. Mol. Endocrinol. 2009; 23(7): 947-54.
  3. Challis J.R., Smith S.K. Fetal endocrine signals and preterm labor. Biol. Neonate. 2001; 79(3-4): 163-7.
  4. Menon R., Debnath C., Lai A., Guanzon D., Bhatnagar S., Kshetrapal P.K. et al. Circulating exosomal miRNA profile during term and preterm birth pregnancies: A Longitudinal Study. Endocrinology. 2019; 160(2): 249-75.
  5. Jin J., Menon R. Placental exosomes: A proxy to understand pregnancy complications. Am. J. Reprod. Immunol. 2018; 79(5): e12788.
  6. Cheng L., Sharples R.A., Scicluna B.J., Hill A.F. Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood. J. Extracell. Vesicles. 2014 Mar 26; 3.
  7. Guarnieri D.J., DiLeone R.J. MicroRNAs: a new class of gene regulators. Ann. Med. 2008; 40(3): 197-208.
  8. Гусар В.А., Тимофеева А.В., Кан Н.Е.,Чаговец В.В., Ганичкина М.Б., Франкевич В.Е. Профиль экспрессии плацентарных микроРНК – регуляторов окислительного стресса при синдроме задержки роста плода. Акушерство и гинекология. 2019; 1: 74-80. [Gusar V.A., Timofeeva A.V., Kan N.E., Chagovets V.V., Ganichkina M.B., Frankevich V.E. The expression profile of placental microRNAs as regulators of oxidative stress in fetal growth restriction. Akusherstvo i Ginekologiya/ Obstetrics and Gynecology. 2019; 1: 74-80. (in Russian)].
  9. Gusar V., Ganichkina M., Chagovets V., Kan N., Sukhikh G. MiRNAs regulating oxidative stress: A correlation with Doppler sonography of uteroplacental complex and clinical state assessments of newborns in fetal growth restriction. J. Clin. Med. 2020; 9(10): 3227.
  10. Шелехин А.П., Баев О.Р., Красный А.М. Роль молекул клеточной адгезии в патогенезе преэклампсии. Акушерство и гинекология. 2021; 6: 22-8. [Shelekhin A.P., Baev O.R., Krasnyi A.M. The role of cell adhesion molecules in the pathogenesis of preeclampsia. Akusherstvo i Ginekologiya/ Obstetrics and Gynecology. 2021; 6: 22-8. (in Russian)].
  11. Williams K.C., Renthal N.E., Gerard R.D., Mendelson C.R.The microRNA (miR)-199a/214 cluster mediates opposing effects of progesterone and estrogen on uterine contractility during pregnancy and labor. Mol. Endocrinol. 2012; 26(11): 1857-67.
  12. Alvarez-Erviti L., Seow Y, Yin H., Betts C., Lakhal S., Wood M.J. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 2011; 29(4): 341-5.
  13. Martinon F., Mayor A., Tschopp J. The inflammasomes: guardians of the body. Annu. Rev. Immunol. 2009; 27: 229-65.
  14. Sivarajasingam S.P., Imami N., Johnson M.R. Myometrial cytokines and their role in the onset of labour. J. Endocrinol. 2016; 231(3): R101-19.
  15. Renthal N.E., Williams K.C., Mendelson C.R. MicroRNAs--mediators of myometrial contractility during pregnancy and labour. Nat. Rev. Endocrinol. 2013; 9(7): 391-401.
  16. Тысячный О.В., Павлова О.А., Вторушина В.В., Кречетова Л.В., Баев О.Р. Содержание цитокинов в периферической крови женщин в зависимости от фазы первого периода родов. Акушерство и гинекология. 2019; 2: 86-92. [Tysyachnyy O.V., Pavlova O.A., Vtorushina V.V., Krechetova L.V., Baev O.R. Peripheral blood cytokine levels in women according to the phase of the first period of labor. Akusherstvo i Ginekologiya/ Obstetrics and Gynecology. 2019; 2: 86-92. (in Russian)].
  17. Romero R., Espinoza J., Gonçalves L.F., Kusanovic J.P., Friel L., Hassan S. The role of inflammation and infection in preterm birth. Semin. Reprod. Med. 2007; 25(1): 21-39.
  18. Montalbano A.P., Hawgood S., Mendelson C.R. Mice deficient in surfactant protein A (SP-A) and SP-D or in TLR2 manifest delayed parturition and decreased expression of inflammatory and contractile genes. Endocrinology. 2013; 154(1): 483-98.
  19. Condon J.C., Hardy D.B., Kovaric K., Mendelson C.R. Up-regulation of the progesterone receptor (PR)-C isoform in laboring myometrium by activation of nuclear factor-kappaB may contribute to the onset of labor through inhibition of PR function. Mol. Endocrinol. 2006; 20(4): 764-75.
  20. Mendelson C.R., Montalbano A.P., Gao L. Fetal-to-maternal signaling in the timing of birth. J. Steroid Biochem. Mol. Biol. 2017; 170: 19-27.
  21. Mesiano S., Chan E.C., Fitter J.T., Kwek K., Yeo G., Smith R. Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium. J. Clin. Endocrinol. Metab. 2002; 87(6): 2924-30.
  22. Condon J.C., Jeyasuria P., Faust J.M., Wilson J.W., Mendelson C.R. A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition. Proc. Natl. Acad. Sci. USA. 2003; 100(16): 9518-23.
  23. Williams K.C., Renthal N.E., Condon J.C., Gerard R.D., Mendelson C.R. MicroRNA-200a serves a key role in the decline of progesterone receptor function leading to term and preterm labor. Proc. Natl. Acad. Sci. USA. 2012; 109(19): 7529-34.
  24. Welsh T., Johnson M., Yi L, Tan H., Rahman R., Merlino A. et al. Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium. J. Endocrinol. 2012; 212(2): 227-38.
  25. Shynlova O., Tsui P., Dorogin A., Lye S.J. Monocyte chemoattractant protein-1 (CCL-2) integrates mechanical and endocrine signals that mediate term and preterm labor. J. Immunol. 2008; 181(2): 1470-9.
  26. Goldenberg R.L., Iams J.D., Miodovnik M., Van Dorsten J.P., Thurnau G., Bottoms S. et al. The preterm prediction study: risk factors in twin gestations. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Am. J. Obstet. Gynecol. 1996; 175(4, Pt. 1): 1047-53.
  27. Reinl E.L., England S.K. Fetal-to-maternal signaling to initiate parturition. J. Clin. Invest. 2015; 125(7): 2569-71.
  28. Myatt L., Sun K. Role of fetal membranes in signaling of fetal maturation and parturition. Int. J. Dev. Biol. 2010; 54(2-3): 545-53.
  29. Gao L., Rabbitt E.H., Condon J.C., Renthal N.E., Johnston J.M., Mitsche M.A. et al. Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition. J. Clin. Invest. 2015; 125(7): 2808-24.
  30. Vannuccini S., Bocchi C., Severi F.M., Challis J.R., Petraglia F. Endocrinology of human parturition. Ann. Endocrinol. (Paris). 2016; 77(2): 105-13.
  31. Menon R., Bonney E.A., Condon J., Mesiano S., Taylor R.N. Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition. Hum. Reprod. Update. 2016; 22(5): 535-60.
  32. Menon R. Human fetal membranes at term: Dead tissue or signalers of parturition? Placenta. 2016; 44: 1-5.
  33. Menon R. Initiation of human parturition: signaling from senescent fetal tissues via extracellular vesicle mediated paracrine mechanism. Obstet. Gynecol. Sci. 2019; 62(4): 199-211.
  34. Polettini J., Richardson L.S., Menon R. Oxidative stress induces senescence and sterile inflammation in murine amniotic cavity. Placenta. 2018; 63: 26-31.
  35. Menon R., Behnia F., Polettini J., Saade G.R., Campisi J., Velarde M. Placental membrane aging and HMGB1 signaling associated with human parturition. Aging (Albany. NY). 2016; 8(2): 216-30.
  36. Davalos A.R., Kawahara M., Malhotra G.K., Schaum N., Huang J., Ved U. et al. p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. J. Cell Biol. 2013; 201(4): 613-29.
  37. Fleshner M., Crane C.R. Exosomes, DAMPs and miRNA: features of stress physiology and immune homeostasis. Trends Immunol. 2017; 38(10): 768-76.
  38. Chikhirzhina E, Starkova T., Beljajev A., Polyanichko A., Tomilin A. Functional diversity of non-histone chromosomal protein HmgB1. Int. J. Mol. Sci. 2020; 21(21): 7948.
  39. Salomon C., Nuzhat Z., Dixon C.L., Menon R. Placental exosomes during gestation: liquid biopsies carrying signals for the regulation of human parturition. Curr. Pharm. Des. 2018; 24(9): 974-82.
  40. Tang Y., Ji H., Liu H., Gu W., Li X., Peng T. Identification and functional analysis of microRNA in myometrium tissue from spontaneous preterm labor. Int. J. Clin. Exp. Pathol. 2015; 8(10): 12811-9.
  41. Renthal N.E., Chen C.C., Williams K.C., Gerard R.D., Prange-Kiel J., Mendelson C.R. miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor. Proc. Natl. Acad. Sci. USA. 2010; 107(48): 20828-33.
  42. Sanders A.P., Burris H.H., Just A.C., Motta V., Svensson K., Mercado-Garcia A. et al. microRNA expression in the cervix during pregnancy is associated with length of gestation. Epigenetics. 2015; 10(3): 221-8.
  43. Weaver-Mikaere L., Gunn A.J., Mitchell M.D., Bennet L., Fraser M. LPS and TNF alpha modulate AMPA/NMDA receptor subunit expression and induce PGE2 and glutamate release in preterm fetal ovine mixed glial cultures. J. Neuroinflammation. 2013; 10: 153.
  44. Bracken C.P., Gregory P.A., Kolesnikoff N., Bert A.G., Wang J., Shannon M.F., Goodall G.J. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 2008; 68(19): 7846-54.
  45. Sun X., Sit A., Feinberg M.W. Role of miR-181 family in regulating vascular inflammation and immunity. Trends Cardiovasc. Med. 2014; 24(3): 105-12.
  46. Gao L., Wang G., Liu W.N., Kinser H., Franco H.L., Mendelson C.R. Reciprocal feedback between miR-181a and E2/ERα in myometrium enhances inflammation leading to labor. J. Clin. Endocrinol. Metab. 2016; 101(10):3646-56.
  47. Li H., Zhou J., Wei X., Chen R., Geng J., Zheng R. et al. miR-144 and targets, c-fos and cyclooxygenase-2 (COX-2), modulate synthesis of PGE2 in the amnion during pregnancy and labor. Sci. Rep. 2016; 6: 27914.
  48. Kim S.Y., Romero R., Tarca A.L., Bhatti G., Lee J., Chaiworapongsa T. et al. miR-143 regulation of prostaglandin-endoperoxidase synthase 2 in the amnion: implications for human parturition at term. PLoS One. 2011; 6(9): e24131.
  49. Montenegro D., Romero R., Kim S.S., Tarca A.L., Draghici S., Kusanovic J.P. et al. Expression patterns of microRNAs in the chorioamniotic membranes: a role for microRNAs in human pregnancy and parturition. J. Pathol. 2009; 217(1): 113-21.

Received 15.11.2021

Accepted 23.12.2021

About the Authors

Asiyat R. Gaidarova, PhD Student, Academician V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia, +7(985)553-76-70,,, 117997, Russia, Moscow, Akademika Oparina str., 4.
Vladislava A. Gusar, PhD, Senior Researcher at the Laboratory of Applied Transcriptomics, Department of Systems Biology in Reproduction, Academician V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia, +7(916)283-72-10,,, 117997, Russia, Moscow, Akademika Oparina str., 4.
Oleg R. Baev, Dr. Med. Sci., Professor, Head of the 1st Maternity Ward, Academician V.I. Kulakov NMRC for OG&P, Ministry of Health of Russia,, 117997, Russia, Moscow, Akademika Oparina str., 4; Professor of the Department of Obstetrics, Gynecology, Perinatology and Reproductology, I.M. Sechenov First MSMU, Ministry of Health of Russia, 119991, Russia, Moscow, Trubetskaya str., 8-2,
Corresponding author: Asiyat R. Gaidarova,

Authors' contributions: Gaidarova A.R., Gusar V.A., Baev O.R. – information collection, text writing and editing.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The investigation has not been sponsored.
For citation: Gaidarova A.R., Gusar V.A., Baev O.R. Initiation of labor activity as a multifactor mechanism of communication between maternal and fetal compartments.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2022; 2: 20-26 (in Russian)

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