Journal of Endocrinological Investigation

, Volume 41, Issue 2, pp 171–177 | Cite as

Placental and maternal serum activin A in spontaneous and induced labor in late-term pregnancy

  • L. Funghi
  • M. Torricelli
  • R. Novembri
  • S. Vannuccini
  • G. Cevenini
  • M. Di Tommaso
  • F. M. Severi
  • F. PetragliaEmail author
Original Article



Feto-placental unit represents an important source of activin A, a member of transforming growth factors-β involved in the mechanisms of labor. No evidences are available on activin A in pregnancies beyond 41 weeks of gestation, where induction of labor is often required. The present study aimed to evaluate activin A maternal serum levels and placental mRNA expression in term and late-term pregnancy, with spontaneous or induced labor, and its possible role to predict the response to labor induction.


Maternal serum samples and placental specimens were collected from women with singleton pregnancy admitted for either term spontaneous labor (n = 23) or induction of labor for late-term pregnancy (n = 41), to evaluate activin A serum levels and placental mRNA expression. Univariate and multivariate analyses on activin A serum levels, maternal clinical parameters, and cervical length were conducted in women undergoing induction of labor.


Maternal serum activin A levels and placental activin A mRNA expression in late-term pregnancies were significantly higher than at term. Late-term pregnancies who did not respond to induction of labor showed significantly lower levels of activin A compared to responders. The combination of serum activin A and cervical length achieved a sensitivity of 100% and a specificity of 93.55% for the prediction of successful induction.


Late-term pregnancy is characterized by hyperexpression of placental activin A and increased maternal activin A secretion. By combining maternal serum activin A levels with cervical length, a good predictive model for the response to induction of labor was elaborated.


Activin A Cervical length Induction of labor Late-term pregnancy 



The authors thank the midwife team of Obstetric Unit of Siena, for contributing to collect data for this study.


This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest

The authors report no conflict of interest.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee (Prot. 325/05 B) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Leduc D, Biringer A, Lee L et al (2013) Induction of labour. J Obstet Gynaecol Can 35:840–860CrossRefPubMedGoogle Scholar
  2. 2.
    Spong CY (2013) Defining “term” pregnancy: recommendations from the Defining “Term” Pregnancy Workgroup. Jama 309:2445–2446. doi: 10.1001/jama.2013.6235 CrossRefPubMedGoogle Scholar
  3. 3.
    ACOG (2014) Practice bulletin no. 146: management of late-term and postterm pregnancies. Obstet Gynecol 124:390–396. doi: 10.1097/01.AOG.0000452744.06088.48 CrossRefGoogle Scholar
  4. 4.
    Alexander JM, McIntire DD, Leveno KJ (2000) Forty weeks and beyond: pregnancy outcomes by week of gestation. Obstet Gynecol 96:291–294. doi: 10.1016/S0029-7844(00)00862-0 PubMedGoogle Scholar
  5. 5.
    Ramirez M, Ramin S (2009) ACOG practice bulletin No. 107: induction of labor. Obstet Gynecol 114:386–397. doi: 10.1097/AOG.0b013e3181b48ef5 CrossRefGoogle Scholar
  6. 6.
    Gatward H, Simpson M, Woodhart L, Stainton MC (2010) Women’s experiences of being induced for late-term pregnancy. Women Birth 231:3–9CrossRefGoogle Scholar
  7. 7.
    Crowley P (2006) WITHDRAWN: Interventions for preventing or improving the outcome of delivery at or beyond term. Cochrane Database Syst Rev CD000170. doi: 10.1002/14651858.cd000170
  8. 8.
    Galal M, Symonds I, Murray H, Petraglia F, Smith R (2012) Postterm pregnancy. Facts Views Vis ObGyn. 4:175–187.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Menon R, Bonney EA, Condon J et al (2016) Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition. Hum Reprod Update 22:535–560. doi: 10.1093/humupd/dmw022 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Reis FM, Gervasi MT, Florio P et al (2003) Prediction of successful induction of labor at term: Role of clinical history, digital examination, ultrasound assessment of the cervix, and fetal fibronectin assay. Am J Obstet Gynecol 189:1361–1367. doi: 10.1067/S0002-9378(03)00725-7 CrossRefPubMedGoogle Scholar
  11. 11.
    Gibson KS, Waters TP (2015) Measures of success: prediction of successful labor induction. Semin Perinatol 39:475–482. doi: 10.1053/j.semperi.2015.07.012 CrossRefPubMedGoogle Scholar
  12. 12.
    Torricelli M, Voltolini C, Conti N et al (2013) Weight gain regardless of pre-pregnancy BMI and influence of fetal gender in response to labor induction in postdate pregnancy. J Matern Fetal Neonatal Med 26:1016–1019. doi: 10.3109/14767058.2013.766712 CrossRefPubMedGoogle Scholar
  13. 13.
    Torricelli M, Voltolini C, Vellucci FL, et al (2013) Fetal gender effects on induction of labor in postdate pregnancies. Reprod Sci 20:670–674. doi: 10.1177/1933719112462631 CrossRefPubMedGoogle Scholar
  14. 14.
    Schoen C, Navathe R (2015) Failed induction of labor. Semin Perinatol 39:483–487. doi: 10.1053/j.semperi.2015.07.013 CrossRefPubMedGoogle Scholar
  15. 15.
    Ling N, Ying SY, Ueno N et al (1986) Pituitary FSH is released by a heterodimer of the beta-subunits from the two forms of inhibin. Nature 321:779–782. doi: 10.1038/321779a0 CrossRefPubMedGoogle Scholar
  16. 16.
    Ueno N, Nishimatsu S, Murakami K (1990) Activin as a cell differentiation factor. Prog Growth Factor Res 2:113–124.Google Scholar
  17. 17.
    Wijayarathna R, de Kretser DM (2016) Activins in reproductive biology and beyond. Hum Reprod Update 22:342–357. doi: 10.1093/humupd/dmv058 CrossRefGoogle Scholar
  18. 18.
    Schneider-Kolsky M, D’Antona D, Evans LW et al (2000) Maternal serum total activin A and follistatin in pregnancy and parturition. BJOG 107:995–1000CrossRefPubMedGoogle Scholar
  19. 19.
    Muttukrishna S, Tannetta D, Groome N, Sargent I (2004) Activin and follistatin in female reproduction. Mol Cell Endocrinol 225:45–56CrossRefPubMedGoogle Scholar
  20. 20.
    Petraglia F, Gallinelli A, de Vita D, et al (1994) Activin at parturition: Changes of maternal serum levels and evidence for binding sites in placenta and fetal membranes. Obstet Gynecol 84:278–282.PubMedGoogle Scholar
  21. 21.
    O’Connor AE, McFarlane JR, Hayward S et al (1999) Serum activin A and follistatin concentrations during human pregnancy: a cross-sectional and longitudinal study. Hum Reprod 14:827–832. doi: 10.1093/humrep/14.3.827 CrossRefPubMedGoogle Scholar
  22. 22.
    Torricelli M, Voltolini C, Novembri R et al (2012) Activin A and its regulatory molecules in placenta and fetal membranes of women with preterm premature rupture of the membranes associated with acute chorioamnionitis. Am J Reprod Immunol 68:392–399. doi: 10.1111/j.1600-0897.2012.01180.x CrossRefPubMedGoogle Scholar
  23. 23.
    Norwitz ER, Robinson JN, Repke JT (2001) Labor and delivery. In: Gabbe SG, Niebyl GR, Simpson JL (eds) Obstetrics: normal and problem pregnancies, 3rd edn. Churchill Livingstone, New York 2003.Google Scholar
  24. 24.
    Gilstrop M, Sciscione A (2015) Induction of labor-Pharmacology methods. Semin Perinatol 39:463–465. doi: 10.1053/j.semperi.2015.07.009 CrossRefPubMedGoogle Scholar
  25. 25.
    Thomas J, Fairclough A, Kavanagh J, Kelly AJ (2014) Vaginal prostaglandin (PGE2 and PGF2a) for induction of labour at term. Cochrane Database Syst Rev 6:CD003101. doi: 10.1002/14651858.CD003101.pub3 Google Scholar
  26. 26.
    Cindrova-Davies T, Yung H-W, Johns J et al (2007) Oxidative stress, gene expression, and protein changes induced in the human placenta during labor. Am J Pathol 171:1168–1179. doi: 10.2353/ajpath.2007.070528 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cindrova-Davies T, Spasic-Boskovic O, Jauniaux E et al (2007) Nuclear factor-κB, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress. Am J Pathol 170:1511–1520. doi: 10.2353/ajpath.2007.061035 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Smith SC, Baker PN, Symonds EM (1997) Placental apoptosis in normal human pregnancy. Am J Obstet Gynecol 177:57–65. doi: 10.1016/S0002-9378(97)70438-1 CrossRefPubMedGoogle Scholar
  29. 29.
    Halperin R, Peller S, Rotschild M et al (2000) Placental apoptosis in normal and abnormal pregnancies. Gynecol Obstet Investig 50:84–87CrossRefGoogle Scholar
  30. 30.
    Jones KL, Brauman JN, Groome NP et al (2000) Activin A release into the circulation is an early event in systemic inflammation and precedes the release of follistatin. Endocrinology 141:1905–1908. doi: 10.1210/en.141.5.1905 CrossRefPubMedGoogle Scholar
  31. 31.
    Jones KL, de Kretser DM, Patella S, Phillips DJ (2004) Activin A and follistatin in systemic inflammation. Mol Cell Endocrinol 225:119–125CrossRefPubMedGoogle Scholar
  32. 32.
    Keelan JA, Zhou RL, Mitchell MD (2000) Activin a exerts both pro- and anti-inflammatory effects on human term gestational tissues. Placenta 21:38–43. doi: 10.1053/plac.1999.0451 CrossRefPubMedGoogle Scholar
  33. 33.
    Keelan JA, Zhou RL, Evans LW, Groome NP, Mitchell MD (2000) Regulation of activin A, inhibin A, and follistatin production in human amnion and choriodecidual explants by inflammatory mediators. J Soc Gynecol Investig 7:291–296CrossRefPubMedGoogle Scholar
  34. 34.
    Della Bella S, Giannelli S, Cozzi V et al (2011) Incomplete activation of peripheral blood dendritic cells during healthy human pregnancy. Clin Exp Immunol 164:180–192. doi: 10.1111/j.1365-2249.2011.04330.x CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Martin JA, Hamilton BE, Sutton PD et al (2003) Births: final data for 2002. Natl Vital Stat Rep 52:1–113PubMedGoogle Scholar
  36. 36.
    Rane SM, Guirgis RR, Higgins B, Nicolaides KH (2003) Pre-induction sonographic measurement of cervical length in prolonged pregnancy: the effect of parity in the prediction of the need for Cesarean section. Ultrasound Obstet Gynecol 22:45–48. doi: 10.1002/uog.166 CrossRefPubMedGoogle Scholar
  37. 37.
    Bueno B, San-Frutos L, Pérez-Medina T et al (2007) The labor induction: integrated clinical and sonographic variables that predict the outcome. J Perinatol 27:4–8. doi: 10.1038/ CrossRefPubMedGoogle Scholar
  38. 38.
    Prado CA de C, Araujo Júnior E, Duarte G, et al (2016) Predicting success of labor induction in singleton term pregnancies by combining maternal and ultrasound variables. J Matern Fetal Neonatal Med 1–35. doi: 10.3109/14767058.2015.1135124 PubMedGoogle Scholar
  39. 39.
    Ben-Harush Y, Kessous R, Weintraub AY, Aricha-Tamir B, Steiner N, Spiegel E, Hershkovitz R (2015) The use of sonographic cervical length assessment for the prediction of time from induction to delivery. J Matern Fetal Neonatal Med 30:1–5CrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2017

Authors and Affiliations

  • L. Funghi
    • 1
  • M. Torricelli
    • 1
  • R. Novembri
    • 1
  • S. Vannuccini
    • 1
  • G. Cevenini
    • 2
  • M. Di Tommaso
    • 3
  • F. M. Severi
    • 1
  • F. Petraglia
    • 1
    Email author
  1. 1.Obstetrics and Gynecology, Department of Molecular and Developmental MedicineUniversity of SienaSienaItaly
  2. 2.Department of Medical BiotechnologyUniversity of SienaSienaItaly
  3. 3.Department of Health SciencesUniversity of FlorenceFlorenceItaly

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