Preterm Birth: An Inflammatory Syndrome, Not Just A Myometrial Disorder

Main Article Content

Thuy-An Mai-Vo
Alexandra Beaudry-Richard

Abstract

Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity. Although the severity of neonatal outcomes is inversely correlated with gestational age, all PTBs can lead to potentially life-threatening neonatal outcomes and major lifelong health complications. Because advances in neonatal care have substantially decreased neonatal mortality, the incidence of PTB and its complications is unabatedly rising. PTB currently affects more than 10% of births worldwide, with similar numbers in developed countries. Correspondingly, improving neonatal outcome is a key objective of the World Health Organization. The recently approved (in Europe) tocolytics drug, Atosiban, used to prolong preterm gestation, has not been shown to improve neonatal outcome, nor have other tocolytic agents used in clinic. Thus, PTB remains an unmet medical need. Recent evidence shows that most, if not all, PTBs are associated with (overt or occult) inflammatory processes in gestational tissues, independent of infection. Pro- inflammatory cytokines are produced from maternal and fetal cells in response to sterile or infectious stressors. These seem to orchestrate a multi-tissue response including myometrial contractility, cervical ripening, and weakening/rupture of fetal membranes, leading to the onset of preterm labor. This integrated system might have been conserved through mammalian evolution due to increased maternal and/or fetal survival when gestation is terminated in specific settings, such as infection. Hence, inflammation may be a common pathway to the numerous aetiologies of PTB. Most importantly, recent evidence suggests that inflammation is transmitted to the fetus, thereby inducing organ injuries that may underlie the development of major neonatal diseases. Targeting inflammation prenatally instead of myometrial contraction could be a more successful and safe approach for the management of PTB, as suggested by recent animal studies. 

Résumé

La naissance prématurée est la principale cause de mortalité et de morbidité néonatale. Bien que la sévérité des issus néonataux soit inversement corrélée avec l’âge gestationnel à la naissance, toutes les naissances prématurées peuvent mener à des issus néonataux potentiellement mortels et à des complications avec répercussions s’échelonnant sur toute la vie. Étant donné que la mortalité néonatale a considérablement diminuée avec les récentes avancées en néonatalogie, l’incidence de la naissance prématurée et de ses complications sont en hausse. La naissance prématurée affecte présentement plus de 10% des naissances à travers le monde, avec des taux similaires dans les pays développés. Conséquemment, d’améliorer l’issu néonatal est un objectif clé de l’Organisation Mondiale de la Santé. Le tocolytique Atosiban récemment approuvé (en Europe) pour prolonger les gestations pré- maturées n’a pas démontré d’efficacité pour améliorer les issus néonataux, tout comme les autres tocolytiques utilisés en clinique, et la naissance prématurée demeure un besoin médical non-atteint. Des données récentes démontrent que la plupart, sinon toutes les naissances prématurées sont associées avec des processus inflammatoires (francs ou silencieux) dans les tissus gestationnels, indépendamment de l’infection. Les cytokines pro-inflammatoires sont produites dans les cellules maternelles et fœtales en réponse à des stresseurs stériles ou infectieux, et semblent orchestrer une réponse multi-tissulaire incluant la contractilité myométriale, la préparation cervicale, et l’affaiblissement/rupture des membranes fœtales, menant au commencement du travail préterme. Ce système intégré pourrait avoir été conservé durant l’évolution mammifère à cause d’une survie accrue de la mère et/ou du fœtus lorsque la gestation est terminée dans un contexte spécifique, comme l’infection. Donc, l’inflammation pourrait constituer une voie commune finale pour les nombreuses causes de la naissance prématurée. De façon importante, des données récentes sug- gèrent que cette inflammation est transmise au fœtus et en retour induit des dommages aux organes qui pourraient sous-tendre le développement de maladies néonatales majeures. De cibler l’inflammation en prénatal plutôt que les contractions myométriales pourrait constituer une approche sécuritaire et plus efficace, comme suggéré par de récentes études animales. 

 

Article Details

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Review & Clinical Practice

References

1. Menon R. Preterm birth: a global burden on maternal and child health. Pathog Glob Health. 2012;106(3):139-40.

2. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. Lancet. 2008;371(9606):75-84.

3. Beck S, Wojdyla D, Say L, et al. The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ. 2010;88(1):31-8.

4. Boyle AK, Rinaldi SF, Norman JE, Stock SJ. Preterm birth: Inflammation, fetal injury and treatment strategies. J Reprod Immunol. 2017;119:62-6.

5. Rubens CE, Sadovsky Y, Muglia L, Gravett MG, Lackritz E, Gravett C. Prevention of preterm birth: harnessing science to address the global epidemic. Sci Transl Med. 2014;6(262):262sr5.

6. Ananth CV, Vintzileos AM. Maternal-fetal conditions necessitating a medical intervention resulting in preterm birth. Am J Obstet Gynecol. 2006;195(6):1557-63.

7. Ward RM, Beachy JC. Neonatal complications following preterm birth. BJOG. 2003;110 Suppl 20:8-16.

8. Perrone S, Negro S, Tataranno ML, Buonocore G. Oxidative stress and antioxidant strategies in newborns. J Matern Fetal Neonatal Med. 2010;23 Suppl 3:63-5.

9. Romero R, Dey SK, Fisher SJ. Preterm labor: one syndrome, many causes. Science. 2014;345(6198):760-5.

10. Gotsch F, Romero R, Kusanovic JP, et al. The fetal inflammatory response syndrome. Clin Obstet Gynecol. 2007;50(3):652-83.

11. Olson DM, Christiaens I, Gracie S, Yamamoto Y, Mitchell BF. Emerging tocolytics: challenges in designing and testing drugs to delay preterm delivery and prolong pregnancy. Expert Opin Emerg Drugs. 2008;13(4):695- 707.

12. Anotayanonth S, Subhedar NV, Garner P, Neilson JP, Harigopal S. Be- tamimetics for inhibiting preterm labour. Cochrane Database Syst Rev. 2004(4):CD004352.

13. Merkatz IR, Peter JB, Barden TP. Ritodrine hydrochloride: a betamimetic agent for use in preterm labor. II. Evidence of efficacy. Obstet Gynecol. 1980;56(1):7-12.

14. King JF, Flenady VJ, Papatsonis DN, Dekker GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane Database Syst Rev. 2002(2):CD002255.

15. Flenady V, Wojcieszek AM, Papatsonis DN, et al. Calcium channel blockers for inhibiting preterm labour and birth. Cochrane Database Syst Rev. 2014(6):CD002255.

16. Nadeau-Vallee M, Chin PY, Belarbi L, et al. Antenatal Suppression of IL-1 Protects against Inflammation-Induced Fetal Injury and Improves Neonatal and Developmental Outcomes in Mice. J Immunol. 2017;198(5):2047-62.

17. Akerlund M, Carlsson AM, Melin P, Trojnar J. The effect on the human uterus of two newly developed competitive inhibitors of oxytocin and vasopressin. Acta Obstet Gynecol Scand. 1985;64(6):499-504.

18. Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev. 2002(4):CD001060.

19. Romero R, Sibai BM, Sanchez-Ramos L, et al. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double- blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol. 2000;182(5):1173-83.

20. Worldwide Atosiban versus Beta-agonists Study G. Effectiveness and safety of the oxytocin antagonist atosiban versus beta-adrenergic agonists in the treatment of preterm labour. The Worldwide Atosiban versus Beta-agonists Study Group. BJOG. 2001;108(2):133-42.

21. Jung EJ, Byun JM, Kim YN, et al. Antenatal magnesium sulfate for both tocolysis and fetal neuroprotection in premature rupture of the membranes before 32 weeks’ gestation. J Matern Fetal Neonatal Med. 2017:1-11.

22. Edwards JM, Edwards LE, Swamy GK, Grotegut CA. Magnesium sulfate for neuroprotection in the setting of chorioamnionitis. J Matern Fetal Neonatal Med. 2017:1-8.

23. Panter KR, Hannah ME, Amankwah KS, Ohlsson A, Jefferies AL, Farine D. The effect of indomethacin tocolysis in preterm labour on perinatal outcome: a randomised placebo-controlled trial. Br J Obstet Gynaecol. 1999;106(5):467-73.

24. Abou-Ghannam G, Usta IM, Nassar AH. Indomethacin in pregnancy: appli- cations and safety. Am J Perinatol. 2012;29(3):175-86.

25. King J, Flenady V, Cole S, Thornton S. Cyclo-oxygenase (COX) inhibitors for treating preterm labour. Cochrane Database Syst Rev. 2005(2):CD001992.

26. da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol. 2003;188(2):419- 24.

27. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348(24):2379-85.

28. Norman JE, Marlow N, Messow CM, et al. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet. 2016;387(10033):2106-16.

29. Martinez de Tejada B, Karolinski A, Ocampo MC, et al. Prevention of preterm delivery with vaginal progesterone in women with preterm labour (4P): randomised double-blind placebo-controlled trial. BJOG. 2015;122(1):80- 91.

30. Galinsky R, Polglase GR, Hooper SB, Black MJ, Moss TJ. The consequences of chorioamnionitis: preterm birth and effects on development. J Pregnancy. 2013;2013:412831.

31. Bukowski R, Sadovsky Y, Goodarzi H, et al. Onset of human preterm and term birth is related to unique inflammatory transcriptome profiles at the maternal fetal interface. PeerJ. 2017;5:e3685.

32. Ireland DJ, Nathan EA, Li S, et al. Preclinical evaluation of drugs to block inflammation-driven preterm birth. Innate Immun. 2017;23(1):20-33.

33. Lim R, Barker G, Lappas M. TLR2, TLR3 and TLR5 regulation of pro-inflammatory and pro-labour mediators in human primary myometrial cells. J Reprod Immunol. 2017;122:28-36.

34. Arthur P, Taggart MJ, Zielnik B, Wong S, Mitchell BF. Relationship between gene expression and function of uterotonic systems in the rat during gestation, uterine activation and both term and preterm labour. J Physiol. 2008;586(24):6063-76.

35. Cook JL, Shallow MC, Zaragoza DB, Anderson KI, Olson DM. Mouse placental prostaglandins are associated with uterine activation and the timing of birth. Biol Reprod. 2003;68(2):579-87.

36. Christiaens I, Zaragoza DB, Guilbert L, Robertson SA, Mitchell BF, Olson DM. Inflammatory processes in preterm and term parturition. J Reprod Immunol. 2008;79(1):50-7.

37. Nadeau-Vallee M, Obari D, Quiniou C, et al. A critical role of interleukin-1 in preterm labor. Cytokine Growth Factor Rev. 2016;28:37-51.

38. Romero R, Mazor M, Tartakovsky B. Systemic administration of interleukin-1 induces preterm parturition in mice. Am J Obstet Gynecol.
1991;165(4 Pt 1):969-71.

39. Kamath BD, Macguire ER, McClure EM, Goldenberg RL, Jobe AH. Neo-
natal mortality from respiratory distress syndrome: lessons for low-resource countries. Pediatrics. 2011;127(6):1139-46.

40. Park CW, Park JS, Jun JK, Yoon BH. FGR in the setting of preterm sterile intra-uterine milieu is associated with a decrease in RDS. Pediatr Pulmonol. 2016;51(8):812-9.

41. Kim SY, Choi CW, Jung E, et al. Neonatal Morbidities Associated with
Histologic Chorioamnionitis Defined Based on the Site and Extent of Inflammation in Very Low Birth Weight Infants. J Korean Med Sci. 2015;30(10):1476-82.

42. Park CW, Park JS, Jun JK, Yoon BH. Mild to Moderate, but Not Minimal or Severe, Acute Histologic Chorioamnionitis or Intra-Amniotic Inflammation Is Associated with a Decrease in Respiratory Distress Syndrome of Preterm Newborns without Fetal Growth Restriction. Neonatology. 2015;108(2):115-23.

43. Willems MGM, Kemp MW, Fast LA, et al. Pulmonary vascular changes in extremely preterm sheep after intra-amniotic exposure to Ureaplasma parvum and lipopolysaccharide. PLoS One. 2017;12(6):e0180114.

44. Vollsaeter M, Roksund OD, Eide GE, Markestad T, Halvorsen T. Lung function after preterm birth: development from mid-childhood to adult- hood. Thorax. 2013;68(8):767-76.

45. Ekici B, Aydinli N, Aydin K, Caliskan M, Eraslan E, Ozmen M. Epilepsy in children with periventricular leukomalacia. Clin Neurol Neurosurg. 2013;115(10):2046-8.

46. Inder TE, Volpe JJ. Mechanisms of perinatal brain injury. Semin Neonatol. 2000;5(1):3-16.

47. Kitanishi R, Matsuda T, Watanabe S, et al. Cerebral ischemia or intrauterine inflammation promotes differentiation of oligodendroglial precursors in preterm ovine fetuses: possible cellular basis for white matter injury. Tohoku J Exp Med. 2014;234(4):299-307.

48. Herzog M, Cerar LK, Srsen TP, Verdenik I, Lucovnik M. Impact of risk factors other than prematurity on periventricular leukomalacia. A population-based matched case control study. Eur J Obstet Gynecol Reprod Biol. 2015;187:57-9.

49. Jung EY, Park KH, Han BR, Cho SH, Yoo HN, Lee J. Amniotic Fluid Infection, Cytokine Levels, and Mortality and Adverse Pulmonary, Intestinal, and Neurologic Outcomes in Infants at 32 Weeks’ Gestation or Less. J Korean Med Sci. 2017;32(3):480-7.

50. Paton MCB, McDonald CA, Allison BJ, Fahey MC, Jenkin G, Miller SL. Perinatal Brain Injury As a Consequence of Preterm Birth and Intrauterine Inflammation: Designing Targeted Stem Cell Therapies. Front Neurosci. 2017;11:200.

51. Choi JY, Rha DW, Park ES. The Effects of the Severity of Periventricular Leukomalacia on the Neuropsychological Outcomes of Preterm Children. J Child Neurol. 2016;31(5):603-12.

52. Tann CJ, Nakakeeto M, Willey BA, et al. Perinatal risk factors for neonatal encephalopathy: an unmatched case-control study. Arch Dis Child Fetal Neonatal Ed. 2017.

53. Celik IH, Demirel G, Canpolat FE, Dilmen U. A common problem for neonatal intensive care units: late preterm infants, a prospective study with term controls in a large perinatal center. J Matern Fetal Neonatal Med. 2013;26(5):459-62.

54. Nikiforou M, Kemp MW, van Gorp RH, et al. Selective IL-1alpha exposure to the fetal gut, lung, and chorioamnion/skin causes intestinal inflammatory and developmental changes in fetal sheep. Lab Invest. 2016;96(1):69-80.

55. Ducey J, Owen A, Coombs R, Cohen M. Vasculitis as part of the fetal response to acute chorioamnionitis likely plays a role in the development of necrotizing enterocolitis and spontaneous intestinal perforation in pre- mature neonates. Eur J Pediatr Surg. 2015;25(3):284-91.

56. Tare M, Bensley JG, Moss TJ, et al. Exposure to intrauterine inflammation leads to impaired function and altered structure in the preterm heart of fetal sheep. Clin Sci (Lond). 2014;127(9):559-69.

57. Park HW, Choi YS, Kim KS, Kim SN. Chorioamnionitis and Patent Ductus Arteriosus: A Systematic Review and Meta-Analysis. PLoS One. 2015;10(9):e0138114.

58. Behbodi E,Villamor-Martinez E,Degraeuwe PL,Villamor E. Chorioamnionitis appears not to be a Risk Factor for Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-Analysis. Sci Rep. 2016;6:37967.

59. Nguyen MU, Wallace MJ, Pepe S, Menheniott TR, Moss TJ, Burgner D. Perinatal inflammation: a common factor in the early origins of cardiovascular disease? Clin Sci (Lond). 2015;129(8):769-84.

60. Bariani MV,Correa F,Leishman E, etal. Resveratrol protects from lipopolysaccharide-induced inflammation in the uterus and prevents experimental preterm birth. Mol Hum Reprod. 2017;23(8):571-81.

61. Facchinetti F, Vergani P, Di Tommaso M, et al. Progestogens for Maintenance Tocolysis in Women With a Short Cervix: A Randomized Controlled Trial. Obstet Gynecol. 2017;130(1):64-70.

62. Brizot ML, Hernandez W, Liao AW, et al. Vaginal progesterone for the prevention of preterm birth in twin gestations: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol. 2015;213(1):82 e1-9.

63. Mold JE, Michaelsson J, Burt TD, et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science. 2008;322(5907):1562-5.

64. La Cava A. Tregs are regulated by cytokines: implications for autoimmunity. Autoimmun Rev. 2008;8(1):83-7.

65. Papayianni A,Serhan CN,Brady HR. Lipoxin A4 and B4 inhibit leukotriene- stimulated interactions of human neutrophils and endothelial cells. J Immunol. 1996;156(6):2264-72.

66. Serhan CN, Maddox JF, Petasis NA, et al. Design of lipoxin A4 stable analogs that block transmigration and adhesion of human neutrophils. Biochemistry. 1995;34(44):14609-15.

67. Rinaldi SF, Catalano RD, Wade J, Rossi AG, Norman JE. 15-epilipoxin A4 reduces the mortality of prematurely born pups in a mouse model of infection-induced preterm birth. Mol Hum Reprod. 2015;21(4):359-68.

68. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633-52.

69. Girard S,Tremblay L,Lepage M,Sebire G. IL-1 receptor antagonist protects against placental and neurodevelopmental defects induced by maternal inflammation. J Immunol. 2010;184(7):3997-4005.

70. Quiniou C, Sapieha P, Lahaie I, et al. Development of a novel noncompetitive antagonist of IL-1 receptor. J Immunol. 2008;180(10):6977-87.

71. Nadeau-Vallee M, Quiniou C, Palacios J, et al. Novel Noncompetitive IL-1 Receptor-Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth. J Immunol. 2015;195(7):3402-15.

72. Di Renzo GC, Roura LC, European Association of Perinatal Medicine-Study Group on Preterm B. Guidelines for the management of spontaneous pre-term labor. J Perinat Med. 2006;34(5):359-66.

73. Hydroxyprogesterone caproate did not reduce the rate of recurrent preterm birth in a prospective cohort study. Am J Obstet Gynecol. 2017;216(6):600 e1- e9.

74. Furuya H, Taguchi A, Kawana K, et al. Resveratrol Protects Against Pathological Preterm Birth by Suppression of Macrophage-Mediated Inflammation. Reprod Sci. 2015;22(12):1561-8.

75. Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 2006;127(6):1109-22.

76. Shen Z, Ajmo JM, Rogers CQ, et al. Role of SIRT1 in regulation of LPS- or two ethanol metabolites-induced TNF-alpha production in cultured macrophage cell lines. Am J Physiol Gastrointest Liver Physiol. 2009;296(5):G1047-53.

77. Lappas M, Mitton A, Lim R, Barker G, Riley C, Permezel M. SIRT1 is a novel regulator of key pathways of human labor. Biol Reprod. 2011;84(1):167-78.

78. Littman DR, Rudensky AY. Th17 and regulatory T cells in mediating and restraining inflammation. Cell. 2010;140(6):845-58.