Changes in Cervical Nitric Oxide Concentration Correlate With Bishop Score and Cervical Length Modifications in Prostaglandin E2-Mediated Induction of Labor
Restricted accessResearch articleFirst published online April, 2006
Changes in Cervical Nitric Oxide Concentration Correlate With Bishop Score and Cervical Length Modifications in Prostaglandin E2-Mediated Induction of Labor
Objective:Nitric oxide (NO) plays a fundamental role in cervical ripening and it is synthesized in the human cervix. We studied the effect of the dinoprostone on cervical NO release in pregnant women, and we investigated the relationship between cervical NO metabolites, cervical length, and Bishop score.
Methods:Seventy-seven women underwent induction of labor at ≥37 weeks of gestation, due to post-term pregnancy (23.8%), oligohydraminos (36.3) or preeclampsia (29.9%). Cervical fluid samples for NO metabolites (NOx), Bishop score, and cervical length assessed immediately before (time 0 [T0]) and 6 hours after (T6) the local application of dinoprostone, a commercially available prostaglandin E2 (PGE2) analog.
Results:The mean patients' age was 34 ± 3.2 years, mean gestational age at enrollment was 284 ± 9.2 days, and nulliparous represented 31.2% of the study population. At time 0, Bishop score was less than 4 in 74% (57/77) of the subjects, mean cervical length was 28.6 ± 5.8 mm, mean NOx concentration was 208.6 ± 10.3 μM/mL; 6 hours later, at T6, the mean cervical length decreased to 19.5 ± 8.8 mm, and the mean NOx concentration increased up to 316.7 ± 240.9 μM/mL. Data were unaffected by parity or by regular uterine contraction patterns. A statistically significant positive correlation was found between changes in cervical NOx levels and Bishop score modification (P <.01; r = .494), as well as between the modification of NO metabolites concentration and cervical shortening (P <.01; r = .307).
Conclusions:Prostaglandin (PG)-induced cervical ripening is associated with local NO release. NO plays an active role in cervical remodeling since it positively correlates with both cervical shortening and Bishop score increase. NO oxide and PG are the two pathways that, cross activating other, trigger the cascade of events responsible of cervical ripening.
1. Liggins GC. Cervical ripening as an inflammatory reaction. In: Ellwood DA, Anderson AB, eds. The cervix in pregnancy and labour, clinical and biochemical investigations. Edinburgh, UK: Churchill Livingstone; 1981:1-9.
2.
2. Danforth DN. The morphology of the human cervix. Clin Obstet Gynecol1983;26:7-13.
3.
3. Junqueira LC, Zugaib M, Montes GS, Toledo OM, Krisztan RM, Shgihara KM. Morphologic and biochemical evidence for the occurrence of collagenolysis and for the role of neutrophilic polymorphonuclear leukocytes during cervical dilatation. Am J Obstet Gynecol1980;138:273-281.
4.
4. Ekman G, Uldbjerg N, Malmstrom A, Ulmsten U. Increased postpartum collagenolytic activity in cervical connective tissue from women treated with prostaglandin E2. Gynecol Obstet Invest1983;16:292-298.
5.
5. Kelly RW. Pregnancy maintenance and paturition: The role of prostglandin in manipulating the immune and inflammatory response. Endocr Rev1994;15:684-706.
6.
6. Garfield RE, Saade G, Buhimschi C, et al. Control and assessment of the uterus and cervix during pregnancy and labour. Hum Reprod Update1998;4:673-695.
7.
7. Rosselli M, Keller PJ, Dubey RK. Role of nitric oxide in the biology, physiology and pathophysiology of reproduction. Hum Reprod Update1998;4:3-24.
8.
8. Ledingham MA, Thomson AJ, Greer IA, Norman JE. Nitric oxide in parturition. BJOG2000;107:581-593.
9.
9. Chwalisz K, Garfield RE. Nitric oxide as the final mediator of cervical ripening. Hum Reprod1998;13:245-252.
10.
10. Chwalisz K, Shao Quin S, Garfield RE, Beier HM. Cervical ripening in guinea pigs after a local application of nitric oxide. Hum Reprod1997;12:2093-2101.
11.
11. Buhimschi I, Ali M, Jain V, Chwalisz K, Garfield RE. Differential regulation of nitric oxide in the rat uterus and cervix during pregnancy and labour. Hum Reprod1996;11:1755-1766.
12.
12. Tschugguel W, Schneeberger C, Lass H, et al. Human cervical ripening is associated with an increase in cervical inducible nitric oxide synthase expression. Biol Reprod1999;60:1367-1372.
13.
13. Ekerhovdt E, Brannstrom M, Weijdegard B, Norstrom A. Nitric oxide synthases in the human cervix at term pregnancy and effects on nitric oxide on cervical smooth muscle contractility. Am J Obstet Gynecol2000;183:610-616.
14.
14. Ekerhovd E, Weijdegard B, Brannstrom M, Mattsby-Baltzer I, Norstrom A. Nitric oxide induced cervical ripening in the human: Involvement of cyclic guanosinemonophosphate, prostaglandin F2α and prostglandin E2. Am J Obstet Gynecol2002;186:745-750.
15.
15. Piccinini F, Fano RA, Volpe A, Facchinetti F. Ripening of the cervix with sodium nitroprusside in non pregnant women. J Soc Gynecol Investig2003;10:438-442.
16.
16. Thomson AJ, Lunan CB, Ledingham M, et al. Randomised trial of nitric oxide donor versus prostaglandin for cervical ripening before first trimester termination of pregnancy. Lancet1998;352:1093-1096.
17.
17. Facchinetti F, Piccinini F, Volpe A. Chemical ripening of the cervix with intracervical application of sodium nitroprusside: A randomized controlled trial. Hum Reprod2000;15:2224-2227.
18.
18. Ledingham MA, Thomson AJ, Lunan CB, Greer IA, Norman JE. A comparison of isosorbide mononitrate, misoprostol, and combination therapy for first trimester pre-operative cervical ripening: A randomised controlled trial. BJOG2001;108:276-280.
19.
19. Li CF, Chan C, Ho PC. A comparison of isosorbic mononitrate and misoprostol cervical ripening before suction evacuation. Obstet Gynecol2003;102:583-588.
20.
20. Vaisanen-Tommiska M, Nuutila M, Aittomaki K, Hiilesmaa V, Ylikorkala O. Nitric oxide metabolites in cervical fluid during pregnancy: Further evidence for the role of cervical nitric oxide in cervical ripening. Am J Obstet Gynecol2003;188:779-785.
21.
21. Vaisanen-Tommiska M, Nuutila M, Ylikorkala O. Cervical nitric Oxide release in women postterm. Obstet Gynecol2004;103:657-662.
22.
22. Facchinetti F, Venturini P, Blasi I, Giannella L. Changes in the cervical competence in preterm labour. BJOG2005;112:23-27.
23.
23. Sennstrom MKB, Brauner A, Lu Y, Granstrom LMM, Malmstrom AL, Ekman GE. Interleukin-8 is a mediator of the final cervical ripening in humans. Eur J obstet Gynecol Reprod Biol1997;74:89-92.
24.
24. Chwalisz K, Benson M, Scholz P, Daum J, Beier HM, Hegelhartung C. Cervical ripening with the cytokines interleukin-8, interleukin-1β and tumor necrosis factor-α in guinea-pigs. Hum Reprod1994;9:2173-2181.
25.
25. Berghella V, Bega G, Tolosa JE, Berghella M. Ultrasound assessment of the cervix. Clin Obstet Gynecol2003;46:947-962.
26.
26. Dystocia and augmentation of labor. ACOG Tech Bull1995;218:1-7.
27.
27. Chwalisz K. The use of progesterone antagonists for cervical ripening and as an adjunct to labour and delivery. Hum Reprod1994;9:131S-161S.
28.
28. Calder AA. Prostaglandins as therapy for labour induction or therapeutic abortion. Reprod Fertil Dev1990;2:553-556.
29.
29. Chewalisz K, Garfield RE. Role of nitroc oxide in the uterus and cervix: Implications for the management of labor. J Perinat Med1998;26:448-457.
30.
30. Ito A, Hiro D, Sakyo K, Mori Y. The role of leukocyte factors on uterine cervical ripening and dilatation. Bio Reprod1987;37:511-517.
31.
31. Kelly RW, Illingworth P, Baldie G, Laesk R, Brower S, Calder AA. Progesterone control of interleukin-8 production in endometrium and chorio-decidual cells underlines the role of neutrophils in menstruation and parturition. Hum Reprod1993;9:253-258.
32.
32. Agro A, Langdon C, Smith F, Richards CD. Prostaglandin E2 enhances interleukin-8 (IL-8) and IL-6 but inhibits GM-CSF production by IL-1 stimulated human synovial fibroblasts in vitro. J Rheumatol1996;23:862-868.
33.
33. Colditz IG. Effect of exogenous prostaglandin E2 and actinomicin D on plasma leakage induced by neutrophil activating peptide-1/interleukin-8. Immunol Cell Biol1990;68:397-403.
34.
34. Denison FC, Calder AC, Kelly RW. The action of prostaglandin E2 on the human cervix: Stimulation of interleukin 8 and inhibition of secretory leukocyte protease inhibitor. Am J Obstet Gynecol1999;180:614-620.
35.
35. Trachtman H, Futterweit S, Garg P, Reddy K, Singhai P. Nitric oxide stimulates the activity of a 72-kDa neutral matrix metalloproteinase in cultural rat mesangial cells. Biochem Biophys Res Commun1996;218:704-708.
36.
36. Sasaki K, Hattori T, Fujisawa T, Takahashi K, Inoue H, Takigawa M. Nitric oxide mediates the interleukin-1 induced gene expression of matrix metalloproteinases and basic fibroblast growth factor in cultured rabbit chondrocytes. J Biochem1998;123:431-439.
37.
37. Brune B, von Knethen A, Sandau KB. Nitric oxide and its role in apoptosis. Eur J Pharmacol1998;351:261-272.
38.
38. Nicotera P, Brune B, Bagetta G. Nitric oxide: Inducer or suppressor of apoptosis?Trends Pharmacol Sci1997;18:189-190.
39.
39. Hauselmann HJ, Opplinger L, Michel BA, Stefanovic-Racic M, Evans CH. Nitric oxide and proteoglycan biosynthesis by human articular chondrocytes in alginate culture. FEBS Lett1994;352:361-364.
40.
40. Hauselmann HJ, Stefanovic-Racic M, Michel BA, Evans CH. Differences in nitric oxide production by superficial and deep human articular chondrocytes: Implications for proteoglycan turnover in inflammatory joint disease. J Immunol1998;160:1444-1448.
41.
41. Salvemini D, Misko TP, Masferrer JLSeibert K, Currie MG, Needelman P. Nitric oxide activates cyclooxygenase enzymes. Proc Natl Acad Sci U S A1993;90:7240-7244.
42.
42. Swierkosz TA, Mitchell JA, Warner TD, Botting RM, Vane JR. Coinduction of nitric oxide synthase and cyclo-oxygenase: Interactions between nitric oxide and prostanoids. Br J Pharmacol1995;114:1335-1342.
43.
43. Jones CP, Paula Neto HA, Assreuy J, Vargaftig BB, Gaspar Elsas MI, Elsas PX. Prostaglandin E2 and dexamethasone regulate eosinophil differentiation and survival through a nitric oxide- and CD95-dependent pathway. Nitric Oxide2004;11:184-193.
44.
44. Onga T, Saura R, Mizuno K, Itoh H. Effect of prostaglandin E2 on nitric oxide synthesis in articular chondrycytes. Kobe J Med Sci2000;46:155-169.
45.
45. Timoshenko AV, Lala PK, Chakraborty C. PGE2 mediated upregulation of iNOS in murine breast cancer cells through the activation of EP4 receptors. Int J Cancer2004;108:384-389.
46.
46. Goharkhay N, Wing DA, Pan V, et al. The expression of EP3-6 and inducible nitric oxide synthase messenger RNA are correlated in pregnant and misoprostol-treated but not in nongravid or menopausal myometrium. Am J Obstet Gynecol2002;186:1202-1206.
47.
47. Vaisanen-Tommiska M, Mikkola TS, Ylikorkala O. Misoprostol induces cervical nitric oxide release in pregnant, but not in nonpregnant women. Am J Obstet Gynecol2005;193:790-796.
48.
48. Laskin DL, Pendino KJ. Macrophages and inflammatory mediators in tissue injury. Ann Rev Pharmacol Toxicol1995;35:655-677.
49.
49. Mocada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med1993;329:2002-2012.
51. Tamura T, Nakamishi T, Kimura Y, et al. Nitric oxide mediates interleukin-1 induced matrix degradation and basic fibroblast growth factor release in cultured rabbit articular chondrocytes: A possible mechanism of pathological neovascularization in arthritis. Endocrinology1996;137:3729-3737.
52.
52. Sennstrom MB, Ekman G, Westergen-Thorsson G, et al. Human cervical ripening, an inflammatory process mediated by cytokines. Mol Hum Reprod2000;6:375-381.
