Download PDF
Am J Perinatol 2018; 35(05): 470-480
DOI: 10.1055/s-0037-1608631
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Impact of Pregnancy History and 17-Hydroxyprogesterone Caproate on Cervical Cytokines and Matrix Metalloproteinases

Steve N. Caritis
1   Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania
,
Gary Hankins
2   Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas
,
Mary Hebert
3   Department of Pharmacy, University of Washington, Seattle, Washington
4   Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington
,
David M. Haas
5   Department of Obstetrics and Gynecology, Indiana University, Indianapolis, Indiana
,
Mahmoud Ahmed
2   Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas
,
Hyagriv Simhan
1   Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania
,
Laura A. Haneline
6   Department of Pediatrics, Indiana University, Indianapolis, Indiana
,
John Harris
1   Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania
,
Justine Chang
4   Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington
,
Alyssa Stephenson Famy
4   Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington
,
Patrick Yorio
1   Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania
,
Zhaoxia Ren
7   Obstetric and Pediatric Pharmacology and Therapeutics Branch, Eunice Shriver National Institute of Child Health and Human Development, National Institutes of Health, Washington
,
Mary E. D'Alton
8   Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, New York
,
Raman Venkataramanan
9   Department of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania
10   Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
› Author Affiliations Funding Funding from grants HD 047905, HD 047892, HD 047891, and HD 063094 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and UL1TR000423 from the National Center for Advancing Translational Sciences of the National Institutes of Health.
Further Information

Publication History

27 July 2017

30 September 2017

Publication Date:
15 November 2017 (online)

Also available at
    Permissions and Reprints

Abstract

Objective The objective of this study was to evaluate the impact of pregnancy history and 17-hydroxyprogesterone caproate (17-OHPC) treatment on cervical fluid cytokines and matrix metalloproteinases (MMPs).

Study Design Cervical fluid was obtained between 160/7 and 246/7 weeks from women with only prior term births (controls, n = 26), women with one or more prior spontaneous preterm births (SPTBs) choosing to receive 17-OHPC (17-OHPC, n = 24), or to not receive 17-OHPC (refusers, n = 12). Cervical fluid collections were repeated 2, 4, and 8 weeks after the first sample and concentrations of MMPs and cytokines were measured by multiplex immune assay.

Results Among women whose earliest prior delivery occurred between 16 and 23 weeks, cervical fluid concentration of interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α at baseline were significantly elevated when compared with cervical cytokines of women whose earliest delivery occurred between 32 and 36 weeks (relative risk ratio was 3.37 for IL-6 [95% confidence interval, CI, 1.08–10.53, p < 0.05], 2.81 for IL-10 [95% CI, 1.39–5.70, p < 0.05], and 6.34 for TNF-α [95% CI, 2.19–18.68, p < 0.001]). Treatment with 17-OHPC had no significant impact on these cytokines.

Conclusion The cervical fluid of women with a history of an early prior SPTB is characterized by inflammation that is unaffected by 17-OHPC.

Keywords

17-hydroxyprogesterone caproate - cytokines - matrix metalloproteinases - cervicovaginal - inflammatory milieu
 

  • References

  • 1 Meis PJ, Klebanoff M, Thom E. , et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003; 348 (24) 2379-2385
    CrossrefPubMedGoogle Scholar
  • 2 Romero R, Nicolaides KH, Conde-Agudelo A. , et al. Vaginal progesterone decreases preterm birth ≤ 34 weeks of gestation in women with a singleton pregnancy and a short cervix: an updated meta-analysis including data from the OPPTIMUM study. Ultrasound Obstet Gynecol 2016; 48 (03) 308-317
    CrossrefPubMedGoogle Scholar
  • 3 Caritis SN, Venkataramanan R, Thom E. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network and Obstetric-Fetal Pharmacology Research Units Network. Relationship between 17-alpha hydroxyprogesterone caproate concentration and spontaneous preterm birth. Am J Obstet Gynecol 2014; 210 (02) 128.e1-128.e6
    CrossrefPubMedGoogle Scholar
  • 4 Iams JD, Goldenberg RL, Meis PJ. , et al; National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network. The length of the cervix and the risk of spontaneous premature delivery. N Engl J Med 1996; 334 (09) 567-572
    CrossrefPubMedGoogle Scholar
  • 5 Owen J, Yost N, Berghella V. , et al; National Institute of Child Health and Human Development, Maternal-Fetal Medicine Units Network. Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth. JAMA 2001; 286 (11) 1340-1348
    CrossrefPubMedGoogle Scholar
  • 6 Stygar D, Wang H, Vladic YS, Ekman G, Eriksson H, Sahlin L. Increased level of matrix metalloproteinases 2 and 9 in the ripening process of the human cervix. Biol Reprod 2002; 67 (03) 889-894
    CrossrefPubMedGoogle Scholar
  • 7 Sennström MB, Brauner A, Byström B, Malmström A, Ekman G. Matrix metalloproteinase-8 correlates with the cervical ripening process in humans. Acta Obstet Gynecol Scand 2003; 82 (10) 904-911
    CrossrefPubMedGoogle Scholar
  • 8 Wang W, Yen H, Chen CH. , et al. Prevention of inflammation-associated preterm birth by knockdown of the endothelin-1-matrix metalloproteinase-1 pathway. Mol Med 2010; 16 (11-12): 505-512
    CrossrefPubMedGoogle Scholar
  • 9 Törnblom SA, Klimaviciute A, Byström B, Chromek M, Brauner A, Ekman-Ordeberg G. Non-infected preterm parturition is related to increased concentrations of IL-6, IL-8 and MCP-1 in human cervix. Reprod Biol Endocrinol 2005; 3: 39
    CrossrefPubMedGoogle Scholar
  • 10 Wei SQ, Fraser W, Luo ZC. Inflammatory cytokines and spontaneous preterm birth in asymptomatic women: a systematic review. Obstet Gynecol 2010; 116 (2 Pt 1): 393-401
    CrossrefPubMedGoogle Scholar
  • 11 Holst RM, Mattsby-Baltzer I, Wennerholm UB, Hagberg H, Jacobsson B. Interleukin-6 and interleukin-8 in cervical fluid in a population of Swedish women in preterm labor: relationship to microbial invasion of the amniotic fluid, intra-amniotic inflammation, and preterm delivery. Acta Obstet Gynecol Scand 2005; 84 (06) 551-557
    CrossrefPubMedGoogle Scholar
  • 12 Lockwood CJ, Ghidini A, Wein R, Lapinski R, Casal D, Berkowitz RL. Increased interleukin-6 concentrations in cervical secretions are associated with preterm delivery. Am J Obstet Gynecol 1994; 171 (04) 1097-1102
    CrossrefPubMedGoogle Scholar
  • 13 Edwards RK, Ferguson RJ, Duff P. The interleukin-1 beta +3953 single nucleotide polymorphism: cervical protein concentration and preterm delivery risk. Am J Reprod Immunol 2006; 55 (04) 259-264
    CrossrefPubMedGoogle Scholar
  • 14 Woodworth A, Grenache DG, Gronowski AM. Cervicovaginal interleukin-6 as a predictor of preterm birth in African American women. Clin Chim Acta 2011; 412 (11-12): 988-992
    CrossrefPubMedGoogle Scholar
  • 15 Dubicke A, Fransson E, Centini G. , et al. Pro-inflammatory and anti-inflammatory cytokines in human preterm and term cervical ripening. J Reprod Immunol 2010; 84 (02) 176-185
    CrossrefPubMedGoogle Scholar
  • 16 Zhang S, Mada SR, Sharma S. , et al. Simultaneous quantitation of 17alpha-hydroxyprogesterone caproate, 17alpha-hydroxyprogesterone and progesterone in human plasma using high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). J Pharm Biomed Anal 2008; 48 (04) 1174-1180
    CrossrefPubMedGoogle Scholar
  • 17 Laughon SK, Albert PS, Leishear K, Mendola P. The NICHD Consecutive Pregnancies Study: recurrent preterm delivery by subtype. Am J Obstet Gynecol 2014; 210 (02) 131.e1-131.e8
    CrossrefPubMedGoogle Scholar
  • 18 Spong CY, Meis PJ, Thom EA. , et al; National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network. Progesterone for prevention of recurrent preterm birth: impact of gestational age at previous delivery. Am J Obstet Gynecol 2005; 193 (3 Pt 2): 1127-1131
    CrossrefPubMedGoogle Scholar
  • 19 Esplin MS, O'Brien E, Fraser A. , et al. Estimating recurrence of spontaneous preterm delivery. Obstet Gynecol 2008; 112 (03) 516-523
    CrossrefPubMedGoogle Scholar
  • 20 Mercer BM, Goldenberg RL, Moawad AH. , et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. The preterm prediction study: effect of gestational age and cause of preterm birth on subsequent obstetric outcome. Am J Obstet Gynecol 1999; 181 (5 Pt 1): 1216-1221
    CrossrefPubMedGoogle Scholar
  • 21 Brik M, Antonio P, Perales-Puchalt A, Diago V, Perales A. Cervical interleukin-6 as a predictive test for preterm delivery in symptomatic women: preliminary results. Eur J Obstet Gynecol Reprod Biol 2011; 155 (01) 14-18
    CrossrefPubMedGoogle Scholar
  • 22 Lange M, Chen FK, Wessel J, Buscher U, Dudenhausen JW. Elevation of interleukin-6 levels in cervical secretions as a predictor of preterm delivery. Acta Obstet Gynecol Scand 2003; 82 (04) 326-329
    CrossrefPubMedGoogle Scholar
  • 23 Jung EY, Park JW, Ryu A, Lee SY, Cho SH, Park KH. Prediction of impending preterm delivery based on sonographic cervical length and different cytokine levels in cervicovaginal fluid in preterm labor. J Obstet Gynaecol Res 2016; 42 (02) 158-165
    CrossrefPubMedGoogle Scholar
  • 24 Torbé A, Czajka R. Proinflammatory cytokines and other indications of inflammation in cervico-vaginal secretions and preterm delivery. Int J Gynaecol Obstet 2004; 87 (02) 125-130
    CrossrefPubMedGoogle Scholar
  • 25 Goepfert AR, Goldenberg RL, Andrews WW. , et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. The Preterm Prediction Study: association between cervical interleukin 6 concentration and spontaneous preterm birth. Am J Obstet Gynecol 2001; 184 (03) 483-488
    CrossrefPubMedGoogle Scholar
  • 26 Caritis SN, Sharma S, Venkataramanan R. , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetrical-Fetal Pharmacology Research Units Network. Pharmacology and placental transport of 17-hydroxyprogesterone caproate in singleton gestation. Am J Obstet Gynecol 2012; 207 (05) 398.e1-398.e8
    CrossrefPubMedGoogle Scholar
  • 27 Facchinetti F, Dante G, Venturini P, Paganelli S, Volpe A. 17alpha-hydroxy-progesterone effects on cervical proinflammatory agents in women at risk for preterm delivery. Am J Perinatol 2008; 25 (08) 503-506
    Article in Thieme ConnectPubMedGoogle Scholar