Am J Perinatol 2020; 37(13): 1289-1295
DOI: 10.1055/s-0040-1710008
SMFM Fellowship Series Article

Predictors of Early Preterm Birth Despite Vaginal Progesterone Therapy in Singletons with Short Cervix

1   Division of Maternal Fetal Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
,
Mackenzie N. Naert
2   Department of Obstetrics Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York
,
Nathan S. Fox
2   Department of Obstetrics Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York
3   Mount Sinai School of Medicine—Obstetrics and Gynecology, Maternal Fetal Medicine Associates, PLLC, New York, New York
,
Sean Hennessy
4   Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania
,
Inna Chervoneva
4   Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania
,
Vincenzo Berghella
1   Division of Maternal Fetal Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
,
Amanda Roman
1   Division of Maternal Fetal Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
› Author Affiliations
Funding R.C.B. was supported by U.S. Department of Health and Human Services, National Institutes of Health, National Institute of General Medical (grant T32GM008562, PhRMA Foundation x, Faculty Development Award); S.H. was supported by grant T32GM075766.

Abstract

Objective This study aimed to identify the incidence of and risk factors for early preterm birth (PTB) (delivery <34 weeks) in women without prior PTB and current short cervix (≤20 mm) prescribed vaginal progesterone.

Study Design Retrospective cohort study of singletons without prior PTB diagnosed with short cervix (≤20 mm) between 180/7 and 236/7 weeks. Women who accepted vaginal progesterone and had delivery outcomes available were included. Demographic/obstetric history, cervical length, and pregnancy characteristics compared between women with early PTB versus delivery ≥34 weeks. Multiple logistic regression analysis used to identify predictors; odds ratio for significant factors used to generate a risk score. Risk score and risk of early PTB assessed with receiver operating characteristic curve (ROCC). Perinatal outcomes compared by risk score.

Results Among 109 patients included, 29 (27%) had a spontaneous PTB <34 weeks. In univariate analysis, only gestational age at ultrasound, presence funneling, and mean cervical length were significantly different between those with and without early sPTB. With multiple logistic regression analysis, only gestational age at diagnosis (odds ratio [OR]: 0.66; 95% confidence interval [CI]: 0.46–0.96; p = 0.028) and index cervical length (OR: 0.84; 95% CI: 0.76–0.93; p = 0.001) remained significantly associated with early PTB. ROCC for the risk score incorporating cervical length and gestational age was predictive of early PTB with an AUC of 0.76 (95% CI: 0.67–0.86; p < 0.001). A high-risk score was predictive of early PTB with a sensitivity of 79%, specificity of 75%, positive predictive value of 54%, and negative predictive value of 91%. Women with a high-risk score had worse perinatal outcomes compared with those with low-risk score.

Conclusion A total of 27% of patients with short cervix prescribed vaginal progesterone will have a sPTB < 34 weeks. Patients at high risk for early PTB despite vaginal progesterone therapy may be identified using gestational age and cervical length at diagnosis of short cervix. Given the narrow window for intervention after diagnosis of short cervix, this has important implications for clinical care.

Note

This study was presented at Society for Maternal Fetal Medicine Annual Pregnancy Meeting on February 2, 2018, Dallas, TX.




Publication History

Received: 13 November 2019

Accepted: 29 March 2020

Article published online:
28 April 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers
333 Seventh Avenue, New York, NY 10001, USA.

 
  • References

  • 1 Martin JA, Hamilton BE, Osterman MJK, Curtin SC, Mathews TJ. National vital statistics reports births : final data for 2015. Natl Vital Stat Rep 2015; 64 (01) 1-104
  • 2 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
  • 3 Berghella V. Universal cervical length screening for prediction and prevention of preterm birth. Obstet Gynecol Surv 2012; 67 (10) 653-658
  • 4 Romero R, Conde-Agudelo A, El-Refaie W. et al. Vaginal progesterone decreases preterm birth and neonatal morbidity and mortality in women with a twin gestation and a short cervix: an updated meta-analysis of individual patient data. Ultrasound Obstet Gynecol 2017; 49 (03) 303-314
  • 5 Boelig RC, Orzechowski KM, Berghella V. Cervical length, risk factors, and delivery outcomes among women with spontaneous preterm birth. J Matern Fetal Neonatal Med 2016; 29 (17) 2840-2844
  • 6 Hassan SS, Romero R, Vidyadhari D. et al; PREGNANT Trial. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2011; 38 (01) 18-31
  • 7 Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH. Fetal Medicine Foundation Second Trimester Screening Group. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007; 357 (05) 462-469
  • 8 Orzechowski KM, Boelig RC, Baxter JK, Berghella V. A universal transvaginal cervical length screening program for preterm birth prevention. Obstet Gynecol 2014; 124 (03) 520-525
  • 9 Temming LA, Durst JK, Tuuli MG. et al. Universal cervical length screening: implementation and outcomes. Am J Obstet Gynecol 2016; 214 (04) 523.e1-523.e8
  • 10 Son M, Grobman WA, Ayala NK, Miller ES. A universal mid-trimester transvaginal cervical length screening program and its associated reduced preterm birth rate. Am J Obstet Gynecol 2016; 214 (03) 365.e1-365.e5
  • 11 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
  • 12 Granese R, Mantegna S, Mondello S. et al. Preterm birth: incidence, risk factors and second trimester cervical length in a single center population. A two-year retrospective study. Eur Rev Med Pharmacol Sci 2017; 21 (19) 4270-4277
  • 13 Dugoff L, Berghella V, Sehdev H, Mackeen AD, Goetzl L, Ludmir J. Prevention of Preterm Birth with Pessary in Singletons (PoPPS): a randomized controlled trial. Ultrasound Obstet Gynecol 2017; ; (September): DOI: 10.1002/uog.18908.
  • 14 Robin X, Turck N, Hainard A. et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 2011; 12: 77
  • 15 R: A language and environment for statistical computing. R Foundation for Statistical Computing. 2019 Available at: https://www.gbif.org/tool/81287/r-a-language-and-environment-for-statistical-computing . Accessed April 8, 2020
  • 16 Venkatraman ES. A permutation test to compare receiver operating characteristic curves. Biometrics 2000; 56 (04) 1134-1138
  • 17 Dugoff L, Berghella V, Mackeen AD, Goetzl L, Ludmir J. Prevention of preterm birth with pessary in singletons (PoPPS): a randomized controlled trial. Am J Obstet Gynecol 2017; 216 (01) S4
  • 18 Romero R, Conde-Agudelo A, Nicolaides KH. There is insufficient evidence to claim that cerclage is the treatment of choice for patients with a cervical length <10 mm. Am J Obstet Gynecol 2018; 219 (02) 213-215
  • 19 Goldenberg, Robert L, McClure EM. The Epidemiology of Preterm Birth. In: Vincenzo Berghella, ed. Preterm Birth Prevention and Management. Hoboken, NC: Blackwell Publishing Ltd; 2010: 22-39
  • 20 Boelig RC, Dugoff L, Roman A, Berghella V, Ludmir J. Predicting asymptomatic cervical dilation in pregnant patients with short mid-trimester cervical length: a secondary analysis of a randomized controlled trial. Acta Obstet Gynecol Scand 2019; 98 (06) 761-768
  • 21 Nold C, Maubert M, Anton L, Yellon S, Elovitz MA. Prevention of preterm birth by progestational agents: what are the molecular mechanisms?. Am J Obstet Gynecol 2013; 208 (03) 223.e1-223.e7
  • 22 Furcron AE, Romero R, Plazyo O. et al. Vaginal progesterone, but not 17α-hydroxyprogesterone caproate, has antiinflammatory effects at the murine maternal-fetal interface. Am J Obstet Gynecol 2015; 213 (06) 846.e1-846.e19
  • 23 Romero R, Yeo L, Miranda J, Hassan SS, Conde-Agudelo A, Chaiworapongsa T. A blueprint for the prevention of preterm birth: vaginal progesterone in women with a short cervix. J Perinat Med 2013; 41 (01) 27-44
  • 24 Boelig RC, Zuppa AF, Kraft WK, Caritis S. Pharmacokinetics of vaginal progesterone in pregnancy. Am J Obstet Gynecol 2019; 221 (03) 263.e1-263.e7
  • 25 Manuck TA. Pharmacogenomics of preterm birth prevention and treatment. BJOG 2016; 123 (03) 368-375
  • 26 Spong CY. Future Research. In: Vincenzo Berghella, ed. Preterm Birth: Prevention and Management. Hoboken, NC: Blackwell Publishing Ltd; 2010: 270-273
  • 27 Manuck TA, Stoddard GJ, Fry RC, Esplin MS, Varner MW. Nonresponse to 17-alpha hydroxyprogesterone caproate for recurrent spontaneous preterm birth prevention: clinical prediction and generation of a risk scoring system. Am J Obstet Gynecol 2016; 215 (05) 622.e1-622.e8
  • 28 Committee on Practice Bulletins—Obstetrics, The American College of Obstetricians and Gynecologists. Practice bulletin no. 130: prediction and prevention of preterm birth. Obstet Gynecol 2012; 120 (04) 964-973
  • 29 Roman AR, Da Silva Costa F, Araujo Júnior E, Sheehan PM. Rescue adjuvant vaginal progesterone may improve outcomes in cervical cerclage failure. Geburtshilfe Frauenheilkd 2018; 78 (08) 785-790