Vaginal Progesterone for the Prevention of Preterm Birth in Women With Arrested Preterm Labor (PAL)

Preterm birth, defined as birth before 37 weeks' gestation, is a leading cause of infant death and disease. Progesterone is the single most effective intervention in the prevention of preterm birth. However, current use of this therapy is limited to certain high-risk groups including women with a history of preterm birth and women with a short cervix. This study seeks to evaluate the efficacy of this preventive therapy in another high-risk group: women with arrested preterm labor. The investigators hypothesize that administration of vaginal progesterone in women who present with preterm labor but remain undelivered 12 hours after cessation of short-term therapy to inhibit contractions will result in lower rates of preterm birth before 37 weeks' than will administration of placebo.

Study Overview

• Status: Terminated
• Conditions: Premature Birth; Obstetric Labor, Premature
• Intervention / Treatment: Drug: Micronized progesterone suppository

Detailed Description

RESEARCH DESIGN AND METHODS

The investigators will perform a randomized, blinded, placebo-controlled trial to evaluate the use of vaginal progesterone in women with arrested preterm labor after 24 weeks' gestation to reduce the risk of preterm birth before 37 weeks' gestation. Women enrolled in the study will be randomized to daily vaginal administration of progesterone (200 mg) or placebo from time of enrollment until 36 6/7 weeks' gestation. Women will be eligible if they have a singleton or twin gestation between 24 0/7 and 33 6/7 weeks' gestation and initially present with regular uterine contractions and a clinical diagnosis of preterm labor but remain undelivered without further cervical change 12 hours after discontinuation of acute tocolytic therapy. Women may also participate if it has been less than if they are considered eligible for discharge based on attending physician judgement prior to the 12 hour period of time.

Randomization and Blinding- Participants in the study will be randomized using a computer-generated randomization scheme with 1:1 allocation to receive progesterone or placebo. Investigators and research team members, participants, and the obstetric providers will be blinded to the allocated intervention.

Procedures-

• Data collection- Information will be recorded from the participant's medical record. Additional study information not included in the medical record will be obtained directly from the participant in an interview with the research team member.
• Follow-up- Regardless of whether the participant remains hospitalized or is discharged prior to delivery, she will meet with a study coordinator every 2 weeks. During the follow-up visit, a study team member will discuss compliance with the study drug and possible side effects. The participant will fill out a 1-page questionnaire that asks questions about compliance and side effects. This information will be recorded and provided to the Data Safety and Monitoring Board at the midpoint review.

SAMPLE SIZE ESTIMATION

The investigators plan to enroll 120 patients, with a 1:1 allocation to treatment and placebo. This sample size is adequate to detect a one-half reduction in the primary outcome, delivery before 37 weeks.

STATISTICAL ANALYSIS

Baseline characteristics of women randomized to progesterone will be compared with women randomized to placebo. Rates of delivery before 37 weeks' gestation will be compared among the groups using the Chi-square test. Secondary outcomes will be evaluated using the Chi-square test for binary outcomes and the Student t-test for continuous outcomes. Length of time from enrollment to delivery will be analyzed using Kaplan-Meier curves and the Cox proportional hazards model. All analyses will be performed using the intention-to-treat principle.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine/ Barnes-Jewish Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Singleton or twin gestation
• Estimated gestational age between 24 0/7 and 33 6/7 weeks' gestation
• Initially present with regular contractions and clinical diagnosis of preterm labor but remain undelivered with 1) no further cervical change 12 hours after discontinuation of acute tocolytic therapy; or 2) be considered eligible for discharge based on attending physician judgment prior to the 12 hour period of time
• The participant's cervix must be at least 1 cm at the time of enrollment

Exclusion Criteria:

• Non-English speaking
• Rupture of membranes
• Chorioamnionitis
• Non-reassuring fetal status
• Maternal indication for delivery
• Placental abruption
• Intrauterine fetal demise
• Prenatally diagnosed major fetal anomaly
• Cervical cerclage in place
• Previous administration of progesterone during the current pregnancy for a history of preterm birth or short cervix
• Participant is either unwilling or unable to attend follow-up study visits following hospital discharge

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Micronized progesterone suppository; Micronized progesterone suppository 200 mg vaginally daily until 36 6/7 weeks' gestation.	Drug: Micronized progesterone suppository
Placebo Comparator: Placebo suppository; One placebo suppository vaginally daily until 36 6/7 weeks' gestation.	Drug: Micronized progesterone suppository

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of Participants Who Delivered Before 37 Weeks'	Duration of current pregnancy, anticipated maximum 18 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Delivered Before 34 Weeks'	Evaluated in women enrolled prior to 32 weeks gestation	Duration of current pregnancy, anticipated maximum 18 weeks
Delivery Within 2 Weeks of Randomization		2 weeks
Number of Weeks Pregnancy Prolongation		Duration of current pregnancy, anticipated maximum 18 weeks
Infant Birth Weight		Day of delivery in current pregnancy
Neonatal Intensive Care Unit Admission		Followed for duration of neonatal hospital stay, estimated maximum 16 weeks
Number of Participants With Chorioamnionitis		Duration of current pregnancy, anticipated maximum 18 weeks
Composite Neonatal Outcome	A composite neonatal outcome comprising neonatal death, respiratory distress syndrome, bronchopulmonary dysplasia, severe (grade III/IV) interventricular hemorrhage, necrotizing enterocolitis, and sepsis.	Followed for duration of neonatal hospital stay, estimated maximum 16 weeks

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Thrasher Research Fund
• Investigators: Study Chair: George A Macones, MD, MSCE, Washington University School of Medicine; Principal Investigator: Heather A Frey, MD, MSCI, Ohio State University

Publications and helpful links

General Publications

• Hassan SS, Romero R, Vidyadhari D, Fusey S, Baxter JK, Khandelwal M, Vijayaraghavan J, Trivedi Y, Soma-Pillay P, Sambarey P, Dayal A, Potapov V, O'Brien J, Astakhov V, Yuzko O, Kinzler W, Dattel B, Sehdev H, Mazheika L, Manchulenko D, Gervasi MT, Sullivan L, Conde-Agudelo A, Phillips JA, Creasy GW; 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 Jul;38(1):18-31. doi: 10.1002/uog.9017. Epub 2011 Jun 15.
• 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 Aug 2;357(5):462-9. doi: 10.1056/NEJMoa067815.
• Lyell DJ, Pullen KM, Mannan J, Chitkara U, Druzin ML, Caughey AB, El-Sayed YY. Maintenance nifedipine tocolysis compared with placebo: a randomized controlled trial. Obstet Gynecol. 2008 Dec;112(6):1221-1226. doi: 10.1097/AOG.0b013e31818d8386.
• Likis FE, Edwards DR, Andrews JC, Woodworth AL, Jerome RN, Fonnesbeck CJ, McKoy JN, Hartmann KE. Progestogens for preterm birth prevention: a systematic review and meta-analysis. Obstet Gynecol. 2012 Oct;120(4):897-907. doi: 10.1097/AOG.0b013e3182699a15.
• Borna S, Sahabi N. Progesterone for maintenance tocolytic therapy after threatened preterm labour: a randomised controlled trial. Aust N Z J Obstet Gynaecol. 2008 Feb;48(1):58-63. doi: 10.1111/j.1479-828X.2007.00803.x.
• Arikan I, Barut A, Harma M, Harma IM. Effect of progesterone as a tocolytic and in maintenance therapy during preterm labor. Gynecol Obstet Invest. 2011;72(4):269-73. doi: 10.1159/000328719. Epub 2011 Nov 12.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): May 7, 2018
• Study Completion (Actual): May 7, 2018

Study Registration Dates

• First Submitted: April 17, 2013
• First Submitted That Met QC Criteria: April 22, 2013
• First Posted (Estimate): April 25, 2013

Study Record Updates

• Last Update Posted (Actual): June 18, 2019
• Last Update Submitted That Met QC Criteria: May 29, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Progesterone; Preterm
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Premature Birth; Obstetric Labor, Premature; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Progesterone
• Other Study ID Numbers: 201301148