The Impact of Vaginal and IM Progestins on the Cervix

Determining the Pharmacodynamic Impact of Vaginal and IM Progestins on the Cervix

The purpose of this study is to analyze how the body handles and responds to progesterone treatment in parous and nulliparous women at risk of pre-term birth.

Study Overview

• Status: Completed
• Conditions: Preterm Birth; Short Cervical Length

Detailed Description

17-hydroxyprogesterone caproate (17-OHPC) has recently been shown to reduce the rate of recurrent preterm birth while intravaginal progesterone has been shown to reduce the rate of preterm birth in women with short cervix. While these interventions have reduced the rate of preterm birth, the mechanisms of action of these medications are unknown. The objective of this study is to collect and analyze blood and cervicovaginal fluids from pregnant women receiving these medications or other interventions such as cerclage, pessary, NSAIDs, and combinations thereof. The goal of the analyses is to assess the impact of these interventions on the cervical proteome, cervical cytokines and cervical structure and to identify potential biomarkers of response and non-response thus providing insights into the mechanisms of action of these drugs.

• Study Type: Observational
• Enrollment (Actual): 89

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • Texas
    • Galveston, Texas, United States, 77555
      • University of Texas Medical Branch
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

This study consists of 4 groups of women who are between 16 0/7 - 23 6/7 weeks gestation. The allocation of a subject to a group is based on two objective assessments (history of preterm birth and cervical length) and the joint clinical decision of the woman and her physician regarding treatment options.

Study participants who have no prior preterm births and a normal cervical length will be assigned to Group 1. If the participant has no prior preterm births and a short cervical length, she will be assigned to Group 2 regardless of treatment or no treatment. Group assignment for women with a prior preterm birth and normal cervical length is based on 17-OHPC use. Participants who elect to use 17-OHPC will be assigned to Group 3 and those who choose not to receive any treatment will be assigned to Group 4.

Description

Inclusion Criteria

All Groups

• Singleton gestation (16 0/7 - 23 6/7 weeks gestation)
• Willing to provide informed consent
• Age 18 - 50 years inclusive

Additionally,

Group 1: One or more prior term births (>37 0/7 weeks); No prior spontaneous birth at 16 0/7 - 36 6/7 weeks; and normal cervical length (>25 mm)

Group 2: Cervical length of 20 mm or less at 16 0/7 - 23 6/7 weeks

Groups 3 and 4: History of prior spontaneous birth at 16 0/7 - 34 0/7 weeks and normal cervical length (> 25mm) at enrollment.

Exclusion Criteria

All Groups

• Active labor
• Active bleeding
• On progestin therapy, chronic steroid, or current NSAID therapy
• Actively receiving study treatment in another clinical trial (observational trials allowed)
• Major fetal malformation lethal anomalies, or anomalies that may lead to early delivery or increased risk of neonatal death e.g., gastroschisis, spina bifida, or serious karyotypic abnormalities
• Amniotic membranes prolapsed beyond the external os (ostium of uterus) or protruding into the vagina
• Pregnancy without a viable fetus
• Prenatal care or delivery planned elsewhere (unless the study visits can be made as scheduled and complete outcome information can be obtained)

Additionally:

Group 1: Cervical dilation greater than or equal to 3cm

Group 2: Prior preterm birth (16 0/7 - 34 0/7); active deep vein thrombosis, pulmonary embolism, or history of these conditions; known liver dysfunction or disease (active hepatitis, HIV)

Group 3: inability or unwillingness to use a 17-OHPC compounded product similar in composition to the FDA-approved product; allergy to 17-OHPC or its components

Groups 1, 3, and 4: cerclage in place or anticipated; congenital mullerian abnormality of the uterus; positive for bacterial vaginosis, chlamydia, gonorrhea, or trichomonas

Groups 3 and 4: current or history of thrombosis or thromboembolic disorders; known or suspected breast cancer, other hormone-sensitive cancer, or history of these conditions; undiagnosed abnormal vaginal bleeding unrelated to pregnancy; cholestatic jaundice of pregnancy, liver tumors, benign or malignant, or active liver disease; uncontrolled hypertension

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Group 1: No prior preterm birth & normal cervix length; Pregnant women at 16 0/7 - 23 6/7 weeks gestation who have had one or more term births (no prior preterm births) and have a normal cervical length (> 25 mm). These women will serve as gestational age controls for all groups.
Group 2: No prior preterm birth & short cervix length; Pregnant women at 16 0/7 - 23 6/7 weeks gestation who have no prior preterm births and have a short cervical length (20mm or less). These women may receive treatment (e.g. vaginal progesterone, cerclage, pessary, NSAIDs, or a combination thereof) or no treatment.
Group 3: Prior preterm birth, normal cervix length, 17-OHPC; Pregnant women at 16 0/7 - 23 6/7 weeks gestation who have had prior preterm birth, have a normal cervical length and will receive 17-OHPC treatment.
Group 4: Prior preterm birth, normal cervix length, no treat; Pregnant women at 16 0/7 - 23 6/7 weeks gestation who have had prior preterm birth, have a normal cervical length, and will not receive any treatment. These women will serve as controls for Group 3.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarkers	Proteins in the cervicovaginal fluid with expression changes two-fold or greater between day 0 and week 2 of either vaginal or IM progestin therapy.	2 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cervical sonographic changes	Changes in cervical sonographic gray scale density/length from weeks 0-2, 0-4, and 0-8 after the start of progestin therapy.	8 Weeks
Protein Expression	Proteins in the cervicovaginal fluid whose expression changes significantly from weeks 0-4 and 0-8 after the start of progestin therapy.	8 Weeks
Cervical cytokines	Changes in cervical cytokine inflammatory ratio weeks 0-2, 0-4, and 0-8 after the start of progestin therapy.	8 Weeks
Individual cytokines	Changes in individual cytokines (IL-1α, IL-1β, IL-1RA, IL-4, IL-6, IL-8, IL-10, IL-13, and TNF-α) from weeks 0-2, 0-4, and 0-8 after the start of progestin therapy.	8 Weeks
Cervical MMPs	Changes in cervical MMPs 1, 2, 8 and 9 from weeks 0-2, 0-4, and 0-8 after the start of progestin therapy.	8 Weeks
Single nucleotide polymorphisms	Test for association between single nucleotide polymorphisms (SNPs) in progestin and estrogen-related candidate genes and changes in the CVF proteome and cervical density and length.	8 Weeks
Biomarkers	Proteins in the cervicovaginal fluid with expression changes two-fold or greater between weeks 0-4 and 0-8 of either vaginal or IM progestin therapy.	8 Weeks

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: University of Washington; University of Texas; Indiana University; RTI International
• Investigators: Principal Investigator: Steve Caritis, MD, University of Pittsburgh; Principal Investigator: David Flockhart, MD, PhD, Indiana University School of Medicine; Principal Investigator: Gary Hankins, MD, University of Texas; Principal Investigator: Mary F Hebert, PharmD, FCCP, University of Washington

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: September 26, 2013
• First Submitted That Met QC Criteria: September 26, 2013
• First Posted (Estimate): October 1, 2013

Study Record Updates

• Last Update Posted (Estimate): December 2, 2015
• Last Update Submitted That Met QC Criteria: December 1, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: 17-OHPC, Prometrium, Cerclage, Pre-term birth, Short cervix
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth
• Other Study ID Numbers: OPRU Progestin