The Impact of Vaginal and IM Progestins on the Cervix

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Preterm Birth, Short Cervical Length

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1: No prior preterm birth & normal cervix length<br>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<br>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<br>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<br>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?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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17-OHPC, Prometrium, Cerclage, Pre-term birth, Short cervix