A Trial of Pessary and Progesterone for Preterm Prevention in Twin Gestation With a Short Cervix (PROSPECT)

A Randomized Trial of Pessary and Progesterone for Preterm Prevention in Twin Gestation With a Short Cervix

This protocol outlines a randomized trial of 630 women evaluating the use of micronized vaginal progesterone or pessary versus control (placebo) to prevent early preterm birth in women carrying twins and with a cervical length of less than 30 millimeters.

Study Overview

• Status: Completed
• Conditions: Short Cervical Length
• Intervention / Treatment: Drug: Vaginal progesterone; Drug: Placebo; Device: Arabin Pessary

Detailed Description

This protocol outlines a randomized trial of 630 women evaluating the use of micronized vaginal progesterone or pessary versus control (placebo) to prevent early preterm birth in women carrying twins and with a cervical length of less than 30 millimeters.

Multiple gestation increases the risk of preterm delivery. Babies born preterm have increased rates of neonatal mortality and long-term neurodevelopmental morbidities. Short cervical length is known to be an important risk factor for spontaneous preterm birth and to occur more frequently in women with a twin gestation. Although there is no evidence that progesterone reduces the risk of preterm birth in multifetal gestation, there is evidence that progesterone reduces the risk of prematurity in singleton gestations complicated with a short cervix. The Arabin pessary has also been shown to reduce the risk of preterm birth among singletons with a short cervix, and in a secondary subgroup analysis of a recent study of the use of pessary in multiple gestations, women with a cervical length < 25th percentile had a significantly reduced risk of the primary composite neonatal adverse outcome. Secondary analysis of studies of vaginal progesterone in multiple gestation with a short cervix also suggest a possible beneficial effect on preterm delivery.

• Study Type: Interventional
• Enrollment (Actual): 1311
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama - Birmingham
  • California
    • San Francisco, California, United States
      • The Regents of the University of California, San Francisco
  • Colorado
    • Denver, Colorado, United States, 80045
      • University of Colorado
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University-Prentice Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina - Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Ohio
    • Cleveland, Ohio, United States, 44109
      • Case Western Reserve University
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee Women's Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Brown University
  • Texas
    • Galveston, Texas, United States, 77555
      • University of Texas - Galveston
    • Houston, Texas, United States, 77030
      • University of Texas - Houston
    • Houston, Texas, United States
      • Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Twin gestation with cardiac activity in both fetuses. Higher order multifetal gestations reduced to twins, either spontaneously or therapeutically, are not eligible unless the reduction occurred by 13 weeks 6 days project gestational age.
2. Gestational age at randomization between 16 weeks 0 days and 23 weeks 6 days based on clinical information and evaluation of the earliest ultrasound.
3. Cervical length on transvaginal examination of less than 30 mm by a study certified sonographer.

Exclusion Criteria:

1. Cervical dilation (internal os) 3 cm or greater on digital examination or evidence of prolapsed membranes beyond the external cervical os either at the time of the qualifying cervical ultrasound examination or at a cervical exam immediately before randomization. There is no lower threshold of cervical length measurement threshold on ultrasound that is an exclusion criterion.
2. Monoamniotic gestation, due to increased risk of adverse pregnancy outcome
3. Twin-twin transfusion syndrome, due to increased risk of adverse pregnancy outcome
4. Evidence of severe IUGR (intrauterine growth restriction) (<5th percentile for gestational age) in either fetus
5. Fetal anomaly in either twin or imminent fetal demise. This includes lethal anomalies, or anomalies that may lead to early delivery or increased risk of neonatal death e.g., gastroschisis, spina bifida, serious karyotypic abnormalities). An ultrasound examination from 14 weeks 0 days to 23 weeks 6 days by project EDC (estimated date of conception) must be performed prior to randomization to evaluate the fetuses for anomalies.
6. Placenta previa, because of risk of bleeding and high potential for indicated preterm birth
7. Active vaginal bleeding greater than spotting at the time of randomization, because of potential exacerbation due to pessary placement.
8. Symptomatic, untreated vaginal or cervical infection, also because of potential exacerbation due to pessary placement. Patients may be treated and if subsequently asymptomatic, randomized.
9. Active, unhealed herpetic lesion on labia minora, vagina, or cervix due to the potential for significant patient discomfort or increasing genital tract viral spread. Once lesion(s) heal and the patient is asymptomatic, she may be randomized. History of herpes is not an exclusion.
10. Rupture of membranes due to likelihood of pregnancy loss and preterm delivery as well as the risk of ascending infection which could be increased with pessary placement
11. More than six contractions per hour reported or documented prior to randomization. It is not necessary to place the patient on a tocodynamometer
12. Known major Mullerian anomaly of the uterus (specifically bicornuate, unicornuate, or uterine septum not resected) due to increased risk of preterm delivery which is unlikely to be affected by progesterone
13. Any fetal/maternal condition which would require invasive in-utero assessment or treatment, for example significant red cell antigen sensitization or neonatal alloimmune thrombocytopenia
14. Major maternal medical illness associated with increased risk for adverse pregnancy outcome or indicated preterm birth (treated hypertension requiring more than one agent, pre-gestational treatment for diabetes prior to pregnancy, chronic renal insufficiency failure defined by creatinine >1.4 mg/dL, carcinoma of the breast, conditions treated with chronic oral glucocorticoid therapy. Specifically, patients with seizure disorders, HIV, and other medical conditions not specifically associated with an increased risk of indicated preterm birth are not excluded. Prior cervical cone/LOOP/LEEP is not an exclusion criterion.
15. Planned cerclage or cerclage already in place since it would preclude placement of a pessary
16. Planned indicated delivery prior to 35 weeks
17. Planned or actual progesterone treatment of any type or form after 15 weeks 6 days during the current pregnancy
18. Allergy to progesterone, silicone, or excipients in the study drug, including peanuts or peanut oil in the study drug or placebo
19. Known, suspected or history of breast cancer because breast cancer is a contraindication to the active study medication.
20. Known liver dysfunction or disease because liver disease is a contraindication to the active study medication.
21. Participation in another interventional study that influences gestational age at delivery or neonatal morbidity or mortality
22. Participation in this trial in a previous pregnancy. Patients who were screened in a previous pregnancy, but not randomized, do not have to be excluded.
23. Prenatal care or delivery planned elsewhere unless the study visits can be made as scheduled and complete outcome information can be obtained

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; placebo capsule	Drug: Placebo; placebo softgel capsule, daily from randomization to < 35 wks
Active Comparator: Progesterone; vaginal progesterone capsule	Drug: Vaginal progesterone; 200mg micronized vaginal progesterone softgel capsule, daily from randomization to < 35 wks; Other Names: Prometrium
Active Comparator: Arabin Pessary	Device: Arabin Pessary; placement and management of an Arabin Pessary from randomization to < 35 wks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Delivery or Fetal Loss of Either Twin Prior to 35 Weeks Gestation	Number of Participants who had preterm delivery or fetal loss of either twin prior to 35 weeks gestation	From randomization to 35 weeks gestation (a period of up to 19 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days From Randomization to Delivery (or Fetal Demise)	Days from the time of randomization (16-23 weeks gestation) to delivery or death of the fetus.	Randomization to delivery (a period of up to 26 weeks)
Gestational Age at Delivery or Fetal Death	Gestational age at the time of delivery or death	Randomization to delivery (a period of up to 26 weeks)
Number of Participants With Preterm Delivery or Fetal Demise of Either Twin Prior to 28 Weeks Gestation	Preterm delivery or fetal loss of either twin prior to 28 weeks gestation	From randomization to up to 28 weeks gestation (a period if up to 12 weeks)
Number of Participants With Preterm Delivery or Fetal Demise of Either Twin Prior to 32 Weeks Gestation	Preterm Delivery or Fetal Demise of Either Twin Prior to 32 Weeks Gestation	From randomization to 32 weeks gestation (a period of up to 16 weeks)
Number of Participants With Preterm Delivery or Fetal Demise of Either Twin Prior to 37 Weeks Gestation	Preterm Delivery or Fetal Demise of Either Twin Prior to 37 Weeks Gestation	randomization to 37 weeks gestation (a period of up to 21 weeks)
Number of Participants With Spontaneous Preterm Delivery < 32 Weeks Gestation	Spontaneous preterm delivery (following preterm labor or pPROM) before 32 weeks gestation	randomization to 32 weeks gestation (a period of up to 16 weeks)
Number of Participants With Spontaneous Preterm Delivery < 35 Weeks Gestation	Spontaneous preterm delivery (following preterm labor or pPROM) before 35 weeks gestation	randomization to 35 weeks gestation (a period of up to 19 weeks)
Number of Participants With Indicated Preterm Delivery for < 35 Weeks	Preterm delivery prior to 35 weeks gestation with medical indications	randomization to 35 weeks gestation (a period of up to 19 weeks)
Number of Participants With Cesarean Delivery	Delivery by cesarean	Randomization to delivery (a period of up to 26 weeks)
Number of Fetal, Neonatal or Infant Deaths	Number of fetal, neonatal or infant deaths	From randomization to up to 28 days post birth (a period of up to 30 weeks)
Number of Neonates Small for Gestational Age < 5th Percentile	The number of neonates whose birthweight compared with gestational age at delivery was less than the 5th percentile, as assessed by sex and race, using United States birth certificate data.	randomization to delivery (a period of up to 26 weeks)
Number of Neonates With the Composite Neonatal Outcome	The number of neonates diagnosed with any one of fetal or neonatal death or Respiratory Distress Syndrome, Grade 3 or 4 Intraventricular Hemorrhage, Periventricular Leukomalacia, Stage 2 or 3 Necrotizing Enterocolitis, Bronchopulmonary Dysplasia, Stage III or higher Retinopathy of Prematurity, or early onset sepsis. IVH grades III or IV are as determined by cranial ultrasounds performed as part of routine clinical care and classified based on the Papile classification system. The number of neonates diagnosed with NEC, defined as modified Bell Stage 2 or 3 where stage 2 represents clinical signs and symptoms with pneumatosis intestinalis on radiographs and stage 3 is defined as advanced clinical signs and symptoms, pneumatosis, impending or proven intestinal perforation. The stages of Retinopathy of Prematurity range from 1 (mild) to 5 (severe).	Birth to neonatal discharge or death, whichever is first (up to 70 weeks)
Number of Neonates Admitted to Intensive Care (NICU) or Intermediate Care	The number of neonates admitted to intensive care (NICU) or intermediate care out of all liveborn infants.	Birth to the time of NICU or Intermediate Care Admission, whichever came first (a maximum of 10 days)
Length of Neonatal Hospital Stay in Days	Number of days the neonate was in the hospital	admission to hospital discharge (a median of 12 days with a maximum of 490 days)
Length of Stay in Neonatal Intensive Care (NICU) or Intermediate Care in Days	Length of stay in neonatal intensive care (NICU) or intermediate care	admission to discharge from NICU or intermediate care (a median of 28 days, with a maximum of 491 days)

Collaborators and Investigators

• Sponsor: The George Washington University Biostatistics Center
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Study Director: Monica Longo, MD, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Study Chair: Joseph Biggio, MD, Maternal Fetal Medicine Units (MFMU) Network

Study record dates

Study Major Dates

• Study Start (Actual): November 13, 2015
• Primary Completion (Actual): December 15, 2024
• Study Completion (Actual): February 18, 2025

Study Registration Dates

• First Submitted: March 18, 2015
• First Submitted That Met QC Criteria: August 7, 2015
• First Posted (Estimated): August 10, 2015

Study Record Updates

• Last Update Posted (Actual): March 10, 2026
• Last Update Submitted That Met QC Criteria: February 17, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: women; short cervix; cervical length of less than 30 millimeters; carrying twins
• Additional Relevant MeSH Terms: Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Pregnanes; Steroids; Fused-Ring Compounds; Gonadal Steroid Hormones; Gonadal Hormones; Pregnenediones; Pregnenes; Corpus Luteum Hormones; Progesterone Congeners; Progesterone
• Other Study ID Numbers: HD36801-PROSPECT; UG1HD087230 (U.S. NIH Grant/Contract); UG1HD027869 (U.S. NIH Grant/Contract); UG1HD040500 (U.S. NIH Grant/Contract); UG1HD034208 (U.S. NIH Grant/Contract); UG1HD027915 (U.S. NIH Grant/Contract); UG1HD040485 (U.S. NIH Grant/Contract); UG1HD053097 (U.S. NIH Grant/Contract); UG1HD040544 (U.S. NIH Grant/Contract); UG1HD040545 (U.S. NIH Grant/Contract); UG1HD040560 (U.S. NIH Grant/Contract); UG1HD040512 (U.S. NIH Grant/Contract); UG1HD087192 (U.S. NIH Grant/Contract); UG1HD068282 (U.S. NIH Grant/Contract); UG1HD068258 (U.S. NIH Grant/Contract); UG1HD068268 (U.S. NIH Grant/Contract); U24HD036801 (U.S. NIH Grant/Contract); UG1HD112063 (U.S. NIH Grant/Contract); UG1HD112092 (U.S. NIH Grant/Contract); UG1HD112096 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The dataset will be shared per NIH policy after the completion and publication of the main analyses.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes