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CompletedNCT02518594PROSPECTUpdated Jun 25, 2026Results posted

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

A Phase 3 interventional study of Vaginal progesterone and Placebo in Short Cervical Length, sponsored by The George Washington University Biostatistics Center. Completed at 16 sites in United States. Open to female participants. Per ClinicalTrials.gov, last updated 2026-06-25.

Sponsored by The George Washington University Biostatistics Center · Phase 3, Interventional, and Prevention

Phase
Phase 3
Study type
Interventional
Enrollment
1,311
Allocation
Randomized
Sex
Female
01

Study summary

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.

Read the 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.

02

Conditions studied

  • Short Cervical Length

Keywords

  • women
  • cervical length of less than 30 millimeters
  • carrying twins
  • short cervix
03

Who can participate

Ages eligible
Child (0–17), Adult (18–64), Older adult (65+)
Sexes eligible
Female
Accepts healthy volunteers
No

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

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
04

Study design

Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
1,311 participants (actual)

Study arms

  • Active comparator
    Progesterone

    vaginal progesterone capsule

    Drug: Vaginal progesterone

  • Placebo comparator
    Placebo

    placebo capsule

    Drug: Placebo

  • Active comparator
    Arabin Pessary

    Arabin Pessary

    Device: Arabin Pessary

Interventions

  • DrugVaginal progesterone

    200mg micronized vaginal progesterone softgel capsule, daily from randomization to \< 35 wks

    Also known as: Prometrium

  • DrugPlacebo

    placebo softgel capsule, daily from randomization to \< 35 wks

  • DeviceArabin Pessary

    placement and management of an Arabin Pessary from randomization to \< 35 wks

05

What researchers measure

Primary outcomes

  1. 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

    Time frame: From randomization to 35 weeks gestation (a period of up to 19 weeks)

Secondary outcomes

  1. 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.

    Time frame: Randomization to delivery (a period of up to 26 weeks)

  2. Gestational Age at Delivery or Fetal Death

    Gestational age at the time of delivery or death

    Time frame: Randomization to delivery (a period of up to 26 weeks)

  3. 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

    Time frame: From randomization to up to 28 weeks gestation (a period if up to 12 weeks)

  4. 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

    Time frame: From randomization to 32 weeks gestation (a period of up to 16 weeks)

  5. 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

    Time frame: randomization to 37 weeks gestation (a period of up to 21 weeks)

  6. Number of Participants With Spontaneous Preterm Delivery < 32 Weeks Gestation

    Spontaneous preterm delivery (following preterm labor or pPROM) before 32 weeks gestation

    Time frame: randomization to 32 weeks gestation (a period of up to 16 weeks)

  7. Number of Participants With Spontaneous Preterm Delivery < 35 Weeks Gestation

    Spontaneous preterm delivery (following preterm labor or pPROM) before 35 weeks gestation

    Time frame: randomization to 35 weeks gestation (a period of up to 19 weeks)

  8. Number of Participants With Indicated Preterm Delivery for < 35 Weeks

    Preterm delivery prior to 35 weeks gestation with medical indications

    Time frame: randomization to 35 weeks gestation (a period of up to 19 weeks)

  9. Number of Participants With Cesarean Delivery

    Delivery by cesarean

    Time frame: Randomization to delivery (a period of up to 26 weeks)

  10. Number of Fetal, Neonatal or Infant Deaths

    Number of fetal, neonatal or infant deaths

    Time frame: From randomization to up to 28 days post birth (a period of up to 30 weeks)

  11. 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.

    Time frame: randomization to delivery (a period of up to 26 weeks)

  12. 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).

    Time frame: Birth to neonatal discharge or death, whichever is first (up to 70 weeks)

  13. 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.

    Time frame: Birth to the time of NICU or Intermediate Care Admission, whichever came first (a maximum of 10 days)

  14. Length of Neonatal Hospital Stay in Days

    Number of days the neonate was in the hospital

    Time frame: admission to hospital discharge (a median of 12 days with a maximum of 490 days)

  15. Length of Stay in Neonatal Intensive Care (NICU) or Intermediate Care in Days

    Length of stay in neonatal intensive care (NICU) or intermediate care

    Time frame: admission to discharge from NICU or intermediate care (a median of 28 days, with a maximum of 491 days)

Other outcomes

  1. Number of Participants With Delivery or Fetal Loss of Either Twin Prior to 35 Weeks Gestation by Race/Ethnicity

    NIH-required analysis. Number of participants who had preterm delivery or fetal loss of either twin prior to 35 weeks gestation

    Time frame: From randomization to 35 weeks gestation (a period of up to 19 weeks)

06

Results

Posted Mar 10, 2026

Participant flow

We conducted the trial at 16 centers. Mothers with twin gestations were enrolled in pregnancy and their offspring followed to discharge or 28 days after expected date of delivery. Infants were enrolled but not consented. The recruitment period was Nov 2015 - Oct 2024 and 437 women were randomized out of the planned sample size of 630.

Participant flow — Overall Study
MilestoneProgesteroneArabin PessaryPlaceboProgesterone - Fetus/Neonates/InfantsArabin Pessary - Fetus/Neonates/InfantsPlacebo - Fetus/Neonates/Infants
Started147153137294306274
Completed146152136292304272
Not completed111222
Withdrew: Lost to follow-up111222

Outcome measures

PrimaryNumber 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

Time frame:
From randomization to 35 weeks gestation (a period of up to 19 weeks)
Reported as:
Count of participants · Participants
Number of Participants With Delivery or Fetal Loss of Either Twin Prior to 35 Weeks Gestation
ParticipantsProgesteroneArabin PessaryPlacebo
Number of Participants With Delivery or Fetal Loss of Either Twin Prior to 35 Weeks Gestation848486
Statistical analysis
  • Progesterone vs Placebo · Risk ratio (rr): 0.91 · 97.5% CI 0.73 to 1.13
  • Arabin Pessary vs Placebo · Risk ratio (rr): 0.87 · 97.5% CI 0.70 to 1.09
SecondaryDays From Randomization to Delivery (or Fetal Demise)

Days from the time of randomization (16-23 weeks gestation) to delivery or death of the fetus.

Time frame:
Randomization to delivery (a period of up to 26 weeks)
Reported as:
Median · days
Days From Randomization to Delivery (or Fetal Demise)
daysProgesteroneArabin PessaryPlacebo
Days From Randomization to Delivery (or Fetal Demise)86 (53 to 106)86 (53 to 106)77 (51 to 101)
Statistical analysis
  • Progesterone vs Placebo · Median difference (net): 9 · 95% CI -4 to 22
  • Arabin Pessary vs Placebo · Median difference (net): 8 · 95% CI -4 to 20
SecondaryGestational Age at Delivery or Fetal Death

Gestational age at the time of delivery or death

Time frame:
Randomization to delivery (a period of up to 26 weeks)
Reported as:
Median · weeks
Gestational Age at Delivery or Fetal Death
weeksProgesteroneArabin PessaryPlacebo
Gestational Age at Delivery or Fetal Death34.1 (29.0 to 36.1)33.9 (28.9 to 36.6)33.1 (27.9 to 36.2)
Statistical analysis
  • Progesterone vs Placebo · Median difference (net): 0.9 · 95% CI -1.0 to 2.7
  • Arabin Pessary vs Placebo · Median difference (net): 0.7 · 95% CI -1.1 to 2.5
SecondaryNumber 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

Time frame:
From randomization to up to 28 weeks gestation (a period if up to 12 weeks)
Reported as:
Count of participants · Participants
Number of Participants With Preterm Delivery or Fetal Demise of Either Twin Prior to 28 Weeks Gestation
ParticipantsProgesteroneArabin PessaryPlacebo
Number of Participants With Preterm Delivery or Fetal Demise of Either Twin Prior to 28 Weeks Gestation333434
Statistical analysis
  • Progesterone vs Placebo · Risk ratio (rr): 0.90 · 95% CI 0.60 to 1.37
  • Arabin Pessary vs Placebo · Risk ratio (rr): 0.89 · 95% CI 0.59 to 1.36
SecondaryNumber 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

Time frame:
From randomization to 32 weeks gestation (a period of up to 16 weeks)
Reported as:
Count of participants · Participants
Number of Participants With Preterm Delivery or Fetal Demise of Either Twin Prior to 32 Weeks Gestation
ParticipantsProgesteroneArabin PessaryPlacebo
Number of Participants With Preterm Delivery or Fetal Demise of Either Twin Prior to 32 Weeks Gestation595258
Statistical analysis
  • Progesterone vs Placebo · Risk ratio (rr): 0.95 · 95% CI 0.72 to 1.25
  • Arabin Pessary vs Placebo · Risk ratio (rr): 0.80 · 95% CI 0.60 to 1.08
SecondaryNumber 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

Time frame:
randomization to 37 weeks gestation (a period of up to 21 weeks)
Reported as:
Count of participants · Participants
Number of Participants With Preterm Delivery or Fetal Demise of Either Twin Prior to 37 Weeks Gestation
ParticipantsProgesteroneArabin PessaryPlacebo
Number of Participants With Preterm Delivery or Fetal Demise of Either Twin Prior to 37 Weeks Gestation124123115
Statistical analysis
  • Progesterone vs Placebo · Risk ratio (rr): 1.00 · 95% CI 0.91 to 1.11
  • Arabin Pessary vs Placebo · Risk ratio (rr): 0.96 · 95% CI 0.86 to 1.06
SecondaryNumber of Participants With Spontaneous Preterm Delivery < 32 Weeks Gestation

Spontaneous preterm delivery (following preterm labor or pPROM) before 32 weeks gestation

Time frame:
randomization to 32 weeks gestation (a period of up to 16 weeks)
Reported as:
Count of participants · Participants
Number of Participants With Spontaneous Preterm Delivery < 32 Weeks Gestation
ParticipantsProgesteroneArabin PessaryPlacebo
Number of Participants With Spontaneous Preterm Delivery < 32 Weeks Gestation514553
Statistical analysis
  • Progesterone vs Placebo · Risk ratio (rr): 0.90 · 95% CI 0.66 to 1.22
  • Arabin Pessary vs Placebo · Risk ratio (rr): 0.76 · 95% CI 0.55 to 1.05
SecondaryNumber of Participants With Spontaneous Preterm Delivery < 35 Weeks Gestation

Spontaneous preterm delivery (following preterm labor or pPROM) before 35 weeks gestation

Time frame:
randomization to 35 weeks gestation (a period of up to 19 weeks)
Reported as:
Count of participants · Participants
Number of Participants With Spontaneous Preterm Delivery < 35 Weeks Gestation
ParticipantsProgesteroneArabin PessaryPlacebo
Number of Participants With Spontaneous Preterm Delivery < 35 Weeks Gestation696572
Statistical analysis
  • Progesterone vs Placebo · Risk ratio (rr): 0.89 · 95% CI 0.71 to 1.13
  • Arabin Pessary vs Placebo · Risk ratio (rr): 0.81 · 95% CI 0.63 to 1.03
SecondaryNumber of Participants With Indicated Preterm Delivery for < 35 Weeks

Preterm delivery prior to 35 weeks gestation with medical indications

Time frame:
randomization to 35 weeks gestation (a period of up to 19 weeks)
Reported as:
Count of participants · Participants
Number of Participants With Indicated Preterm Delivery for < 35 Weeks
ParticipantsProgesteroneArabin PessaryPlacebo
Number of Participants With Indicated Preterm Delivery for < 35 Weeks151814
Statistical analysis
  • Progesterone vs Placebo · Risk ratio (rr): 1.0 · 95% CI 0.50 to 1.99
  • Arabin Pessary vs Placebo · Risk ratio (rr): 1.15 · 95% CI 0.60 to 2.22
SecondaryNumber of Participants With Cesarean Delivery

Delivery by cesarean

Time frame:
Randomization to delivery (a period of up to 26 weeks)
Reported as:
Count of participants · Participants
Number of Participants With Cesarean Delivery
ParticipantsProgesteroneArabin PessaryPlacebo
Number of Participants With Cesarean Delivery969584
Statistical analysis
  • Progesterone vs Placebo · Risk ratio (rr): 1.06 · 95% CI 0.89 to 1.26
  • Arabin Pessary vs Placebo · Risk ratio (rr): 1.00 · 95% CI 0.84 to 1.20
SecondaryNumber of Fetal, Neonatal or Infant Deaths

Number of fetal, neonatal or infant deaths

Time frame:
From randomization to up to 28 days post birth (a period of up to 30 weeks)
Reported as:
Count of participants · Participants
Number of Fetal, Neonatal or Infant Deaths
ParticipantsProgesterone - Fetus/Neonates/InfantsArabin Pessary - Fetus/Neonates/InfantsPlacebo - Fetus/Neonates/Infants
Number of Fetal, Neonatal or Infant Deaths303240
Statistical analysis
  • Progesterone - Fetus/Neonates/Infants vs Placebo - Fetus/Neonates/Infants · Risk ratio (rr): 0.69 · 95% CI 0.38 to 1.27adjusted for correlation between twins
  • Arabin Pessary - Fetus/Neonates/Infants vs Placebo - Fetus/Neonates/Infants · Risk ratio (rr): 0.71 · 95% CI 0.40 to 1.27adjusted for correlation between twins
SecondaryNumber 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.

Time frame:
randomization to delivery (a period of up to 26 weeks)
Reported as:
Count of participants · Participants
Number of Neonates Small for Gestational Age < 5th Percentile
ParticipantsProgesterone - Fetus/Neonates/InfantsArabin Pessary - Fetus/Neonates/InfantsPlacebo - Fetus/Neonates/Infants
Number of Neonates Small for Gestational Age < 5th Percentile271627
Statistical analysis
  • Progesterone - Fetus/Neonates/Infants vs Placebo - Fetus/Neonates/Infants · Risk ratio (rr): 0.92 · 95% CI 0.52 to 1.60adjusted for correlation between twins
  • Arabin Pessary - Fetus/Neonates/Infants vs Placebo - Fetus/Neonates/Infants · Risk ratio (rr): 0.52 · 95% CI 0.28 to 0.94adjusted for correlation between twins
SecondaryNumber 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).

Time frame:
Birth to neonatal discharge or death, whichever is first (up to 70 weeks)
Reported as:
Count of participants · Participants
Number of Neonates With the Composite Neonatal Outcome
ParticipantsProgesterone - Fetus/Neonates/InfantsArabin Pessary - Fetus/Neonates/InfantsPlacebo - Fetus/Neonates/Infants
Number of Neonates With the Composite Neonatal Outcome124126114
Statistical analysis
  • Progesterone - Fetus/Neonates/Infants vs Placebo - Fetus/Neonates/Infants · Risk ratio (rr): 1.01 · 95% CI 0.78 to 1.30adjusted for correlation between twins
  • Arabin Pessary - Fetus/Neonates/Infants vs Placebo - Fetus/Neonates/Infants · Risk ratio (rr): 0.98 · 95% CI 0.76 to 1.27adjusted for correlation between twins
SecondaryNumber 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.

Time frame:
Birth to the time of NICU or Intermediate Care Admission, whichever came first (a maximum of 10 days)
Reported as:
Count of participants · Participants
Number of Neonates Admitted to Intensive Care (NICU) or Intermediate Care
ParticipantsProgesterone - Fetus/Neonates/InfantsArabin Pessary - Fetus/Neonates/InfantsPlacebo - Fetus/Neonates/Infants
Number of Neonates Admitted to Intensive Care (NICU) or Intermediate Care197178185
Statistical analysis
  • Progesterone - Fetus/Neonates/Infants vs Placebo - Fetus/Neonates/Infants · Risk ratio (rr): 0.97 · 95% CI 0.84 to 1.12adjusted for correlation between twins
  • Arabin Pessary - Fetus/Neonates/Infants vs Placebo - Fetus/Neonates/Infants · Risk ratio (rr): 0.83 · 95% CI 0.71 to 0.98adjusted for correlation between twins
SecondaryLength of Neonatal Hospital Stay in Days

Number of days the neonate was in the hospital

Time frame:
admission to hospital discharge (a median of 12 days with a maximum of 490 days)
Reported as:
Median · days
Length of Neonatal Hospital Stay in Days
daysProgesterone - Fetus/Neonates/InfantsArabin Pessary - Fetus/Neonates/InfantsPlacebo - Fetus/Neonates/Infants
Length of Neonatal Hospital Stay in Days11 (3 to 37)11 (3 to 37)14 (3 to 42)
Statistical analysis
  • Progesterone - Fetus/Neonates/Infants vs Placebo - Fetus/Neonates/Infants · Median difference (net): -3 · 95% CI -5 to 4adjusted for correlation between twins
  • Arabin Pessary - Fetus/Neonates/Infants vs Placebo - Fetus/Neonates/Infants · Median difference (net): -3 · 95% CI -6 to 5adjusted for correlation between twins
SecondaryLength of Stay in Neonatal Intensive Care (NICU) or Intermediate Care in Days

Length of stay in neonatal intensive care (NICU) or intermediate care

Time frame:
admission to discharge from NICU or intermediate care (a median of 28 days, with a maximum of 491 days)
Reported as:
Median · days
Length of Stay in Neonatal Intensive Care (NICU) or Intermediate Care in Days
daysProgesterone - Fetus/Neonates/InfantsArabin Pessary - Fetus/Neonates/InfantsPlacebo - Fetus/Neonates/Infants
Length of Stay in Neonatal Intensive Care (NICU) or Intermediate Care in Days24 (11 to 57)29 (15 to 63)30 (12 to 55)
Statistical analysis
  • Progesterone - Fetus/Neonates/Infants vs Placebo - Fetus/Neonates/Infants · Median difference (net): -7 · 95% CI -11 to 5adjusted for correlation between twins
  • Arabin Pessary - Fetus/Neonates/Infants vs Placebo - Fetus/Neonates/Infants · Median difference (net): -2 · 95% CI -5 to 11adjusted for correlation between twins
Other pre-specifiedNumber of Participants With Delivery or Fetal Loss of Either Twin Prior to 35 Weeks Gestation by Race/Ethnicity

NIH-required analysis. Number of participants who had preterm delivery or fetal loss of either twin prior to 35 weeks gestation

Time frame:
From randomization to 35 weeks gestation (a period of up to 19 weeks)
Reported as:
Count of participants · Participants
Number of Participants With Delivery or Fetal Loss of Either Twin Prior to 35 Weeks Gestation by Race/Ethnicity
ParticipantsProgesteroneArabin PessaryPlacebo
Non-Hispanic black343832
Non-Hispanic white292632
Hispanic191717
Asian211
More than 1 race012
Unknown / not reported012

Adverse events

Collected over Adverse Events were assessed in mothers/fetuses from randomization to 28 days past the project due date (approximately up to 28 weeks) and in infants from birth through neonatal discharge, up to 70 weeks. Adverse events were collected for maternal participants and their fetuses/neonates.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Progesterone0/147 (0%)10/147 (6.8%)125/146 (85.6%)
Arabin Pessary0/153 (0%)6/153 (3.9%)129/152 (84.9%)
Placebo0/137 (0%)7/137 (5.1%)113/136 (83.1%)
Progesterone - Infants30/294 (10.2%)37/294 (12.6%)—
Arabin Pessary - Infants32/306 (10.5%)43/306 (14.1%)—
Placebo - Infants40/274 (14.6%)52/274 (19%)—
Most frequent serious events
Showing 10 of 28
Most frequent serious events
EventProgesteroneArabin PessaryPlaceboProgesterone - InfantsArabin Pessary - InfantsPlacebo - Infants
Neonatal/infant deathGeneral disorders0/1470/1530/13718/29420/30625/274
Fetal deathGeneral disorders0/1470/1530/13712/29412/30615/274
Postpartum hemorrhageBlood and lymphatic system disorders2/1474/1531/1370/2940/3060/274
Pre-eclampsiaPregnancy, puerperium and perinatal conditions3/1471/1531/1370/2940/3060/274
Physical anomalyGeneral disorders0/1470/1530/1373/2946/3061/274
RSV bronchiolitisInfections and infestations0/1470/1530/1370/2940/3063/274
Ventricular septal defectCardiac disorders0/1470/1530/1370/2940/3063/274
Anemia requiring transfusionBlood and lymphatic system disorders1/1470/1531/1370/2940/3060/274
TraumaGeneral disorders0/1471/1531/1370/2940/3060/274
Bronchitis with asthmaInfections and infestations0/1470/1531/1370/2940/3060/274
Most frequent other events
Most frequent other events
EventProgesteroneArabin PessaryPlaceboProgesterone - InfantsArabin Pessary - InfantsPlacebo - Infants
Vaginal dischargeInfections and infestations107/146114/15297/136———
Vaginal soreness/discomfortReproductive system and breast disorders30/14657/15232/136———
Lower abdominal or pelvic pressureGeneral disorders45/14648/15240/136———
Lower abdominal or pelvic painGeneral disorders30/14636/15231/136———
Vaginal itchingInfections and infestations27/14620/15232/136———
Vaginal odorInfections and infestations22/14631/15210/136———
Incontinence or change in urinary frequencyRenal and urinary disorders18/14625/15216/136———
Vaginal burningInfections and infestations12/14615/15215/136———

Baseline characteristics

Baseline characteristics are for the pregnant mothers only as the offspring were not born at the time of randomization.

Age, Continuous
Age, Continuous(years)ProgesteroneArabin PessaryPlaceboProgesterone-Fetus/Neonates/InfantsArabin Pessary-Fetus/Neonates/InfantsPlacebo-Fetus/Neonates/InfantsTotal
Mean29.3 ± 6.429.9 ± 5.129.7 ± 5.7———29.6 ± 5.8
Sex: Female, Male
Sex: Female, Male(Participants)ProgesteroneArabin PessaryPlaceboProgesterone-Fetus/Neonates/InfantsArabin Pessary-Fetus/Neonates/InfantsPlacebo-Fetus/Neonates/InfantsTotal
Female147153137———437
Male000———0
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)ProgesteroneArabin PessaryPlaceboProgesterone-Fetus/Neonates/InfantsArabin Pessary-Fetus/Neonates/InfantsPlacebo-Fetus/Neonates/InfantsTotal
American Indian or Alaska Native000———0
Asian346———13
Non-Hispanic Black616749———177
Hispanic302926———85
Native Hawaiian or Pacific Islander000———0
Non-Hispanic White514952———152
More than 1 Race122———5
Not reported or Unknown122———5
Body mass index at first clinic visit
Body mass index at first clinic visit(kilograms per meter squared)ProgesteroneArabin PessaryPlaceboProgesterone-Fetus/Neonates/InfantsArabin Pessary-Fetus/Neonates/InfantsPlacebo-Fetus/Neonates/InfantsTotal
Median28.0 (24.0 to 33.2)27.0 (23.1 to 33.0)29.2 (24.7 to 35.1)———28.1 (23.7 to 33.7)
Number of participants by body mass index at first clinic visit (categorical)
Number of participants by body mass index at first clinic visit (categorical)(Participants)ProgesteroneArabin PessaryPlaceboProgesterone-Fetus/Neonates/InfantsArabin Pessary-Fetus/Neonates/InfantsPlacebo-Fetus/Neonates/InfantsTotal
BMI <30 kg/m^2879574———256
BMI 30-34.9 kg/m^2342627———87
BMI <35-39.9 kg/m^2111318———42
BMI >=40 kg/m^2131616———45
Number of participants reporting cigarette use during pregnancy
Number of participants reporting cigarette use during pregnancy(Participants)ProgesteroneArabin PessaryPlaceboProgesterone-Fetus/Neonates/InfantsArabin Pessary-Fetus/Neonates/InfantsPlacebo-Fetus/Neonates/InfantsTotal
Count of participants81514———37
Number of participants reporting alcohol use during pregnancy
Number of participants reporting alcohol use during pregnancy(Participants)ProgesteroneArabin PessaryPlaceboProgesterone-Fetus/Neonates/InfantsArabin Pessary-Fetus/Neonates/InfantsPlacebo-Fetus/Neonates/InfantsTotal
Count of participants582———15
Number of participants married or living with partner
Number of participants married or living with partner(Participants)ProgesteroneArabin PessaryPlaceboProgesterone-Fetus/Neonates/InfantsArabin Pessary-Fetus/Neonates/InfantsPlacebo-Fetus/Neonates/InfantsTotal
Count of participants9310490———287

16 further baseline measures are reported on the registry.

07

Study locations

16 sites
  • University of Alabama - Birmingham
    Birmingham, Alabama 35294, United States
  • The Regents of the University of California, San Francisco
    San Francisco, California, United States
  • University of Colorado
    Denver, Colorado 80045, United States
  • Northwestern University-Prentice Hospital
    Chicago, Illinois 60611, United States
  • Columbia University
    New York, New York 10032, United States
  • University of North Carolina - Chapel Hill
    Chapel Hill, North Carolina 27599, United States
  • Duke University
    Durham, North Carolina 27710, United States
  • Case Western Reserve University
    Cleveland, Ohio 44109, United States
  • Ohio State University
    Columbus, Ohio 43210, United States
  • Hospital of the University of Pennsylvania
    Philadelphia, Pennsylvania 19104, United States
  • Magee Women's Hospital
    Pittsburgh, Pennsylvania 15213, United States
  • Brown University
    Providence, Rhode Island 02905, United States
  • University of Texas - Galveston
    Galveston, Texas 77555, United States
  • University of Texas - Houston
    Houston, Texas 77030, United States
  • Baylor College of Medicine
    Houston, Texas, United States
  • University of Utah Medical Center
    Salt Lake City, Utah 84132, United States
08

References and documents

Study documents

  • Protocol, analysis plan and consent form · Feb 1, 2024

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — The dataset will be shared per NIH policy after the completion and publication of the main analyses.

09

Registry details

Key details

Study ID
NCT02518594
Lead sponsor
The George Washington University Biostatistics Center
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Responsible party
Sponsor
First posted
Aug 10, 2015
Start date
Nov 13, 2015
Primary completion
Dec 15, 2024
Completion
Feb 18, 2025
Results posted
Mar 10, 2026
Last update
Jun 25, 2026

Study contacts

Joseph Biggio, MD
study chair · Maternal Fetal Medicine Units (MFMU) Network
Monica Longo, MD
study director · Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
Yes
View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Jun 2026. You cannot join it, but the record below documents what was studied.

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