Short Cervical Length
Conditions
Keywords
women, cervical length of less than 30 millimeters, carrying twins, short cervix
Brief 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.
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.
Interventions
DRUGVaginal progesterone
200mg micronized vaginal progesterone softgel capsule, daily from randomization to \< 35 wks
DRUGPlacebo
placebo softgel capsule, daily from randomization to \< 35 wks
DEVICEArabin Pessary
placement and management of an Arabin Pessary from randomization to \< 35 wks
Sponsors
The George Washington University Biostatistics Center
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Participants and care providers will be blinded to active study drug vs. placebo.
Intervention model description
Women will be randomly assigned to study drug (200 mg micronized progesterone daily), placebo study drug appearing identical to progesterone capsule, or Arabin pessary.
Eligibility
Sex/Gender
FEMALE
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
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With 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) | Number of Participants who had preterm delivery or fetal loss of either twin prior to 35 weeks gestation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Days From Randomization to Delivery (or Fetal Demise) | Randomization to delivery (a period of up to 26 weeks) | Days from the time of randomization (16-23 weeks gestation) to delivery or death of the fetus. |
| Gestational Age at Delivery or Fetal Death | Randomization to delivery (a period of up to 26 weeks) | Gestational age at the time of delivery or death |
| Number of Participants With Preterm Delivery or Fetal Demise of Either Twin Prior to 28 Weeks Gestation | From randomization to up to 28 weeks gestation (a period if up to 12 weeks) | Preterm delivery or fetal loss of either twin prior to 28 weeks gestation |
| Number of Participants With 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) | Preterm Delivery or Fetal Demise of Either Twin Prior to 32 Weeks Gestation |
| Number of Participants With 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) | Preterm Delivery or Fetal Demise of Either Twin Prior to 37 Weeks Gestation |
| Number of Participants With Spontaneous Preterm Delivery < 32 Weeks Gestation | randomization to 32 weeks gestation (a period of up to 16 weeks) | Spontaneous preterm delivery (following preterm labor or pPROM) before 32 weeks gestation |
| Number of Participants With Spontaneous Preterm Delivery < 35 Weeks Gestation | randomization to 35 weeks gestation (a period of up to 19 weeks) | Spontaneous preterm delivery (following preterm labor or pPROM) before 35 weeks gestation |
| Number of Participants With Indicated Preterm Delivery for < 35 Weeks | randomization to 35 weeks gestation (a period of up to 19 weeks) | Preterm delivery prior to 35 weeks gestation with medical indications |
| 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 fetal, neonatal or infant deaths |
| Number of Neonates Small for Gestational Age < 5th Percentile | randomization to delivery (a period of up to 26 weeks) | 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. |
| Number of Neonates With the Composite Neonatal Outcome | Birth to neonatal discharge or death, whichever is first (up to 70 weeks) | 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). |
| Number of Neonates Admitted to Intensive Care (NICU) or Intermediate Care | Birth to the time of NICU or Intermediate Care Admission, whichever came first (a maximum of 10 days) | The number of neonates admitted to intensive care (NICU) or intermediate care out of all liveborn infants. |
| Length of Neonatal Hospital Stay in Days | admission to hospital discharge (a median of 12 days with a maximum of 490 days) | Number of days the neonate was in the hospital |
| Number of Participants With Cesarean Delivery | Randomization to delivery (a period of up to 26 weeks) | Delivery by cesarean |
| Length of Stay in Neonatal Intensive Care (NICU) or Intermediate Care in Days | admission to discharge from NICU or intermediate care (a median of 28 days, with a maximum of 491 days) | Length of stay in neonatal intensive care (NICU) or intermediate care |
Countries
United States
Contacts
STUDY_CHAIRJoseph Biggio, MD
Maternal Fetal Medicine Units (MFMU) Network
STUDY_DIRECTORMonica Longo, MD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Participant flow
Recruitment details
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.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 29.6 years STANDARD_DEVIATION 5.8 |
| Body mass index at first clinic visit | 28.1 kilograms per meter squared |
| Cervical length at screening | 21.9 millimeters |
| Days from screening to randomization | 0 days |
| Gestation at enrollment | 21.6 weeks |
| Number of nulliparous participants | 74 Participants |
| Number of participants by body mass index at first clinic visit (categorical) BMI 30-34.9 kg/m^2 | 27 Participants |
| Number of participants by body mass index at first clinic visit (categorical) BMI <30 kg/m^2 | 95 Participants |
| Number of participants by body mass index at first clinic visit (categorical) BMI <35-39.9 kg/m^2 | 13 Participants |
| Number of participants by body mass index at first clinic visit (categorical) BMI >=40 kg/m^2 | 45 Participants |
| Number of participants by chorionicity Dichorionic | 109 Participants |
| Number of participants by chorionicity Monochorionic | 35 Participants |
| Number of participants by type of insurance Government | 68 Participants |
| Number of participants by type of insurance Private | 79 Participants |
| Number of participants by type of insurance Self-Pay | 1 Participants |
| Number of participants by type of pregnancy In Vitro Fertilization | 21 Participants |
| Number of participants by type of pregnancy Ovulation induction / artificial insemination | 15 Participants |
| Number of participants by type of pregnancy Spontaneous | 125 Participants |
| Number of participants employed full- or part-time | 89 Participants |
| Number of participants married or living with partner | 287 Participants |
| Number of participants reporting alcohol use during pregnancy | 2 Participants |
| Number of participants reporting cigarette use during pregnancy | 15 Participants |
| Number of participants reporting more than 12 years of education | 91 Participants |
| Number of participants with amniotic cavity debris on screening ultrasound | 12 Participants |
| Number of participants with any prior preterm deliveries | 21 Participants |
| Number of participants with cervical length at screening <15mm | 120 Participants |
| Number of participants with cervical length at screening <20mm | 61 Participants |
| Number of participants with funneling on screening ultrasound | 62 Participants |
| Number of participants with prior cervical surgery | 16 Participants |
| Number of participants with vaginal infection prior to enrollment, No. (%) | 35 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants |
| Race/Ethnicity, Customized Hispanic | 30 Participants |
| Race/Ethnicity, Customized More than 1 Race | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Non-Hispanic Black | 177 Participants |
| Race/Ethnicity, Customized Non-Hispanic White | 49 Participants |
| Race/Ethnicity, Customized Not reported or Unknown | 2 Participants |
| Sex: Female, Male Female | 137 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 147 | 0 / 153 | 0 / 137 | 30 / 294 | 32 / 306 | 40 / 274 |
| other Total, other adverse events | 125 / 146 | 129 / 152 | 113 / 136 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 10 / 147 | 6 / 153 | 7 / 137 | 37 / 294 | 43 / 306 | 52 / 274 |
Outcome results
None listed