Cervical Softening and the Prediction of Preterm Birth (STIPP)

• ClinicalTrials.gov Identifier: NCT05477381
• Recruitment Status: Recruiting
• First Posted: July 28, 2022
• Last Update Posted: February 10, 2023
• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborator: Pregnolia AG
• Information provided by (Responsible Party): M.A. Oudijk, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Tracking Information

• First Submitted Date: July 19, 2022
• First Posted Date: July 28, 2022
• Last Update Posted Date: February 10, 2023
• Actual Study Start Date: August 18, 2022
• Estimated Primary Completion Date: September 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 25, 2022)

• Spontaneous Preterm Birth < 34 weeks [ Time Frame: Maximum time frame up to 28 weeks: from inclusion at 14 weeks of gestational age until delivery, with a maximum of 42 weeks of gestational age. ]
  Spontaneous preterm birth before 34 weeks of gestation in the asymptomatic cohort
• Delivery within seven days after inclusion [ Time Frame: From inclusion until 7 days later ]
  Delivery within seven days after inclusion in the symptomatic cohort

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 25, 2022)

• Spontaneous preterm birth <37 weeks [ Time Frame: From inclusion (symptomatic cohort 24-34 weeks, asymptomatic cohort 14 weeks) until delivery with a maximum of 42 weeks of gestational age ]
  Spontaneous preterm birth <37 weeks of gestational age
• Spontaneous preterm birth <34 weeks [ Time Frame: From inclusion (symptomatic cohort 24-34 weeks, asymptomatic cohort 14 weeks) until delivery with a maximum of 42 weeks of gestational age ]
  Spontaneous preterm birth <34 weeks of gestational age
• Spontaneous preterm birth <32 weeks [ Time Frame: From inclusion (symptomatic cohort 24-34 weeks, asymptomatic cohort 14 weeks) until delivery with a maximum of 42 weeks of gestational age ]
  Spontaneous preterm birth <32 weeks of gestational age
• Spontaneous preterm birth <28 weeks [ Time Frame: From inclusion (symptomatic cohort 24-34 weeks, asymptomatic cohort 14 weeks) until delivery with a maximum of 42 weeks of gestational age ]
  Spontaneous preterm birth <28 weeks of gestational age
• Prediction of preterm birth using cervical softening. [ Time Frame: From inclusion (symptomatic cohort 24-34 weeks, asymptomatic cohort 14 weeks) until delivery with a maximum of 42 weeks of gestational age ]
  Development of a prediction model using cervical softening to predict the risk of preterm birth before 37, 34, 32 and 28 weeks.
• Prediction of preterm birth using the combination of cervical softening and transvaginal cervical length measurement. [ Time Frame: From inclusion (symptomatic cohort 24-34 weeks, asymptomatic cohort 14 weeks) until delivery with a maximum of 42 weeks of gestational age ]
  Development of a prediction model using the combination of cervical softening and transvaginal cervical length measurement to predict the risk of preterm birth before 37, 34, 32 and 28 weeks.
• Prediction of preterm birth using the combination of cervical softening, transvaginal cervical length measurement, and fetal fibronectin. [ Time Frame: From inclusion (symptomatic cohort 24-34 weeks) until delivery with a maximum of 42 weeks of gestational age ]
  Development of a prediction model using the combination of cervical softening, transvaginal cervical length measurement, and fetal fibronectin to predict the risk of preterm birth before 37, 34, 32 and 28 weeks. (only for symptomatic women)
• Prediction of latency time using cervical softening. [ Time Frame: From inclusion (symptomatic cohort 24-34 weeks, asymptomatic cohort 14 weeks) until delivery with a maximum of 42 weeks of gestational age ]
  Development of a prediction model using cervical softening to predict the latency time (interval between inclusion and delivery).
• Prediction of latency time using the combination of cervical softening and transvaginal cervical length measurement. [ Time Frame: From inclusion (symptomatic cohort 24-34 weeks, asymptomatic cohort 14 weeks) until delivery with a maximum of 42 weeks of gestational age. ]
  Development of a prediction model using the combination of cervical softening and transvaginal cervical length measurement to predict the latency time (interval between inclusion and delivery).
• Prediction of latency time using the combination of cervical softening, transvaginal cervical length measurement, and fetal fibronectin [ Time Frame: From inclusion (symptomatic cohort 24-34 weeks) until delivery with a maximum of 42 weeks of gestational age. ]
  Development of a prediction model using the combination of cervical softening, transvaginal cervical length measurement, and fetal fibronectin to predict the latency time. (interval between inclusion and delivery). (only for symptomatic women)

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: July 25, 2022)

• Patient discomfort of Pregnolia measurement [ Time Frame: In asymptomatic cohort at 14, 16, 18, 20, 22 and 24 weeks of gestational age, in the symptomatic cohort at moment of inclusion ]
  Pain during Pregnolia measured on a visual analogue scale (VAS) from "no pain"to "worst possible pain"
• Vaginal or Cervical blood loss (directly after measurement) [ Time Frame: In asymptomatic cohort at 14, 16, 18, 20, 22 and 24 weeks of gestational age, in the symptomatic cohort at moment of inclusion ]
  Vaginal or Cervical blood loss, noticed directly (= within 30 minutes) after measurement
• Infections within seven days of measurement [ Time Frame: From inclusion up to 1 week ]
  Infections within seven days of measurement (urinary tract infections, vaginal infections, intra-uterine infections)
• Preterm Prelabour Rupture of membranes at moment of measurement [ Time Frame: Within 1 hour after measurement ]
  Preterm Prelabour Rupture of membranes at moment of measurement
• Irritation and sensitization of mucosal tissue [ Time Frame: Within 1 hour after measurement ]
  Irritation and sensitization of mucosal tissue as noticed by the researcher performing the measurement
• Superficial lacerations or minor tissue abrasions [ Time Frame: Within 1 hour after measurement ]
  Superficial lacerations or minor tissue abrasions

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Cervical Softening and the Prediction of Preterm Birth
• Official Title: Assessment of Cervical SofTening and the Prediction of Preterm Birth'

Brief Summary

Currently, transvaginal cervical length measurement is used to screen in asymptomatic pregnant women with a history of PTB. In symptomatic women, presenting with threatened PTB cervical length in combination with the fibronectin test is used to identify women at high risk to deliver preterm. However, the predictive capacity of transvaginal cervical length measurement is limited. In pregnant women with a history of PTB, it only identifies a proportion of women who will have recurrent PTB. For symptomatic women, 30-60% of these women admitted to the hospital, do not deliver within seven days, leading to overtreatment of these women.

Cervical softening is precursor of cervical shortening, effacement and dilatation and therefore cervical softening is a promising new marker that is based on tissue elasticity. However, the predictive value of cervical softening and the relation with spontaneous PTB still has to be determined. With the newly developed Pregnolia® System cervical softness could be measured on a standardized and safe manner. This study could help to improve care for women with a history of spontaneous PTB.

Detailed Description

Preterm birth (PTB) is amongst the leading causes of perinatal and childhood morbidity and mortality. Therefore, accurate identification of pregnant women at high risk of PTB is important. Identifying these women, enables obstetric healthcare professionals to apply interventions to postpone delivery and/or to prevent PTB to improve perinatal and childhood outcomes.

Currently, transvaginal cervical length measurement is used to screen asymptomatic pregnant women with a history of PTB to identify women requiring a cerclage. In symptomatic women, presenting with threatened (PTB), cervical length in combination with the fetal fibronectin(fFN) test is used to identify women at high risk to deliver within 7 days of presentation. However, the predictive capacity of transvaginal cervical length measurement is limited. In pregnant women with a history of PTB, it only identifies a proportion of women who will have recurrent PTB. For symptomatic women, 30-60% of these women admitted to the hospital, do not deliver within seven days, leading to overtreatment of these women.

Since cervical softening is a precursor of cervical shortening, effacement and dilatation, cervical softening is a promising new marker that is based on tissue elasticity. It can be measured with the CE-marked Pregnolia® System for accurate characterization of cervical softening status. It provides a value for tissue elasticity on a continuous scale.

A previous study has shown that softening of the cervix can be detected before shortening of the cervix. The Pregnolia® System may allow to detect women at risk for PTB earlier compared to traditional transvaginal ultrasound that measures shortening of the cervix, and therefore may prove useful for a more accurate risk assessment of PTB.

This current study is a single centre cohort study, where Two cohorts of women will be investigated. 1) Asymptomatic pregnant women with a history of spontaneous PTB before 34 weeks of gestation (Cohort A-STIPP). 2) Symptomatic women presenting with threatened PTB between 24 and 34 weeks (Cohort S-STIPP).

Objective: The aim of this study is to evaluate the predictive capacity of cervical softening and risk of PTB.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided
• Biospecimen: Not Provided
• Sampling Method: Non-Probability Sample

Study Population

Women with an increased risk of preterm birth. Women are eligible when they fall in one of following categories:

• Medical History of Spontaneous Preterm Birth before 34 weeks of gestation or
• Threatened Preterm Birth between 24 and 34 weeks of gestation

Condition

• Preterm Birth
• Threatened Preterm Labor
• Premature Birth
• Premature Labor
• Diagnosis
• Cervical Incompetence, With Delivery
• Cervical Incompetence in Pregnancy as Antepartum Condition

Intervention

Diagnostic Test: Measurement of cervical stiffness by Pregnolia Device

The Pregnolia® System is designed to provide information about the mechanical properties of the cervical tissue by assessing the CSI (Cervical Stiffness Index) through a probe that will create a weak vacuum to retract tissue. The Pregnolia® System is designed with the purpose to provide an alternative diagnostic marker to identify women at risk of spontaneous PTB.

The Pregnolia® System is a CE-marked device developed for quantitative assessment of softening of the uterine cervix.

The Pregnolia® System will be applied within its intended use.

Study Groups/Cohorts

• Asymptomatic women with a history of preterm birth
  Pregnant women >18 years of age, with a history of spontaneous PTB before 34 weeks. All women have biweekly visits for routine transvaginal cervical length measurement between 14-24 weeks of gestation. During these visits data on cervical softening will be collected as additional marker.
  Intervention: Diagnostic Test: Measurement of cervical stiffness by Pregnolia Device
• Symptomatic women with symptoms of threatened preterm birth
  Pregnant women >18 years of age, between 24 and 34 weeks of gestation, presenting with symptoms of threatened Preterm birth (e.g. abdominal pain, blood loss, contractions, or other complaints suggestive for threatened Preterm birth).
  Intervention: Diagnostic Test: Measurement of cervical stiffness by Pregnolia Device

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 25, 2022): 326
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 2024
• Estimated Primary Completion Date: September 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Age 18 years or above.
• Ability to understand Dutch or English (both spoken and written).
• Ultrasound-based gestational age determined by measurement of crown rump length (CRL) determined between 9 and 11 weeks of gestation.
• Singleton and twin pregnancies.

Cohort A-STIPP specific:

- Medical history of spontaneous preterm birth before 34 weeks of gestation

Cohort S-STIPP specific:

• Threatened Preterm birth between 24 and 34 weeks of gestation.

• Threatened preterm birth is defined as:

  • abdominal pain
  • (Braxton Hicks) contractions
  • vaginal blood loss.

Exclusion Criteria:

• Under 18 years of age.
• Signs of intrauterine infection.
• Obstetric indication for immediate delivery (advanced labor, cord prolapse, abruption, signs of fetal distress).
• Confirmed fetal abnormality.
• Confirmed preterm rupture of membranes.
• Confirmed vasa / placenta praevia.
• Severe vaginal bleeding and light bleeding that cannot be stopped.
• Signs of imminent labor such as blood loss, regular contractions.

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: The study includes pregnant women

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Sofie Breuking, drs; + 31205669111; s.h.breuking@amsterdamumc.nl

Contact: Frederik Hermans, PhD, MSc; +31205669111; f.j.hermans@amsterdamumc.nl

• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT05477381
• Other Study ID Numbers: NL80642.000.22
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: M.A. Oudijk, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Original Responsible Party: Same as current
• Current Study Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Original Study Sponsor: Same as current
• Collaborators: Pregnolia AG

Investigators

• Principal Investigator: Eva Pajkrt, Prof. Dr.; Amsterdam UMC, location AMC
• Principal Investigator: Martijn Oudijk, Prof. Dr.; Amsterdam UMC, location AMC

• PRS Account: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Verification Date: February 2023