Cervical Softening and the Prediction of Preterm Birth (STIPP)

Assessment of Cervical SofTening and the Prediction of Preterm Birth'

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.

Study Overview

• Status: Recruiting
• Conditions: Premature Birth; Preterm Birth; Diagnosis; Threatened Preterm Labor; Cervical Incompetence in Pregnancy as Antepartum Condition; Premature Labor; Cervical Incompetence, With Delivery
• Intervention / Treatment: Diagnostic test: Measurement of cervical stiffness by Pregnolia Device

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
• Enrollment (Estimated): 390

Contacts and Locations

• Study Contact: Name: Sofie Breuking, drs; Phone Number: + 31205669111; Email: s.h.breuking@amsterdamumc.nl
• Study Contact Backup: Name: Frederik Hermans, PhD, MSc; Phone Number: +31205669111; Email: f.j.hermans@amsterdamumc.nl

Study Locations

• Netherlands
  • North-Holland
    • Amsterdam, North-Holland, Netherlands, 1105 AZ
      • Recruiting
      • Amsterdam UMC, location AMC
      • Contact: Sofie Breuking, MD, PhD; Email: s.h.breuking@amsterdamumc.nl
      • Contact: Martijn Oudijk, Prof. Dr. MD.; Email: m.a.oudijk@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• 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

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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.	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.
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).	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spontaneous Preterm Birth < 34 weeks	Spontaneous preterm birth before 34 weeks of gestation in the asymptomatic cohort	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.
Delivery within seven days after inclusion	Delivery within seven days after inclusion in the symptomatic cohort	From inclusion until 7 days later

Secondary Outcome Measures

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

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Pregnolia AG
• Investigators: Principal Investigator: Eva Pajkrt, Prof. Dr., Amsterdam UMC, location AMC; Principal Investigator: Martijn Oudijk, Prof. Dr., Amsterdam UMC, location AMC

Study record dates

Study Major Dates

• Study Start (Actual): August 18, 2022
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: July 19, 2022
• First Submitted That Met QC Criteria: July 25, 2022
• First Posted (Actual): July 28, 2022

Study Record Updates

• Last Update Posted (Actual): September 5, 2023
• Last Update Submitted That Met QC Criteria: August 30, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Uterine Cervical Diseases; Uterine Diseases; Pregnancy Complications; Obstetric Labor Complications; Abortion, Habitual; Abortion, Spontaneous; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Premature Birth; Obstetric Labor, Premature; Uterine Cervical Incompetence
• Other Study ID Numbers: NL80642.000.22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All agreements regarding data sharing are defined in a signed Clinical Trial Agreement (CTA), GDPR are applicable to this agreement.
• IPD Sharing Time Frame: After publication of the manuscript
• IPD Sharing Access Criteria: Data are available upon reasonable request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No