Multimodal Monitoring of Fetal Risk of Inflammation in Preterm Premature Rupture of Membranes (MuMFI-PPROM)

Multimodales Monitoring Des Fetalen Inflammationsrisikos Bei frühem Vorzeitigen Blasensprung (PPROM)

The purpose of this study is to examine whether the value of vaginal fluid cytokine levels as well as computerized fetal ECG analysis are suitable clinical parameters to detect an imminent intra-amniotic inflammation with a high risk of fetal inflammatory response syndrome (FIRS) or a neonatal early onset sepsis (EOS) and whether these parameters can be determined on a daily basis in the clinical monitoring of pregnancies complicated by PPROM.

Study Overview

• Status: Completed
• Conditions: Preterm Premature Rupture of Membranes; Early Onset Neonatal Sepsis; Fetal Inflammatory Response Syndrome; Infection of Amniotic Cavity
• Intervention / Treatment: Other: single arm

Detailed Description

Preterm premature rupture of membranes (PPROM) is one of the leading causes for preterm birth and adverse neonatal outcome. Between 24 0/7 and 34 0/7 weeks of gestation the prolongation of pregnancy is the recommended course of action to reduce the risks of prematurity in most countries. An intra-amniotic infection resulting in fetal inflammatory response syndrome (FIRS) or early onset neonatal sepsis (EOS) is often associated with high morbidity and mortality.

Standard monitoring includes the maternal response to inflammation (i.e. maternal serum parameters) as well as fetal signs of acute FIRS (i.e. fetal tachycardia, high cytokine level in amniotic fluid obtained by amniocentesis). Changes of fetal ECG-parameters are also a sign of an acute FIRS.

Currently, there is no adequate parameter for the surveillance of a possible ongoing intra-amniotic infection. Other studies have reported a correlation between vaginal fluid interleukine 6 (IL6) collected noninvasively and the risk of FIRS and EOS. Information obtained by computerized fetal ECG analysis might be suitable to detect early signs of fetal infection before the manifestation of FIRS.

With the implementation of a vaginal fluid collector it is possible to detect the vaginal fluid cytokine in clinical everyday routine. With the improvement of fetal ECG monitoring it is possible to record the fetal ECG daily. This study examines the correlation between these new parameters and the onset of fetal infection before the manifestation of a severe systemic fetal inflammation.

• Study Type: Observational
• Enrollment (Actual): 57

Contacts and Locations

Study Locations

• Germany
  • Sachsen-Anhalt
    • Halle, Sachsen-Anhalt, Germany, 06110
      • St. Elisabeth Hospital Halle
    • Halle (Saale), Sachsen-Anhalt, Germany, 06120
      • Maternity Clinic/Perinatal Treatment Center, university hospital, Martin-Luther-Universität Halle-Wittenberg
  • Saxony
    • Leipzig, Saxony, Germany, 04103
      • Maternity clinic, University of Leipzig
  • Thüringen
    • Jena, Thüringen, Germany, 07743
      • Maternity Clinic, Jena University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Women with PPROM-complicated pregnancies who referre to one of the participating tertiary referreal care centers.

Description

Inclusion Criteria:

• Clinical diagnosis of preterm rupture of the fetal membranes
• Pregnancy between 24 0/7 and 34 0/7 weeks of gestation
• Ability to give informed consent in german or english

Exclusion Criteria:

• Sign of acute amniotic infection syndrome
• independent indication for urgent delivery
• Active labor
• Missing informed consent

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Single arm; daily multimodal monitoring during pregnancy after PPROM, Analysis of neonatal routine parameters and histologic examination of placenta	Other: single arm; Daily monitoring of vaginal fluid IL6 and fetal ECG. Daily maternal monitoring and delivery according to standard operating procedure. Post partum diagnosis of FIRS or EOS by analysing of fetal cord blood IL6 and clinical signs of sepsis. Diagnosis of histologic amniotic infection by histological analysis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Odds ratio for severe fetal/early onset neonatal Infection	combined outcome - rate of: early onset neonatal sepsis, elevated IL6 concentration in cord blood sample, histological signs of funisitis	postpartum one point assessment/ first three days post partum

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
combined neonatal adverse outcome	rate of severe intraventricular hemorrhage, necrotizing enterocolitis, late onset sepsis, white matter damage within the first 28 days of life	28 days
late onset neonatal sepsis	clinical Sepsis after first 72h of life	28 days
Severe neonatal cerebral hemorrhage	IVH II+IV°	28 days
necrotizing enterocolitis	NEC	28 days
umbilical cord blood IL 6 concentration	IL-6-concentration in cord blood sample after delivery or in fetal Serum during first hour of life	first day after delivery
neonatal early onset sepsis	clinical Sepsis during first 72h of life	3 days
histological funisitis	redline maternal stage >1, fetal stage >0	first day after delivery

Collaborators and Investigators

• Sponsor: Martin-Luther-Universität Halle-Wittenberg
• Collaborators: University of Leipzig; Jena University Hospital; St. Elisabeth Hospital Halle
• Investigators: Principal Investigator: Gregor Seliger, Dr. med, Maternity Clinic/Perinatal Treatment Center, Halle university hospital, Martin-Luther-Universität Halle-Wittenberg; Principal Investigator: Michael Bergner, Maternity Clinic/Perinatal Treatment Center, Halle university hospital, Martin-Luther-Universität Halle-Wittenberg; Principal Investigator: Uwe Schneider, Prof., Maternity Clinic; Jena University Hospital; Principal Investigator: Frank Bernhard Kraus, PD; PhD, Department of Laboratory Medicine; Halle university hospital, Martin-Luther-Universität Halle-Wittenberg; Principal Investigator: Roland Haase, PD, Department of Pediatrics; Halle university hospital, Martin-Luther-Universität Halle-Wittenberg; Principal Investigator: Holger Stepan, Prof., Maternity clinic, University of Leipzig

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 7, 2016
• Primary Completion (ACTUAL): February 28, 2018
• Study Completion (ACTUAL): November 10, 2018

Study Registration Dates

• First Submitted: February 22, 2016
• First Submitted That Met QC Criteria: March 2, 2016
• First Posted (ESTIMATE): March 8, 2016

Study Record Updates

• Last Update Posted (ACTUAL): November 14, 2018
• Last Update Submitted That Met QC Criteria: November 12, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: PROM; PPROM; adverse neonatal outcome; amniotic fluid; Preterm premature rupture of the membranes; fetal membranes; premature rupture; neonatal early onset sepsis; amniotic infection; fetal inflammatory response syndrome; FIRS
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Wounds and Injuries; Infant, Newborn, Diseases; Sepsis; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Rupture; Premature Birth; Fetal Membranes, Premature Rupture; Neonatal Sepsis
• Other Study ID Numbers: MuMFI-PPROM

Drug and device information, study documents

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