Multimodal Monitoring of Fetal Risk of Inflammation in Preterm Premature Rupture of Membranes

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Preterm Premature Rupture of Membranes, Fetal Inflammatory Response Syndrome, Early Onset Neonatal Sepsis, Infection of Amniotic Cavity

Intervention / Treatment
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* Other: single arm


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Single arm<br>daily multimodal monitoring during pregnancy after PPROM, Analysis of neonatal routine parameters and histologic examination of placenta | Other: single arm<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FIRS, Preterm premature rupture of the membranes, PPROM, PROM, fetal membranes, premature rupture, neonatal early onset sepsis, amniotic fluid, amniotic infection, fetal inflammatory response syndrome, adverse neonatal outcome