Treatment of Classic Mid-trimester PPROM by Means of Continuous Amnioinfusion

Phase 3

Not yet recruiting

• Conditions: Bronchopulmonary Dysplasia; Intracranial Hemorrhages; Necrotizing Enterocolitis
• Interventions: Combination Product: Continuous amnioinfusion with Amnion Flush Solution through the intraamniotic catheter

• Registration Number: NCT04696003
• Lead Sponsor: Martin-Luther-Universität Halle-Wittenberg

Brief Summary

Objective: Mid-trimester preterm premature rupture of membranes (PPROM), defined as rupture of fetal mem-branes prior to 28 weeks' gestation (WG), complicates approximately 0.4-0.7% of all pregnancies and associated with very high neonatal mortality and morbidity. Antibiotics have limited success to prevent bacteremia, chorioamnionitis and fetal inflammation because of reduced placental transport. The repetitive amnioinfusion doesn't work because of immediately fluid lost after the intervention). The continuous amnioinfusion with Amnion Flush Solution through the perinatal port system in patients with classic PPROM prolonged the PPROM-to-delivery interval to 49 days in average by flush out of bacteria and inflammatory components from the amniotic cavity.

Aim: This multicenter trial tests the effect of continuous amnioinfusion on the neonatal survival without major morbidities, like severe bronchopulmonary dysplasia, intraventricular hemorrhage, cystic periventricular leukomalacia and necrotizing enterocolitis.

Design: randomized multicenter controlled trial; two-arm parallel design. Control group: 34 PPROM patients between 22/0 (20/0) -26/0 WG treating with antibiotics and corticosteroids in according to DGGG guide-lines. In interventional group (n=34) the standard PPROM therapy will be complemented by "Amnion -Flush" method with the amnioinfusion of artificial amniotic fluid (Amnion Flush Solution, Serumwerk AG, Germany, 2400 ml/d).

Subjects: Patients with classic PPROM between 22/0-26/0 WG. Expected outcome:The investigators expect significant reduction of neonatal mortality and morbidity in the "Amnion-Flush" group.

Detailed Description

Objective:

Mid-trimester preterm premature rupture of membranes (PPROM), defined as rupture of fetal mem-branes prior to 28 weeks' gestation (WG), complicates approximately 0.4-0.7% of all pregnancies and associated with very high neonatal mortality and morbidity. Antibiotics have limited success to prevent bacteremia, chorioamnionitis and fetal inflammation because of reduced placental transport. The repetitive amnioinfusion doesn't work because of immediately fluid lost after the intervention). The continuous amnioinfusion with Amnion Flush Solution through the perinatal port system in patients with classic PPROM prolonged the PPROM-to-delivery interval to 49 days in average by flush out of bacteria and inflammatory components from the amniotic cavity.

Aim: This multicenter trial tests the effect of continuous amnioinfusion on the neonatal survival without major morbidities, like severe bronchopulmonary dysplasia, intraventricular hemorrhage, cystic periventricular leukomalacia and necrotizing enterocolitis.

Design: randomized multicenter controlled trial; two-arm parallel design.

Control group:

34 PPROM patients between 22/0 (20/0) -26/0 WG treating with antibiotics and corticosteroids in according to DGGG guide-lines (7 days Amoxicillin/Clarithromycin therapy or 7 days Amoxicillin and once Azithromycin 1 g and corticosteroids' RDS prophylaxis).

Experimental group:

34 PPROM patients between 22/0 (20/0) -26/0 WG, continuous amnioinfusion (100 ml/h) in pregnant women with classic PPROM with oligo-/anhydramnion between 22/0- 26/0 weeks' gestation and systemic antibiotic therapy (7 days Amoxicil-lin/Clarythromycin or 7 days Amoxicillin and once Azithromycin 1 g) and corticosteroids' RDS prophylaxis.

Duration of intervention: Maximum till 34/0 weeks of gestation, or preterm delivery if indicated.

Follow-up per patient: 12 months post-partum. Subjects: Patients with classic PPROM between 22/0 (20/0) -26/0 WG. Primary efficacy endpoint: survival without major morbidity (severe bron-chopulmonary dysplasia (BPD), and/or grades 3 and 4 intraventricular hemor-rhage (IVH 3-4), and/or cystic periventricular leukomalacia (cPVL), and/or necrotizing enterocolitis (NEC)) since randomization (event time).

Expected outcome: The envestigators expect significant reduction of neonatal mortality and morbidity in the "Amnion-Flush" group.

Study Timeline

• Study First Submitted: 2020-12-21
• Status Verified: 2021-01
• Study Start: 2021-01-01
• Study First Submitted QC: 2021-01-04
• Study First Posted: 2021-01-06
• Last Update Submitted: 2021-01-08
• Last Update Posted: 2021-01-12
• Primary Completion: 2024-08-31
• Study Completion: 2025-05-30

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: Female
• Target Recruitment: 68

Inclusion Criteria

• Singleton pregnancy (from 22/0 to 26/0 weeks of gestation)
• Evidence of PPROM from clinical and instrumental investigations
• Oligo/anhydramnion (< 2 cm deepest amniotic fluid pocket)

Read More

Exclusion Criteria

• fetal death
• placental abnormalities
• labor
• evidence of major structural or chromosomal abnormalities
• signs of chorioamnionitis (maternal fever > 38° C and one or more of the following criteria: uterine tenderness, malodorous vag-inal discharge, maternal leukocytosis > 15000 cells/mm3, maternal tachycardia > 100 beats/min, and fetal heart rate > 160 bpm).

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Amnion Flush group (continuous amnioinfusion)	Continuous amnioinfusion with Amnion Flush Solution through the intraamniotic catheter	In the "Amnion Flush" group additionally to the standard treatment the amniotic cavity will be punctured with a 18 gauge needle under ultrasound control. The intra-amniotic catheter (0.65 mm Diameter, CE 0481, PakuMed GmbH, Essen, Germany) will be placed under local anesthesia with Xylocaine 1% 10 ml. Amnion Flush Solution (CE 0483, Serumwerk AG Bernburg, Germany) will be carried out with an infusion rate of 100 ml/h (2400 ml/d) under periodic ultrasound using the standard i.v. pump. The deepest pool of amniotic fluid should be stabilized by about 4 cm. The ultrasound control will be performed daily. Induction of the labour or c-section at 34/0 week of gestation or earlier if indicated.

Primary Outcome Measures

Name	Time	Method
Number of Participants with bronchopulmonary dysplasia	through study completion, an average of 1 year	Number of Participants with severe bronchopulmonary dysplasia (BPD)
Number of Participants with intraventricular hemorrhage	through study completion, an average of 1 year	Number of Participants with intraventricular hemorrhage (IVH 3-4)
Number of Participants with necrotizing enterocolitis	through study completion, an average of 1 year	Number of Participants with necrotizing enterocolitis (NEC)

Secondary Outcome Measures

Name	Time	Method
Duration of PPROM to delivery interval	up to 15 weeks	Duration of PPROM to delivbery interval (days)
Gesatational age at delivery	34 weeks	gestational age at delivery
Rate of Newborns with FIRS	1 week	Rate of Newborns with FIRS (fetal inflammatory response syndrome) (binary)

Trial Locations

Locations (1)

Martin Luther University, Clinic of Obstetrics and Prenatal Medicine; 🇩🇪 Halle, Sachsen Anhalt, Germany