Clinical trial NCT04696003: Treatment of Classic Mid-trimester PPROM by Means of Continuous Amnioinfusion
Official title: Treatment of Classic Mid-trimester Preterm Premature Rupture of Membranes (PPROM) With Oligo/Anhydramnion Between 22/0-26/0 Week of Gestation by Means of Continuous Amnioinfusion: a Multicenter Prospectiv Randomized Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Bronchopulmonary Dysplasia
Necrotizing Enterocolitis
Intracranial Hemorrhages
Keywords: PPROM, Amnion Flush Solution, outcome, amnioinfusion
Lead sponsor: Martin-Luther-Universität Halle-Wittenberg
Sponsor class: OTHER
First posted: 2021-01-06
Enrollment: 68
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized multicenter controlled trial; two-arm parallel design.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

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).

Primary outcomes:
measure: Number of Participants with bronchopulmonary dysplasia
timeFrame: through study completion, an average of 1 year
measure: Number of Participants with intraventricular hemorrhage
timeFrame: through study completion, an average of 1 year
measure: Number of Participants with necrotizing enterocolitis
timeFrame: through study completion, an average of 1 year
Secondary outcomes:
measure: Duration of PPROM to delivery interval
timeFrame: up to 15 weeks
measure: Gesatational age at delivery
timeFrame: 34 weeks
measure: Rate of Newborns with FIRS
timeFrame: 1 week
Other outcomes:
Locations:
city: Halle
country: Germany
facility: Martin Luther University, Clinic of Obstetrics and Prenatal Medicine
state: Sachsen Anhalt
Study officials:
affiliation: University Clinic of Obstetrics and Prenatal Medicine
name: Michael Tchirikov, MD, Ph.D.
role: STUDY_DIRECTOR
References:
citation: Tchirikov M, Zhumadilov Z, Winarno AS, Haase R, Buchmann J. Treatment of Preterm Premature Rupture of Membranes with Oligo-/Anhydramnion Colonized by Multiresistant Bacteria with Continuous Amnioinfusion and Antibiotic Administrations through a Subcutaneously Implanted Intrauterine Port System: A Case Report. Fetal Diagn Ther. 2017;42(1):71-76. doi: 10.1159/000438483. Epub 2015 Oct 9.
citation: Tchirikov M, Bapayeva G, Zhumadilov ZSh, Dridi Y, Harnisch R, Herrmann A. Treatment of PPROM with anhydramnion in humans: first experience with different amniotic fluid substitutes for continuous amnioinfusion through a subcutaneously implanted port system. J Perinat Med. 2013 Nov;41(6):657-63. doi: 10.1515/jpm-2012-0296.
citation: Tchirikov M, Schlabritz-Loutsevitch N, Maher J, Buchmann J, Naberezhnev Y, Winarno AS, Seliger G. Mid-trimester preterm premature rupture of membranes (PPROM): etiology, diagnosis, classification, international recommendations of treatment options and outcome. J Perinat Med. 2018 Jul 26;46(5):465-488. doi: 10.1515/jpm-2017-0027.
citation: Tchirikov M, Haiduk C, Tchirikov M, Riemer M, Bergner M, Li W, Henschen S, Entezami M, Wienke A, Seliger G. Treatment of Classic Mid-Trimester Preterm Premature Rupture of Membranes (PPROM) with Oligo/Anhydramnion between 22 and 26 Weeks of Gestation by Means of Continuous Amnioinfusion: Protocol of a Randomized Multicentric Prospective Controlled TRIAL and Review of the Literature. Life (Basel). 2022 Aug 30;12(9):1351. doi: 10.3390/life12091351.