PeRinatal Outcomes With ACTive Versus Expectant Management of Women With Pre-labor Rupture Of Membranes (PROACT PROM)

PeRinatal Outcomes With ACTive Versus Expectant Management of Women With Pre-labor Rupture Of Membranes: a Phase III, Open-label, Randomized Controlled Multicentric Trial

Term pre-labor rupture of membranes (PROM) occurs in about 12% of pregnancies and the time between PROM and delivery increases the risk of maternal/fetal infections. However, conflicting results are reported by studies investigating risks and benefits of expectant management versus induction of labor (IOL). Expectant management was associated with maternal and fetal infectious complications and subsequent increased risk of maternal and neonatal morbidity. Studies suggest that the increase in infectious risk for both is proportional to the increase in the time interval between the ROM and the birth, others reject this assumption.

In PeRinatal Outcomes With ACTive Versus Expectant Management of Women With Pre-labor Rupture Of Membranes (PROACTIVE PROM) on admission, PROM will be diagnosed. After 6 hours from the rupture of membranes, the woman will then be assessed for eligibility. A 1:1 randomization will follow within two hours (6-8 hours from PROM) in two distinct arms: 1) Expectant management 2) Active menagement (early IOL within 8 hours of rupture of membranes).

The first objective of this study is to evaluate whether active management of women with PROM (early induction) reduces the newborn need of respiratory support.

The secondary objectives of this study are related to the safety of the active management assessed through the rate of stillbirths, the onset of infections in both mother and fetus and the length of hospitalization of the dyads. Moreover, another objective is to reduce the use of antibiotic treatments (ATB) in both mothers and newborns.

The rationale of this study is that reducing the time between the PROM and delivery through an early IOL will reduce the adverse maternal and neonatal outcomes.

The hypothesis underneath this trial comes from a preliminary retrospective cohort study conducted in Modena, which included 2689 mother-neonates dyads from singleton pregnant women at term. In deliveries of ROM >24 hours significantly more neonates required ventilatory support than those born within 24 hours, although no significant differences were found regarding overt infections. According to the Cochrane database, expectant management of PROM is associated with maternal and fetal infectious complications and subsequent increased risk of maternal and neonatal morbidity together with an increased risk of ATB use. The increase of infectious risk is proportional to the time elapsed since the rupture of the membranes (ROM) and birth. However, unpublished data from our group suggest that respiratory distress requiring interventions may be frequently caused by intrinsic inflammatory-related effects of prolonged ROM rather than infection; this is suggested by an increase of C-reactive protein levels in neonates with mild respiratory signs untreated with antibiotics.

In addition, in a survey performed in our country expectant management increased intrapartum antibiotic prophylaxis (IAP), although not strictly indicated by the most current guidelines.

On the light of these data, it appears reasonable to promote induction of labor, to prevent complication caused not only by the infectious risk mentioned above, but also respiratory distress, probably associated to a neonatal maladaptation, in non-infectious newborns.

On the other hand, it should also be considered that 75% of women enter labor spontaneously within 24 hours from PROM and induction of labor (IOL) might not be needed in such cases.

Study Overview

• Status: Not yet recruiting
• Conditions: Rupture of Membranes; Premature; Maternal Sepsis; Distress; Fetal, Complicating Delivery; Delayed Delivery After Spontaneous or Unspecified Rupture of Membranes
• Intervention / Treatment: Procedure: Induction of Labor IoL

• Study Type: Interventional
• Enrollment (Estimated): 1400
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Fabio Facchinetti, Professor; Phone Number: 0039 059 4225334; Email: fabio.facchinetti@unimore.it

Study Locations

• Italy
  • Modena, Italy, 41120
    • AUO Policlinico di Modena
    • Contact: Anna Luna Tramontano, MD; Phone Number: 0039 327 0184948; Email: tranalu@iclou.com
    • Contact: Matteo Visconti, MD; Phone Number: 0039 3403502265; Email: matteo.visconti1@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years of age at the time of randomization
2. Gestational age ≥ 37 weeks
3. Negative rectovaginal GBS swab
4. Absent/poor uterine contractile activity 6 h after PROM (0-2 contractions /10 min)
5. Cephalic presentation
6. Ability to provide an informed consent
7. Signed informed consent

Exclusion Criteria:

1. Prematurity (<37 weeks)
2. GBS positive vagino-rectal swab or with an unknown swab
3. Multiple pregnancies
4. Previous cesarean section (CS)
5. Breech presentation, transverse lie or other indication for elective CS
6. Suspected clinic for intra-amniotic infection (According to the Triple I criteria)
7. Stained amniotic fluid
8. Alterations of the FHR
9. Unknown exact ROM time
10. Known hypersensitivity to drugs for IOL or their excipients
11. Presence of unknown vaginal bleeding
12. Presence of maternal kidney disease (GFR <15 ml/min/1,73 m2).
13. Every condition contraindicating vaginal delivery

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: active management; early IOL within 8 hours of rupture of membranes. Center-specific IOL protocols will be used.	Procedure: Induction of Labor IoL; Center-specific IOL protocols, based on international guidelines, will be used.
No Intervention: Expectant management; monitoring until 24 hours from rupture of membranes, with subsequent induction of labor (IOL).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of respiratory support in newborns	The primary objective of this study is to evaluate whether active management of women with PROM (early induction) reduces the newborn need of respiratory support, collecting data on Apgar score, neonatal blood gas analysis and the rate of respiratory distress after birth and rate of respiratory support divided by type. The need for neonatal ventilatory support will be evaluated at delivery and include at least one of the following measures: free flowing oxygen in incubator, low flow oxygen (<2 LPM), high flow oxygen (>3 LPM), NCPAP or other NIV, mechanical ventilation.	On day 1 or 2 post-partum all relevant delivery and post-partum as well as neonatal variables will be collected.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stillbirth and infection rate	This secondary objectives of this study are related to the safety of the active management assessed through the rate of stillbirths, the onset of infections in the mother and fetus and through the length of hospitalization of the dyads. Moreover, another objective is to reduce the use of antibiotic treatments (ATB) in both mothers and newborns.	On day 1 or 2 post-partum all relevant delivery and post-partum as well as neonatal variables will be collected.
length of hospitalization expressed in days	The lenght of hospitalization and the need for re-hospitalizations are related to the safety of the active management assessed through the rate of stillbirths, the onset of infections in the mother and fetus and through the length of hospitalization of the dyads. Moreover, another objective is to reduce the use of antibiotic treatments (ATB) in both mothers and newborns.	From day 1 after delivery to the end of the puerperium (42 days after delivery)
use of antibiotics in both mother and newborn as quantity (mg) and quality.	The use of antibiotics will be recorded	From admission in the Hospital to 42 days after delivery
neonatal infection as the yield of pathogen from blood or CFS coltures	Suspected infection is based on the presence of clinical symptoms (neonatal tachycardia, hyperpyrexia, alteration of the skin color) and abnormal laboratory markers, i.e. an increase in C reactive proteins above 1.5 mg/dl.	From birth to 42 days after delivery
Rate of Pathogen isolation in placenta's speciemen	Placentas and umbilical cord will be collected only in the Milano Buzzi center	Collection of speciemens immediately after delivery

Collaborators and Investigators

• Sponsor: University of Modena and Reggio Emilia

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2023
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): November 12, 2025

Study Registration Dates

• First Submitted: June 6, 2023
• First Submitted That Met QC Criteria: July 14, 2023
• First Posted (Actual): July 25, 2023

Study Record Updates

• Last Update Posted (Actual): July 25, 2023
• Last Update Submitted That Met QC Criteria: July 14, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Wounds and Injuries; Pregnancy Complications; Obstetric Labor Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Rupture; Pregnancy Complications, Infectious; Fetal Membranes, Premature Rupture
• Other Study ID Numbers: 2022-002480-30

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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