Antibiotic Prophlaxis for High-risk Laboring Women in Low Income Countries

Azithromycin With or Without Amoxicillin to Prevent Peripartum Infection and Sepsis in Laboring High-risk Women: 3-Arm RCT

This study, performed over a course of 3 years in 5 collaborating hospitals in Cameroon, Africa, will randomize 750 women in labor with prolonged rupture of membranes ≥ 8 hours or prolonged labor ≥ 18 hours to identical oral regimens of 1 gram of azithromycin, 1 gram of azithromycin+2 grams of amoxicillin or placebo. Women will be followed to ascertain maternal infectious outcomes and perinatal outcomes.

Study Overview

• Status: Completed
• Conditions: Postpartum Sepsis; Postpartum Endometritis; Postpartum Fever
• Intervention / Treatment: Drug: Placebo; Drug: Azithromycin; Drug: Azithromycin and amoxicillin

Detailed Description

This 3-arm study is a large randomized clinical trial designed to evaluate the comparative effectiveness and safety of single dose oral azithromycin or combined azithromycin+amoxicillin compared to placebo for the prevention of peripartum infections and sepsis in laboring women. We have previously shown the effectiveness of azithromycin for extended spectrum antibiotic prophylaxis in addition to the standard cephalosporin alone for reduction of post-cesarean infections. In LICs, the fraction of maternal infection and sepsis from cesarean delivery is minimal. Therefore, it is necessary to evaluate strategies aimed at reducing these morbidities in women who have vaginal births. There is an increased risk of infection in women who have prolonged labor or prolonged rupture of membranes. Drawing from our findings with azithromycin-based extended antibiotic prophylaxis for cesarean delivery, we propose to adapt the intervention and evaluate a single oral dose of azithromycin (with or without oral amoxicillin) to prevent maternal peripartum infection and sepsis. This study, performed over a course of 3 years in 5 collaborating hospitals in Cameroon, Africa, will randomize 750 women in labor with prolonged rupture of membranes ≥ 8 hours or prolonged labor ≥18 hours to 1 gram of oral azithromycin, 1 gram of azithromycin+2 grams of amoxicillin, compared to usual care (placebo). Women will be followed to ascertain maternal infectious outcomes and perinatal outcomes.

• Study Type: Interventional
• Enrollment (Actual): 756
• Phase: Phase 4

Contacts and Locations

Study Locations

• Cameroon
  • Bamenda, Cameroon
    • Cameroon Baptist Convention Health Services

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Women ≥ 37 weeks' viable singleton or twin gestation in labor planning a vaginal delivery with

  1. Prolonged membrane rupture (≥8 hours) or
  2. Prolonged labor (≥18 hours).

Exclusion Criteria:

• Clinical chorioamnionitis or any other active bacterial infection (e.g. pyelonephritis, pneumonia, abscess) at time of randomization: because standard antibiotic therapy for these conditions may confound trial intervention.
• Allergy to azithromycin or amoxicillin
• Plan for cesarean delivery prior to enrollment
• Fetal demise or major congenital anomaly: Major congenital anomalies may confound assessment of neonatal outcomes and every attempt will be made up front to exclude them from randomization. However, some unrecognized fetal anomalies may inevitably be randomized. These will not be excluded post-randomization from the primary (maternal outcome) analysis; they will be taken into consideration in the secondary analyses of neonatal outcomes.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Azithromycin and amoxicillin placebo; Patients in this arm will receive 1 gram oral azithromycin as a single dose and amoxicillin placebo.	Drug: Placebo; Placebo tablet; Drug: Azithromycin; Azithromycin tablet
Experimental: Azithromycin + amoxicillin; Patients in this arm will receive 1 gram oral azithromycin and 2 grams oral amoxicillin in a single dose.	Drug: Azithromycin and amoxicillin; azithromycin and amoxicillin; Other Names: azithromycin, amoxicillin
Placebo Comparator: Usual Care; This arm will consist of routine care at the clinical sites (which is usually no antibiotic). They will receive placebo (for azithromycin) and placebo (for amoxicillin)	Drug: Placebo; Placebo tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced Composite Peripartum Infection or Death	Maternal peripartum infection including chorioamnionitis, endometritis, wound infection/abscess, sepsis, and death	Up to 6 weeks after delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced Pyelonephritis	Other Infections	Up to hospital discharge
Number of Participants Who Experienced Breast Infection	Other infections	Up to 6 weeks after delivery
Number of Participants Who Experienced Other Infection	Includes Hepatitis B, thyroid infection, vaginal infection, viral infection, leg cellulitis, unknown abdominal infection,malaria	up to 6 weeks after delivery
Number of Participants Who Experienced Fever	Any fever higher than 38C	up to 6 weeks after delivery
Number of Participants Who Experienced Hypothermia	Any hypothermia less than 36C	up to 6 weeks after delivery
Number of Participants Who Needed PP Antibiotic	Any postpartum antibiotic	up to 6 weeks after delivery
Number of Participants Who Experienced Transfusion	Blood transfusion	up to 6 weeks after delivery
Number of Participants Who Experienced Stillbirth	Any stillbirth	delivery
Length of Stay	Length of stay in days	up to 6 weeks postpartum
Number of Participants Who Experienced a Clinic Visit	Clinic visit after discharge	up to 6 weeks after delivery
Number of Participants Who Experienced a Maternal Readmission	Maternal readmission	up to 6 weeks after delivery

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Alan Tita, MD, PhD, University of Alabama at Birmingham

Publications and helpful links

General Publications

• Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for Prevention of Surgical Site Infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control. 1999 Apr;27(2):97-132; quiz 133-4; discussion 96.
• ASHP Therapeutic Guidelines on Antimicrobial Prophylaxis in Surgery. American Society of Health-System Pharmacists. Am J Health Syst Pharm. 1999 Sep 15;56(18):1839-88. doi: 10.1093/ajhp/56.18.1839. No abstract available.
• Tita ATN, Boggess K, Saade G. Adjunctive Azithromycin Prophylaxis for Cesarean Delivery. N Engl J Med. 2017 Jan 12;376(2):182. doi: 10.1056/NEJMc1614626. No abstract available.
• WHO. WHO recommendations for prevention and treatment of maternal peripartum infections. Sept 2015 http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/peripartum-infections-guidelines/en/
• Subramaniam A, Ye Y, Mbah R, Mbunwe DM, Pekwarake S, Bunwi EY, Fondzeyuf A, Ngong MG, Dionne-Odom J, Harper LM, Jauk VC, Carlo WA, Halle-Ekane G, Szychowski JM, Tih P, Tita AT. Single Dose of Oral Azithromycin With or Without Amoxicillin to Prevent Peripartum Infection in Laboring, High-Risk Women in Cameroon: A Randomized Controlled Trial. Obstet Gynecol. 2021 Nov 1;138(5):703-713. doi: 10.1097/AOG.0000000000004565.

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2018
• Primary Completion (Actual): May 15, 2020
• Study Completion (Actual): October 1, 2020

Study Registration Dates

• First Submitted: July 25, 2017
• First Submitted That Met QC Criteria: August 11, 2017
• First Posted (Actual): August 14, 2017

Study Record Updates

• Last Update Posted (Actual): July 18, 2022
• Last Update Submitted That Met QC Criteria: March 18, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Uterine Diseases; Adnexal Diseases; Pregnancy Complications; Puerperal Disorders; Pelvic Inflammatory Disease; Pregnancy Complications, Infectious; Sepsis; Endometritis; Puerperal Infection; Anti-Infective Agents; Anti-Bacterial Agents; Amoxicillin; Azithromycin
• Other Study ID Numbers: CHI UAB MISP # 54628

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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