Antipyretic Treatment for Intrapartum Fever: Dipyrone vs Acetaminophen (RCT) (PARADIP)

Intravenous Dipyrone Compared With Intravenous Acetaminophen for Maternal Fever During Labor: A Randomised Controlled Trial

Chorioamnionitis, or intraamniotic infection, is a common condition affecting 2-5% of all term births. This condition poses well-recognized maternal and neonatal risks, and entails a series of clinical management decisions concerning both the mother and neonate. Therefore, timely detection and treatment of chorioamnionitis is of paramount importance. The occurrence of chorioamnionitis is associated with a higher risk of labor abnormalities, which increase the risk of cesarean delivery (CD) 3 to 4 fold.

As recommended by current guidelines, treatment of suspected intraamniotic infection should include broad-spectrum antibiotics. In addition, the use of antipyretics is advocated. This is particularly important during the intrapartum period since fetal acidosis in the setting of fever has been associated with a marked increase in the incidence of neonatal encephalopathy. Maternal fever even in the absence of documented fetal acidosis is associated with adverse neonatal outcomes, particularly neonatal encephalopathy, though it is unclear to what extent the etiology of the fever rather than the fever itself is causative . Furthermore, treating intrapartum fever with antipyretics may also be helpful in reducing fetal tachycardia thereby avoiding the tendency to perform cesarean for a non-reassuring fetal status. Nevertheless, it remains understudied which is the most appropriate antipyretic agent in this regard, where both dipyrone and acetaminophen are safe alternatives . Antipyretic agent with a faster onset of action may be preferable in this setting.

Study Overview

• Status: Not yet recruiting
• Conditions: Chorioamnionitis; Intrapartum Fever
• Intervention / Treatment: Drug: dipyrone; Drug: Acetaminophen

Detailed Description

Chorioamnionitis, or intraamniotic infection, affects 2-5% of term deliveries and is associated with significant maternal and neonatal risks, including a 3- to 4-fold increase in cesarean delivery. Management includes prompt antibiotic treatment and antipyretic use, particularly during labor, where maternal fever may contribute to fetal acidosis and increased risk of neonatal encephalopathy. Even in the absence of acidosis, maternal fever alone is linked to adverse neonatal outcomes. Antipyretics may also help resolve fetal tachycardia, potentially avoiding unnecessary cesarean sections. While both dipyrone and acetaminophen are considered safe, it remains unclear which has superior efficacy in the intrapartum setting, and an agent with faster onset may offer clinical advantages.

Stages of study: Following the diagnosis of suspected intrapartum intraamniotic infection, eligible women will be offered to participate. All women will be treated with the same broad-spectrum antibiotic regimen. As stated above, those who gave their informed consent will be randomly assigned to either dipyrone or acetaminophen.

After administering antipyretic treatment, oral temperature will be monitored every 5 minutes for up to 40 minutes.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Hagit Eisenberg, MD; Phone Number: +972523397843; Email: hagit.haramati@gmail.com
• Study Contact Backup: Name: Ilia Kleiner, MD; Phone Number: +972528305195; Email: kleiner.ilia@gmail.com

Study Locations

• Israel
  • Tel Aviv
    • Holon, Tel Aviv, Israel, 6997107
      • Wolfson Medical Center
      • Contact: Hagit Eisenberg, MD; Phone Number: +972523397843; Email: hagit.haramati@gmail.com
      • Principal Investigator: Hagit Eisenberg, MD
      • Principal Investigator: Amihai Rottenstreich, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Women undergoing a trial of vaginal delivery, with suspected intra-amniotic infection defined as isolated maternal fever of 39°C or greater, or an sustained oral temperature of 38-38.9°C for at least 30 minutes or with one or more of the following: maternal leukocytosis, purulent cervical drainage, or fetal tachycardia.

Exclusion Criteria:

• Known history of adverse events for dipyrone or acetaminophen
• Age <18 years
• Gestational age <24 weeks
• Intrauterine fetal death
• Fever onset prior to delivery
• Known liver disease
• Known leukopenia
• In addition, those who will develop allergic event or any adverse event possible related to any of the antipyretics used will be excluded from the

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dipyrone; Dipyrone IV 1 g once	Drug: dipyrone; Dipyrone IV 1 g once
Experimental: Acetaminophen; Acetaminophen 1 g IV once	Drug: Acetaminophen; Acetaminophen 1 g IV once

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to defervesce	Time (minutes) from drug administration to temperature < 38 °C	120 min

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to resolution of fetal tachycardia	Time to resolution of fetal tachycardia (min)	120 min
Mode of delivery	Mode of delivery (vaginal / cesarean)	From enrollment to delivery
Apgar scores	Apgar scores - Standard newborn assessment	At 1 and 5 minutes after birth
Neonatal arterial pH level	Neonatal arterial pH level	Immediately after birth

Collaborators and Investigators

• Sponsor: Wolfson Medical Center
• Investigators: Principal Investigator: Ilia Kleiner, MD, Wolfson Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2025
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: April 22, 2025
• First Submitted That Met QC Criteria: April 22, 2025
• First Posted (Actual): April 30, 2025

Study Record Updates

• Last Update Posted (Actual): July 3, 2025
• Last Update Submitted That Met QC Criteria: June 30, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: acetaminophen; metamizole; dipyrone; labour; maternal fever
• Additional Relevant MeSH Terms: Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Obstetric Labor Complications; Pregnancy Complications; Fetal Diseases; Placenta Diseases; Body Temperature Changes; Fetal Membranes, Premature Rupture; Fever; Chorioamnionitis; Physiological Effects of Drugs; Anti-Inflammatory Agents; Peripheral Nervous System Agents; Antirheumatic Agents; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Antipyretics; Anti-Inflammatory Agents, Non-Steroidal; Acetaminophen; Dipyrone
• Other Study ID Numbers: WOMC-0093-25

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Time to defervescence, fetal heart rate response, delivery mode, Apgar scores, neonatal pH
• IPD Sharing Time Frame: Beginning 6 months after study completion; available for 2 years
• IPD Sharing Access Criteria: Qualified researchers with institutional ethics approval will be able to access de-identified individual participant data, including time to fever resolution, fetal heart rate response, delivery mode, Apgar scores, and neonatal arterial pH. Data will be available upon reasonable request to the Principal Investigator via email. Requests must include a brief study proposal and evidence of ethical approval. If approved, data will be shared in a secure, password-protected format. Supporting documents such as the study protocol and statistical analysis plan will also be made available upon request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

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