Antibiotics and Gut Microbiota Among Newborn Infants

Antibiotic Prophylaxis for Postpartum Infections Following Caesarean Section

Background Women undergoing Caesarean Section (CS) have an increased risk of postpartum infections compared to women undergoing vaginal delivery. In Denmark the incidence of post-CS infections is 7-10%. The most common infections are endometritis, Urinary tract infections (UTI) and wound infections (WI).

Prophylactic antibiotics are effective in preventing postoperative infections and national guidelines recommend that antibiotics should be administered as a single dose immediately before surgical incision. CS is an exception to this pre-incision administration approach. National guidelines recommend administration of antibiotics after umbilical cord clamping to avoid exposure of the child to antibiotics before birth. Recent studies of antibiotic prophylaxis for CS suggest that prophylactic antibiotics administered before incision compared to after umbilical cord clamping may reduce post-CS infections by up to 50%. Two Cochrane reviews from 2012 criticize these types of studies for lack of data for outcomes on the baby and on late infection in the mother.

At birth, all mammals must rapidly adapt to intake of complex milk nutrients via the gut and simultaneously tolerate the invasion of billions of microbes. This requires rapid maturation of the digestive and immune functions to avoid gut disorders and infections. Full-term, breast-fed infants normally adapt well, but factors such as caesarean birth, high hygiene levels, antibiotics treatment and formula feeding may inhibit immune development both short and long term. Birth by caesarean section in high-hygiene hospital environments, and widespread use of antibiotics, are factors that reduce gut microbiota density and diversity in the newborn for some time after birth. On the other hand, high-hygiene environments and antibiotics are essential tools to combat infections, especially for the weakest newborn infants.

This pilot study will be a feasibility study to the original study, which examines the effect of change in timing of prophylactic antibiotics on the rate of post-CS infections (endometritis, UTI and WI). The pilot study focus on antibiotic and changes in the gut microbiota of newborn infants. The feasibility study will only include pregnant women in Odense with a body mass index below 30, and planned cesarean section.

Study Overview

• Status: Completed
• Conditions: Surgical Wound Infection; Complications; Cesarean Section; Infection; Cesarean Section
• Intervention / Treatment: Drug: Cefuroxime

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Fyn
    • Odense, Fyn, Denmark, 5000
      • Odense University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Age ≥ 18 year
• Women, who can read and understand Danish
• A gestational age ≥ completed 28 weeks of gestation
• Rupture of membranes and active labour (uterine contractions) is allowed.
• BMI < 30

Exclusion Criteria:

• Hypersensitivity to cefuroxime or to any other cephalosporin antibiotics
• Previous immediate and/or severe hypersensitivity reaction to penicillin or any other beta-lactam antibiotic.
• Systemic exposure to any antibiotic agent within 1 week before delivery Antibiotic indicated due to PROM, fever, group B Streptococcus or other indications at the time of caesarean section.
• Women being immunologically incompetent (e.g. HIV positive)
• Very sick newborn infants transferred to a neonatal intensive care unit and treated with antibiotics will be excluded from the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: preoperative antibiotic; iv Cefuroxime 1,5g administered 15-60 minutes before incision	Drug: Cefuroxime; iv Cefuroxime 1,5g administered 15-60 minutes before incision versus iv Cefuroxime 1,5g administered after umbilical cord clamping; Other Names: Cefuroxime "Fresenius Kabi"
ACTIVE_COMPARATOR: postoperative antibiotic; iv Cefuroxime 1,5g administered after umbilical cord clamping	Drug: Cefuroxime; iv Cefuroxime 1,5g administered 15-60 minutes before incision versus iv Cefuroxime 1,5g administered after umbilical cord clamping; Other Names: Cefuroxime "Fresenius Kabi"

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maternal: incidence of post-CS infection (endometritis, urinary tract infections and wound infection) in each study group	Within the first 30 days after surgery
Infant: fecal microbiota at the tenth day of life	on the tenth day of life

Secondary Outcome Measures

Outcome Measure	Time Frame
Maternal: Length of hospitalization	Within the first 30 days after Caesarean Section
Maternal: readmissions to hospital on suspicion of postpartum infection following cesarean section	Within the first 30 days after Caesarean Section
Antibiotic treatment	within the first 30 days after Caesarean Section
Infant: concentration of cefuroxime in blood samples	during the first 24 hours of life
Infant: immunological analyses in blood samples on day 3	On the third day of life

Collaborators and Investigators

• Sponsor: Odense University Hospital
• Collaborators: University of Copenhagen; University of Southern Denmark; Region of Southern Denmark; Aase and Ejnar Danielsens Foundation

Publications and helpful links

General Publications

• Kamal SS, Hyldig N, Krych L, Greisen G, Krogfelt KA, Zachariassen G, Nielsen DS. Impact of Early Exposure to Cefuroxime on the Composition of the Gut Microbiota in Infants Following Cesarean Delivery. J Pediatr. 2019 Jul;210:99-105.e2. doi: 10.1016/j.jpeds.2019.03.001. Epub 2019 Apr 30.

Helpful Links

• "The NEOMUNE centre" is a research platform aiming to improve clinical care of newborn infants, particular those born with developmental problems

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (ACTUAL): July 1, 2014
• Study Completion (ACTUAL): August 1, 2014

Study Registration Dates

• First Submitted: February 25, 2014
• First Submitted That Met QC Criteria: February 25, 2014
• First Posted (ESTIMATE): February 27, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): August 12, 2014
• Last Update Submitted That Met QC Criteria: August 10, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Caesarean Section; Surgical Site Infections; Wound Infections; Infectious Morbidity
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Wounds and Injuries; Disease Attributes; Infections; Communicable Diseases; Surgical Wound; Surgical Wound Infection; Wound Infection; Anti-Infective Agents; Anti-Bacterial Agents; Cefuroxime; Cefuroxime axetil
• Other Study ID Numbers: s-20130117; 2012-002068-29 (EUDRACT_NUMBER)