The Influence of Timing of Maternal Administration of Antibiotics During Caesarean Section on the Intestinal Microbial Colonization in Infants (MAMI-Trial): A Randomized Controlled Trial

Abstract

Objectives and Study: In order to reduce the risk of maternal infectious complications, revised international guidelines for caesarean section (CS) now advise maternal antibiotic administration prior to skin incision instead of after clamping of the umbilical cord. Unintentionally, this alteration results in perinatal exposure to broad-spectrum antibiotics in all CS born neonates. Effects of this exposure on neonatal gut colonization and long-term health related outcomes are unknown. Methods: In this randomized controlled trial, women scheduled for an elective CS were randomized to receive antibiotics (1500 mg cefuroxime) either prior to skin incision (group A: intrauterine antibiotic exposed infants) or after clamping of the umbilical cord (group B: intrauterine unexposed infants). Women delivering vaginally and their infants, both not exposed to antibiotics, were included as controls (group C). Faecal microbiota was determined from all infants at one, seven and twenty-eight days and three years after birth by means of whole-metagenome shotgun sequencing and 16S rRNA gene sequencing. The trial is registered with https://www.trialregister.nl/, NTR6000. Results: Differences between intrauterine antibiotic exposed infants (Group A, n=20) and nonexposed infants (Group B, n=20) born via CS were limited at day one and seven. However, at twentyeight days, the whole metagenome based microbiome of antibiotic exposed infants from group A consisted of a lower abundance of bifidobacteria compared to the latter group (p< 0•001). In the first month of life evident differences between CS and vaginally born infants (Group C, n=23) were present. The microbiota of CS born infants was characterized by a decreased diversity (p< 0.001), and lower abundancy of Bacteroidetes (p< 0.001) with a concurrent increase in Proteobacteria (p=0.002) in the first month of life, regardless of the timing of antibiotic administration. At three years of age, no differences in microbiota were observed between the three subgroups. Conclusion: We observed that maternal administration of antibiotics during CS according to the revised guidelines leads to disturbance of gut colonization with bifidobacteria in the infant. This has previously been associated with disturbed priming of the immune system, even when these microbial disturbances are restored later in infancy. Our results therefore challenge the statement in the current guidelines that prophylactic maternal prescription of antibiotics prior to CS does not influence infant health.