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

Background: To reduce the risk of maternal infections, revised guidelines for caesarean section (CS) now advise maternal antibiotic administration prior to skin incision instead of after cord clamping. Unintentionally, this results in perinatal exposure to antibiotics in all CS born neonates. Aim of this study is to investigate the effect of timing of maternally administered antibiotics during CS on the infant microbiome. Methods: In this randomized controlled trial, women scheduled for an elective CS received antibiotics 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 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. Findings: Differences between intrauterine antibiotic exposed infants (n=20) and non-exposed infants (n=20) born via CS were limited at day one and seven. However, at twenty-eight days, the whole metagenome based microbiome of infants from the former group consisted of a lower abundance of bifidobacteria compared to the latter (p<0·001). In the first month of life evident differences between CS and vaginally born infants (n=23) were present. At three years of age, no differences in microbiota were observed between the three subgroups. Interpretation: 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.Funding: Danone Nutricia Research. Trial Registration Number: The trial is registered with https://www.trialregister.nl/, NTR6000. Funding: Danone Nutricia Research. Conflict of Interest: All authors have completed the Conflict of Interest Statement fromhttps://www.thelancet.com/for-authors/forms?section=icmje-coi and declare: financial support from Danone Nutricia Research for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. NKH de Boer has served as a speaker for AbbVie and MSD. He has served as consultant and/orprincipal investigator for TEVA Pharma BV and Takeda. He has received a (unrestricted)research grant from Dr. Falk, TEVA Pharma BV and Takeda. The other authors have nofinancial disclosures that would be a potential conflict of interest. All authors declare no conflict of interest. Ethical Approval: The study protocol of this study (NTR6000)8 was approved by the local medical ethical committee (2014.468). Written informed consent for participation was obtained from all parents.