gms | German Medical Science

Background: The global rate of Caesarean section (CS) is 21.1 % (2021) and is rising worldwide. CS presents the third highest cumulative incidence for surgical site infections. Maternal infections around the time of childbirth account for 1 out of 10 maternal deaths worldwide. Therefore, perioperative antibiotic prophylaxis (PAP) during CS is common standard of care and part of numerous recommendations from expert bodies such as the World Health Organization (WHO) and different national gynecological professional associations. According to these, first and second generation cephalosporins like cefuroxime are the agents of choice for this indication. In fact, the use of PAP significantly reduces maternal morbidity and mortality rates. Whereas the side effect of this measure on the microbiome of the newborn has been the subject of repeated clinical studies, data on specific and especially long-term effects on the gut microbiome of the mothers are still lacking. MAMA is the first study to specifically and systematically investigate this question.

Materials and Methods: This multicenter, two-arm, non-interventional, observational study analyzes the qualitative and quantitative changes in the gut microbiome of mothers at birth due to antibiotic prophylaxis with cefuroxime. We recruited pregnant women from two level 1 perinatal centers in Germany and from outpatient facilities. Women with C-section were recruited for the study group, women with vaginal birth and without use of antibiotics as control. They gave their informed consent to participate in the study after a detailed consultation with the study coordinator. Each participant submitted three stool samples (T0, T1, T2) for microbiome analysis. Stool samples were collected by the participant following a detailed description and using “DNA/RNA ShieldTM Fecal Collection Tube – DX” by Zymo Research to prevent quality loss during postal transport. Collection took place at home or in the hospital, in case of prolonged inpatient treatment after delivery. Required metadata was collected via questionnaires. Stool samples and questionnaires were then sent back to the study coordinator. Thus, no additional on-site visits were required.

The taxonomic identification and quantification of the microbiome is performed by sequencing the 16S rRNA gene (V3-V4). The biostatistical analysis includes OTU clustering as well as determination of α- and β-diversity. The changes in the microbiome (diversity, frequency, variance) of the study groups will show whether and which permanent (> 3 months) changes in the intestinal microbiome are caused by PAP with cefuroxime in mothers at birth. In particular, the (new) occurrence of potentially pathogenic species (induced dysbiosis) and changes in the physiological flora will be investigated, as women towards the end of pregnancy have an especially vulnerable microbiome. Permanent dysbiosis can be a risk factor for gestational diabetes in subsequent pregnancies.

Ethical approval for the study was granted by the ethics committee of Witten/Herdecke University (vote 274-2021).

The study is registered at the International Clinical Trials Registry Platform (ICTRP) under DRKS00027305.

Results: In the two-year recruitment phase, a total of 37 participants were included, 13 of whom completed participation according to the study protocol: 7 in the CS group and 6 in the control group. 18 women were lost to follow-up, 6 participants had to be excluded because they no longer met the inclusion criteria during the course of the study.

We will first determine a baseline microbiome prior to delivery (time point T0) and then analyze as well as compare its changes due to delivery (control group) or to antibiotic prophylaxis (CS group).

We expect the occurrence of induced dysbiosis in the CS group at time point T1, i.e. reduced α-diversity, decrease of beneficial gut bacteria, possible (new) emergence of potentially pathogenic species, including Clostridioides, increase of Enterobacteriaceae such as Enterococcus species. For the first time, however, we will be able to observe this effect specifically in women in the peripartum period and also to precisely describe it quantitatively and qualitatively by comparison with the control group. The latter is also crucial for the assessment of recolonization at time point T2. We will show for the first time whether and which long-term consequences the single shot antibiotic prophylaxis with cefuroxime causes in women giving birth.

Conclusion: MAMA shows that even for established methods (PAP in gynecology) not all clinically relevant aspects have yet been scientifically investigated. There is still need for further research in this area. Our study is also a successful example of cooperation between different healthcare professions (pharmacists, doctors, nurses) as well as medical care and research institutions. In this way, we demonstrate in an exemplary manner how translational research improves medication therapy and patient safety in an especially vulnerable group.