Marilen Benner

CHAPTER 8 228 combining copy numbers from qPCR and 16S rRNA gene amplicon sequencing showed detectable reads above potential background noise and negative controls (90, 91). The example of Lactobacilli (e.g. L.iners or L.crispatus ), identified as dominant by some (92-94), or as rare to absent by others (91) underlines how a joint, standardized effort might be needed to unite the side of researchers who support the notion that uterine microbiota deserve to be studied. Multicentered studies with strict guidelines regarding all steps from cohort selection to sampling, sample processing to analysis, are needed to credibly replace the concept of the sterile womb by the definition of a healthy endometrial microbiome. Recent investigations showing an altered microbial profile prior to RPL, or in case of IUGR, support the notion that, whether as cause or consequence, varying uterine microbiota profiles are associated with different reproductive outcomes (94, 95). Increasing knowledge on a healthy endometrial microbiome, prior to pregnancy, might lead to treatment options for women struggling to conceive. Diet and medication can steer a microbial profile (96-100). The beneficial effect of interfering with microbiota to improve reproductive outcome can be illustrated by bacterial vaginosis, an imbalance of the vaginal flora correlating with poor reproductive outcome (101, 102). Its association with PTB can be counteracted with antibiotic intervention, if occurring in the first half of gestation (103). The importance of timing reflects that healthy pregnancy is determined in its early stages. The altered immunological profile observed in menstrual blood of RPL patients (Chapter 5) might (for some individuals) be connected to an unfavorable microbial profile. In that case, proper diagnosis might offer therapeutic options. 16S rRNA sequencing becomes increasingly accessible, and currently, self-testing of vaginal microbiota is already commercially available to predict ART success (104-106). As there is only limited overlap between uterine microbiota and the vaginal microbiome (90, 92), including the immune profile of menstrual blood, or sampling endometrial microbiome directly (although warranting a professional approach rather than at-home swabs) might offer improved prediction of reproductive outcome or pinpoint treatment targets. MANIPULATING MICROBIOTA: CHANCES AND THREATS As shown by the example of successful reduction of PTB risk in case of bacterial vaginosis, treating antibiotic disbalance to improve reproductive outcome is tempting to consider. Indeed, antibiotic treatment can alter endometrial microbiota (107). However, antibiotic intervention around the time of, or after, conception needs to be treated extremely carefully. A central theme of this thesis is how reproductive immunology relies on well-balanced, connected mechanisms, and, as such, any interference can be detrimental. However, in many cases, gestational use of antibiotics cannot be avoided as progression of an infection would be detrimental to mother and child. Urinary tract infections (UTI) are one of the most common pregnancy complications (108).