Abstract
Study question
Is there an association between the composition of the endometrial microbiota and the reproductive outcomes in infertile patients undergoing in vitro fertilization (IVF)?
Summary answer
The composition of the endometrial microbiota (EM) prior to embryo transfer is associated with the different reproductive outcomes: live birth, no pregnancy or clinical miscarriage.
What is known already
The investigation of bacterial communities in the female reproductive tract using molecular methods has revealed the existence of a continuum microbiota that extends from the vagina to the upper genital tract.
Previous evidence suggests the existence of an association between the vaginal and endometrial microbiome composition with reproductive and obstetrical outcomes. Specifically, the presence of specific pathogens together with low abundance of Lactobacilli has been associated with poor IVF outcomes.
Study design, size, duration
Multicentre prospective observational clinical study analysing the EM of infertile patients undergoing IVF (with maternal age ≤40) or ovum donation (≤50 years). A total of 452 infertile patients undergoing IVF/ovum donation were assessed for eligibility in 13 reproductive clinics in Europe, America, and Asia. The duration of the study was 30 months and the recruitment period extended between August 2017 and February 2019 (ct.gov 03330444).
Participants/materials, setting, methods
Endometrial fluid and endometrial biopsy were collected during a hormonal replacement therapy cycle after 5 days of progesterone (P) administration prior to a frozen embryo transfer cycle. Endometrial microbiota (EM) composition was analyzed using 16S rRNA gene sequencing using compositional data to transform scale-invariant values in both sample types. The EM in fluid and biopsy was associated with live birth, biochemical pregnancy, clinical miscarriage, or no pregnancy.
Main results and the role of chance
Of the 452 patients assessed, 44 did not meet the selection criteria and were excluded for the study and 66 patients were lost to follow-up. Of the 342 remaining patients, 198 (57.9%) became pregnant [141 (41.2%) had a live birth, 27 (7.9%) had a biochemical pregnancy, 2 (0.6%) had an ectopic pregnancy, and 28 (8.2%) a clinical miscarriage], while 144 (42.1%) did not become pregnant. The baseline characteristics, clinical and embryological variables were homogeneous and no bias toward the clinical outcome categories was observed.
Our association study showed that the composition of the EM was associated with the reproductive outcome in both endometrial fluid and biopsy. A dysbiotic endometrial microbiota profile composed of Atopobium, Bifidobacterium, Chryseobacterium, Gardnerella, Haemophilus, Klebsiella, Neisseria, Staphylococcus and Streptococcus was significantly associated with unsuccessful outcomes, especially no pregnancy and clinical miscarriage. In contrast, Lactobacillus was consistently enriched in patients with live birth outcomes. The EM in endometrial fluid did not fully reflect that in endometrial biopsy, although their association with clinical outcome was consistent.
Limitations, reasons for caution
The main limitation was the small number of biochemical pregnancy and clinical miscarriage analysed. During transcervical collection of endometrial samples caution was taken to avoid contamination with the cervix although cervical contamination cannot be fully discarded.
Wider implications of the findings
Our data indicate that EM dysbiosis is associated with poor clinical outcome in ART. Thus, the EM composition before embryo transfer could be a useful biomarker to consider offering an opportunity to further improve diagnosis and treatment strategies.
Trial registration number
Clinical trials.gov 03330444
Endometrial microbiota composition is associated with reproductive outcome in infertile patients
