Effect of clindamycin and a live biotherapeutic on the reproductive outcomes of IVF patients with abnormal vaginal microbiota: protocol for a double-blind, placebo-controlled multicentre trial

Abstract

IntroductionRecent studies in in vitro fertilisation (IVF) patients have associated abnormal vaginal microbiota (AVM) with poor clinical pregnancy rates of 6%–9% per embryo transfer. The biological plausibility for this finding is hypothesised to be ascending infection to the endometrium which in turn hampers embryo implantation. New molecular based diagnosis may offer advantages compared to microscopical diagnosis of AVM which has huge inter-study variability ranging from 4 to 38%; however, the important question is whether screening and treatment of AVM would improve reproductive outcomes in IVF patients. Herein, we describe a protocol for an ongoing double-blind, placebo-controlled multicentre trial of IVF patients diagnosed with AVM and randomised in three parallel groups 1:1:1.Methods and analysisThis is a drug intervention study where IVF patients will be screened for AVM, using a qPCR assay targeting Atopobium vaginae and Gardnerella vaginalis. If positive, patients will be randomised to one of the three study arms. The first arm consists of clindamycin 300 mg ×2 daily for 7 days followed by vaginal Lactobacillus crispatus CTV-05 until clinical pregnancy scan week 7–9. The second arm consists of clindamycin and placebo L. crispatus CTV-05, whereas patients in the third arm will be treated with placebo/placebo. We used a superiority design to estimate that active treatment in both arms will increase the primary outcome, clinical pregnancy rate per embryo transfer, from 20% to 40%. A potential difference between the two active arms was considered exploratory. With a power of 80% and an alpha at 5%, the sample size is estimated to be 333 patients randomised. A pre-planned interim analysis is scheduled at 167 patients randomised.Ethics and disseminationAll patients have to give informed consent. Dissemination of results is ensured in clinical trial agreements whether they be positive or not. Ethics committee, Central Denmark Region approved this protocol.Trial registration numberICH-GCP monitored trial, EudraCT 2016-002385-31; Pre-results.

The Association between Vaginal Dysbiosis and Reproductive Outcomes in Sub-Fertile Women Undergoing IVF-Treatment: A Systematic PRISMA Review and Meta-Analysis

“…Previously, it was assumed that the endometrium was a sterile cavity, but recent studies suggest the opposite—i.e., that bacteria are present in the endometrium [ 4 , 6 ]. This has led to the hypothesis that vaginal bacteria may ascend into the endometrium and, thus, affect reproduction [ 7 ]. Although the genital tract microbiota is a complex ecosystem of more than 200 different bacterial species [ 8 ], it is commonly accepted that a healthy genital tract microbiota is dominated by facultative anaerobic Lactobacillus spp., i.e., a Lactobacillus dominant (LD) microbiota [ 9 ].…”

Effect of L. crispatus M247 Administration on Pregnancy Outcomes in Women Undergoing IVF: A Controlled, Retrospective, Observational, and Open-Label Study

“…In fact, the trial was performed using a probiotic product containing strains of L. gasseri and L. rhamnosus. A double-blind, placebo-controlled, multicentre trial to evaluate the reproductive outcomes of IVF patients with abnormal vaginal microbiota treated with the likely most investigated strain of L. crispatus (strain CTV-05) is currently ongoing [31].…”