A double-blind multi-centre randomised placebo-controlled trial of doxycycline in women with recurrent miscarriage and chronic endometritis defined by CD138 positive stromal cells.

study questionDoes preconceptual doxycycline prevent miscarriage in women with recurrent miscarriage (RM) and chronic endometritis (CE) defined by CD138+ stromal cells? SUMMARY ANSWER: Preconceptual doxycycline was not associated with improved livebirth rates in women with CE and a history of RM. WHAT IS KNOWN ALREADY: CE is characterised by asymptomatic endometrial inflammation and has been associated with RM. Some national and international RM guidelines advise testing and treating for CE with antibiotics, most commonly doxycycline, whereas others do not. STUDY DESIGN, SIZE, DURATION: Definitions of CE vary widely; in this study, all CD138+ cells, not only morphological plasma cells were included in the assessment. This was an adaptive, multi-centre, parallel-arm, double-blind, placebo-controlled, randomised trial. Recruitment started on January 2020, and follow-up finished on October 2023. Of 2178 women screened, 505 were positive for CD138 and 438 were randomised. A subgroup (202) had repeat endometrial biopsies in the luteal phase of their treatment cycle analysed. A screen negative group (208) were followed up in their first pregnancies. Screen positive women were randomised using an online web tool to preconceptual doxycycline 100 mg or an identical placebo from day 1 of the menstrual cycle, twice daily for 14 days. Patients, their clinicians and outcome assessors were blinded to treatment allocation. PARTICIPANTS/MATERIALS, SETTING,

methodsWomen, aged ≥18 to <42 years with ≥2 consecutive first trimester miscarriages were recruited in specialist RM clinics from 27 UK sites. Screening was by luteal phase endometrial biopsy with immunohistochemistry for CD138. The primary outcome was cumulative live birth and pregnancies ≥24 + 0 weeks gestation at cessation of the trial. Secondary outcomes included first pregnancy outcome, time to first conception and pregnancy complication rates. A prospective Bayesian analysis with no prior information was undertaken to estimate posterior probabilities. MAIN RESULTS AND THE ROLE OF CHANCE: There were 113/219 (52%) cumulative livebirths or ongoing pregnancies in the doxycycline group and 109/219 (50%) in the placebo group (adjusted Relative Risk (aRR)1.02; Credible Interval (CrI) 0.85-1.21). Sensitivity analysis did not influence these results. In the CE negative group, there were 62/208 (30%) livebirths or ongoing first pregnancies compared to 89/219 (41%) in the placebo group (aRR 0.73; CrI 0.56-0.95). The amount and pattern of CD138 staining varied equally before and after placebo (98 paired biopsies) and doxycycline (104 paired biopsies) treatments. LIMITATIONS, REASONS FOR CAUTION: In keeping with the adaptive Bayesian design, the trial was stopped at interim analyses. Whilst a higher-than-expected prevalence of CD138+ CE occurred in this study, a sensitivity analysis increasing the diagnostic threshold did not alter the findings. The second biopsies occurred within the treatment menstrual cycle; hence, we did not exclude a difference in CD138+ CE after menstruation. A few participants obtained additional doxycycline; however, a sensitivity analysis excluding these showed no difference in outcome. WIDER IMPLICATIONS OF THE

findingsNeither the primary nor secondary outcome measures supported the use of doxycycline in the management of CD138+ CE in this first placebo-controlled trial. Similar differences in CD138 expression before and after placebo or doxycycline suggesting inter-cycle variation may account for previously reported findings.

fundingThis study was funded by the Efficacy and Mechanism Evaluation Programme, a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership (Funder reference: 17/60/22). DISCLOSURES: All authors declare no competing interests. TRIAL REGISTRATION NUMBER: ISRCTN 2394773 https://doi.org/10.1186/ISRCTN23947730. TRIAL REGISTRATION DATE: 12 September 2019. DATE OF FIRST PATIENT’S ENROLMENT: 3 January 2020.