Around 1,500 women who have had two or more consecutive first-trimester miscarriages will receive either a 14-day course of the antibiotic doxycycline or a placebo, to see whether treating a chronic uterine infection improves their chances of a live birth. Recurrent miscarriage affects roughly 1–2% of couples, and most receive only emotional support because few proven treatments exist. Chronic endometritis—a persistent inflammation of the uterine lining, often linked to an imbalance in the endometrial microbiome—has been proposed as a hidden cause. Small studies suggest antibiotics can clear the inflammation, but no robust trial has confirmed whether this translates into more babies born. If doxycycline proves effective, it would offer the first evidence-based treatment for a substantial subset of women with recurrent miscarriage. The trial’s adaptive design allows early stoppage if the drug works better than expected or proves futile, saving time and resources. A subgroup analysis will also clarify how doxycycline affects the endometrial microbiome and the process of decidualisation—the uterine lining’s preparation for pregnancy—providing mechanistic insight even if the primary outcome is negative.
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Recurrent miscarriage (RM) causes considerable distress and psychological morbidity for women and their partners. The vast-majority of couples only receive supportive care, as few treatments have been shown to prevent miscarriage. There is evidence to suggest chronic endometritis (CE) is a cause of recurrent miscarriage. CE is a chronic inflammation of the endometrium, diagnosed using CD138 immunohistochemistry. The pathophysiology of CE is poorly understood but may be due to chronic infection, secondary to dysbiosis of the endometrial microbiome. Dysbiosis is caused by the presence of an array of microorganisms and a lack of lactobacilli in the endometrium. The endometrial microbiome has been proposed to be distinct from the vaginal microbiome. A comparison of the microbial profile in recurrent implantation failure patients has shown that those with CE have specific species indicative of dysbiosis and poor pregnancy outcomes. Studies have shown that antibiotics can improve CE. The most frequently used antibiotic regime in published studies is doxycycline, in addition, to its antibacterial properties, doxycycline has a well-documented anti-inflammatory effect, raising the possibility that it is useful for the treatment of CE not associated with endometrial dysbiosis. Although antibiotic treatment is available at private clinics and in some European countries, there is no robust evidence to support this approach and the effect of antibiotics on the microbiome is unclear. To find out if doxycycline given prior to conception improves the number of on-going pregnancies and total live births in women who have experienced two or more consecutive first trimester miscarriages, we are undertaking a prospective, multi-centre, randomised, double blind adaptive designed trial. We will compare a pre-conception course of doxycycline (100mg twice daily for 14 days) to placebo in up to 1500 women with recurrent miscarriage associated with CE. Participants will be screened for CE using an endometrial biopsy. Screen positive patients will be eligible for randomisation. The use of adaptive design will allow early stoppage in the case of better than expected efficacy or in the case of futility. Primary outcomes will be on-going pregnancy at 12 weeks and total live births. A sub-group will additionally have endometrial and biopsies swabs taken both before and after intervention to assess the effect of doxycycline on, endometritis, decidualisation and the endometrial microbiome.
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