Efficacy of the combination of antimicrobial therapy with immunomodulators in the management of immunological female infertility due to anti-sperm antibodies associated with bacterial vaginosis during unexplained infertility: double-blind factorial randomised controlled trial

Abstract

BACKGROUND: Unexplained infertility (UI) is a subject of major concern in reproduction and can be associated with bacterial vaginosis (BV) and/or antisperm antibodies (ASA), yet therapeutic strategies for these conditions in resource-limited settings are poorly defined. This study aimed to evaluate the efficacy of immunomodulators compared with placebo following antimicrobial therapy among infertile women with UI linked to ASA and BV. METHODS: This double-blind, 2 × 3 factorial randomised controlled trial was conducted at a tertiary referral hospital in Kisangani, Democratic Republic of the Congo. 123 women with UI, positive ASA, and BV were randomised to receive either metronidazole alone or combined antimicrobial therapy (metronidazole, clotrimazole, and clindamycin) for Factor 1, followed by prednisolone, zinc acetate, or placebo (paracetamol 100 mg) for Factor 2. The primary outcome was time to clinical pregnancy within six months, analysed in the modified intention-to-treat population as a time-to-event endpoint using Kaplan-Meier methods, the log-rank test, and Cox proportional hazards models. The study protocol was initially approved by the provincial health district ethics committee (701/FBL/DPS/TSHOPO/SEC/0173/2023). The trial has been retrospectively registered with the Pan African Clinical Trials Registry on 08 October 2024 under the identifier PACTR202410672612184. RESULTS: Among 123 participants, immunomodulators significantly increased clinical pregnancy rates compared with placebo (38.55% vs. 12.5%; aHR = 3.43 [1.34-8.81]; p = 0.010). Adjusted analyses showed significantly higher pregnancy rates for both zinc acetate (40.48%; aHR 3.46 [1.27-9.40]; p = 0.012) and prednisolone (36.59%; aHR 2.75 [1.01-7.68]; p = 0.027) compared with placebo, with no significant difference between the two active agents (p = 0.623). Combined antimicrobial therapy was superior to metronidazole alone in achieving therapeutic BV cure at visit 2 (58.06% vs. 37.7%; RR 1.52 [1.04-2.22]; p = 0.023) and, at the margins of the factorial design, was associated with a higher cumulative conception rate (aHR 2.20 [1.09-4.43]; p = 0.027). The Factor 1 × Factor 2 interaction was not statistically significant (likelihood-ratio p = 0.59). While the overall incidence of adverse events was comparable between zinc (16.67%) and prednisolone (21.95%) (p = 0.541), zinc acetate was associated with significantly higher patient-reported tolerance (p = 0.007). CONCLUSION: Sequential treatment involving combined antimicrobial therapy followed by immunomodulation significantly improves clinical pregnancy rates in women with UI associated with BV and ASA. Zinc acetate offers an effective and better-tolerated alternative to prednisolone for this indication.