Prevention of recurrent spontaneous preterm delivery using probiotics: results from a prospective, single-arm, multicenter trial.

Abstract

The rate of recurrent spontaneous preterm delivery is 30% (95% confidence interval, 27%-34%) globally and 22.3% in Japan. Probiotics containing Clostridium species may reduce spontaneous preterm delivery by inducing regulatory T cells, which play an important role in maintaining pregnancy. We investigated whether the administration of probiotics including Clostridium butyricum prevented recurrent spontaneous preterm delivery in high-risk pregnant women. We conducted a prospective, single-arm, nonblinded, multicenter trial across 31 hospitals in Japan between May 2021 and October 2024. Pregnant women (aged 18-43 years) with a history of spontaneous preterm delivery received oral probiotics (Clostridium butyricum [10 mg/tablet], Enterococcus faecium [2 mg/tablet], and Bacillus subtilis [10 mg/tablet]) from 10 to 14 weeks to 36 weeks 6 days of gestation. The primary endpoint was the rate of recurrent spontaneous preterm delivery at <37 weeks, compared against the historical rate of 22.3% from Japan's national perinatal database. The rate of spontaneous preterm delivery before 34 weeks and neonatal outcomes among spontaneous preterm delivery were evaluated as secondary outcomes. Recurrent spontaneous preterm delivery before 28 weeks was evaluated among women with a history of spontaneous preterm delivery before 28 weeks. Among 343 enrolled patients, 315 (91.8%) were included in the analysis. The recurrence rate of spontaneous preterm delivery at <37 weeks was 14.9% (47/315; 95% confidence interval, 11.2%-19.3%), which was significantly lower than the historical rate (P=.0013). The secondary endpoint analysis showed that the rate of spontaneous preterm delivery before 34 weeks was 3.5% (11/315; 95% confidence interval, 1.8%-6.2%). Among women with a history of extreme preterm delivery (<28 weeks), the rate of recurrent spontaneous preterm delivery before 28 weeks was 1.5% (1/65; 95% confidence interval, 0.0%-8.3%). There were no stillbirths, defined as fetal death at or after 22 weeks of gestation. No serious adverse events, defined as events resulting in death or persistent disability, were reported, and the incidence of nonserious adverse events was consistent with expectations. In this prospective study, oral administration of probiotics was associated with a lower recurrence rate of spontaneous preterm delivery compared with nationally reported historical rate. These findings suggest that this approach may be a potential strategy to reduce recurrent spontaneous preterm delivery and should be further evaluated in a controlled trial.