Timing of progesterone treatment to prevent preterm birth in pregnancies with a short cervix: A population-based historical cohort study.

Introduction: Randomized trials have shown that progesterone treatment in mothers with a short cervix may reduce the risk of preterm birth, but the optimal time window for treatment remains unknown. We aimed to investigate progesterone treatment for the prevention of preterm birth by gestational age at diagnosis and initiation of treatment.

Material and methods: This was a population-based historical cohort study of 1162 mothers with singleton pregnancies diagnosed with a cervix <20 mm from 16 to 31 gestational weeks receiving progesterone treatment (n = 390) or no preventive treatment (n = 772). Data were collected from the Medical Birth Registry of Norway from 2014 to 2020 and linked to national health registries providing demographic, diagnostic, and prescription information. Risks of preterm birth <28, <34, and <37 gestational weeks were compared between mothers with and without progesterone treatment in the full study sample and in three periods of gestational age at diagnosis (16-21, 22-27, and 28-31 weeks) using log-binomial regression analyses.

Results: The absolute risk of preterm birth <28 gestational weeks was 0.8% in mothers treated with progesterone and 3.4% in mothers who did not receive treatment (adjusted relative risk (aRR) 0.25, 95% confidence interval (CI) 0.08-0.81). The strongest protective association was observed in mothers diagnosed from 16 to 21 weeks (aRR 0.13, 95% CI 0.02-0.98). Preterm birth <34 weeks occurred in 8.7% of mothers in the progesterone group and 11.1% in the untreated group (aRR 0.80, 95% CI 0.54-1.17), and the relative risk reduction associated with treatment diminished with increasing gestational age at diagnosis: aRR 0.27 (95% CI 0.08-0.96) from 16 to 21 weeks; aRR 0.68 (95% CI 0.38-1.23) from 22 to 27 weeks; and aRR 1.30 (95% CI 0.71-2.39) from 28 to 31 weeks. There was no difference in the risk of birth <37 weeks in mothers treated with progesterone (23.1%) and untreated mothers (22.3%), and the risk estimates were similar in the three periods of gestational age at diagnosis.

Conclusions: Compared to no treatment, progesterone treatment is associated with a reduced risk of preterm birth <28 gestational weeks in pregnancies with a short cervix. The preventive effect of treatment may extend to 34 weeks if treatment is initiated early in the second trimester.