Preconception and first trimester metformin on pregnancy outcomes in women with polycystic ovary syndrome: a systematic review and meta-analysis.

Abstract

Objective: To explore the effects of preconception and first trimester metformin use on pregnancy outcomes in women with polycystic ovary syndrome (PCOS).

Data sources: MEDLINE, Embase and the Cochrane Central Register of Controlled Trials were searched from database inception to August 1^st 2024.

Study eligibility criteria: Randomised controlled trials of metformin started preconception and continued at least until a positive pregnancy test compared to either placebo or no treatment in women with PCOS were included.

Methods: A systematic review and meta-analysis were performed. Pooled odds ratio (OR) with 95% confidence intervals (CI) were calculated for key outcomes: miscarriage (primary) and clinical pregnancy and live birth (secondary). Studies were assessed for quality using the Cochrane risk-of-bias tool for randomised trials (RoB-2) and Grading of Recommendations, Assessment, Development and Evaluation approach. Indirect comparisons were performed for all key outcomes, on the timing of metformin treatment, using the Bucher's technique.

Results: A total of 12 trustworthy studies (1,708 women) were included in the meta-analysis; all graded low to moderate quality. Women who received preconception metformin which was continued throughout the first trimester showed higher clinical pregnancy rates (OR 1.57, 95% CI 1.11-2.23), a possible reduction in miscarriage (OR 0.64, 95% CI 0.32-1.25) and possible increase in live birth (OR 1.24, 95% CI 0.59-2.61), compared to either placebo or no treatment. In women who stopped metformin once pregnant, there was an increase in clinical pregnancy rate (OR 1.35, 95% CI 1.01-1.80), but also a suggestion of an increase in miscarriage rate (OR 1.46, 95% CI 0.73-2.90), compared to placebo or no treatment. Indirect comparisons of metformin continued through first trimester vs metformin stopped once pregnant consistently demonstrated a trend favouring the continuation of metformin: clinical pregnancy OR 1.16 (95% CI 0.74-1.83), miscarriage OR 0.44 (95% CI 0.17-1.16) and live birth OR 1.14 (95% CI 0.41-3.13).

Conclusions: Continuing metformin treatment throughout the first trimester may reduce the risk of miscarriage and may increase live birth rates in women with PCOS. Continuation of metformin appears to have greater clinical benefit than stopping at positive pregnancy test. There is a need for further high-quality research.