P-665 Timing of metformin treatment in women with polycystic ovarian syndrome and associated pregnancy outcomes: a systematic review and meta-analysis
Authors: Cheshire J , Garg A , Smith P , Coomarasamy A , Dhillon-Smith R 
Published: June 2023

Abstract

Study question
Does giving women with polycystic ovarian syndrome (PCOS) preconception metformin and continuing it through at least the first trimester improve pregnancy outcomes?

Summary answer
Giving women with PCOS preconception metformin and continuing throughout the first trimester significantly reduces the risk of early miscarriage, and can improve pregnancy outcomes.

What is known already
Metformin, either alone or in combination with other ovulation induction agents, can improve ovulation and clinical pregnancy rates in women with PCOS. Its impact on miscarriage and live birth rate are less well understood. Furthermore the impact of both the timing and duration of metformin treatment on subsequent pregnancy outcomes, in women with PCOS, is unknown. We sought to evaluate the role that preconception metformin, continued until at least the point of positive pregnancy test, may have on pregnancy outcomes in women with PCOS and the effect that stopping metformin once pregnant might have.

Study design, size, duration
We conducted a systematic review and meta-analysis. A search within MEDLINE, Embase and the Cochrane Central Register of Controlled Trials for studies listed from database inception to 13th October 2022 was conducted. Potentially eligible studies identified through other sources (such as the reference lists of the selected primary studies and review articles) were also screened for inclusion. We adopted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) for determining the quality of the evidence.

Participants/materials, setting, methods
The full-text of studies identified as being potentially suitable for inclusion were obtained. Those meeting the study selection criteria, outlined, were included in the systematic review and meta-analysis. Studies were included if they were prospective randomised controlled trials, comparing the use of metformin in women with PCOS, which had been started pre-conceptually and continued at least until pregnant (confirmed urinary pregnancy test), to either placebo or no treatment.

Main results and the role of chance
A total of 12 studies (1517 women) were included in the systematic review and meta-analysis. Women who were given preconception metformin which was continued until at least the end of the first trimester showed a significantly reduced risk of early miscarriage [OR 0.51 95% CI (0.27-0.96), 6 studies, n = 294, I2=0%], compared to either placebo or no treatment. Continuing preconception metformin until at least the end of first trimester also significantly increased clinical pregnancy rates [OR 1.92 95% CI (1.43-2.59), 5 studies, n = 793, I2=67%]. Only 3 studies, looked at live birth outcome which showed an increased odds of live birth in the metformin group, but this was not statistically significant [OR 1.38 95% CI (0.65-2.92), 3 studies, n = 212, I2=0%]. In women who stopped taking metformin following a positive pregnancy test, there was a suggestion of improvement in clinical pregnancy [OR 1.36 95% CI (0.99-1.87), 6 studies, n = 663, I2=45%] and live birth rates [OR 1.15 95% CI (0.57-2.35), 5 studies, n = 244, I2=0%]; but these were not statistically significant. Conversely, there was an increased odds of early miscarriage [OR 1.22 95% CI (0.59-2.52), 6 studies, n = 244, I2=0%], but this was also not statistically significant.

Limitations, reasons for caution
Whilst a role for commencing metformin pre-conceptually and continuing until at least the end of the first trimester has been demonstrated to be effective in improving clinical pregnancy rates and reducing miscarriage risk, the effectiveness and safety of continuing it throughout the remainder of the pregnancy remains unclear.

Wider implications of the findings
Continuing metformin treatment until at least the end of first trimester can increase the clinical pregnancy rate and reduce the risk of miscarriage. Stopping metformin once pregnant could be harmful and increase the risk of miscarriage. These findings should be considered when managing women with PCOS wishing to conceive.

Trial registration number
CRD42017073976