First-trimester metformin use linked to pregnancy outcomes in PCOS patients

In a recent study published in the American Journal of Obstetrics & Gynecology, continuing preconception metformin through the first trimester was associated with greater clinical pregnancy rates and a signal toward fewer miscarriages compared with placebo or no treatment, while discontinuation at pregnancy confirmation was linked to different outcome patterns.¹

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age and is associated with ovulatory dysfunction, hyperandrogenism, and polycystic ovarian morphology.² Women with PCOS frequently experience insulin resistance, obesity, and metabolic syndrome and have increased risks of infertility and adverse pregnancy outcomes.¹ Miscarriage risk is elevated in this population, with previously reported odds ratios of 11.98 (95% CI, 10.34–13.87; P < .001) compared with women without PCOS.

"Metformin, either alone or in combination with other... agents, can improve ovulation and clinical pregnancy rates, although its overall effect on live birth rate is less clear," wrote investigators.

Assessing outcomes after metformin use

A systematic review and meta-analysis evaluated whether the timing of metformin use before and during early pregnancy influenced pregnancy outcomes in women with PCOS. The study specifically compared women who began metformin before conception and either discontinued it after a positive pregnancy test or continued it through at least the first trimester, with women receiving placebo or no treatment.

Investigators searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from database inception through August 1, 2024. Eligible studies were prospective randomized controlled trials that enrolled women diagnosed with PCOS according to Rotterdam criteria and compared preconception metformin with placebo or no treatment.

A total of 826 records were screened, and 15 studies met eligibility criteria for the systematic review. Three studies were judged untrustworthy based on trial registration concerns and were excluded from quantitative synthesis. Twelve trials involving 1708 women were included in the meta-analysis. Data on miscarriage were available from 10 studies (1338 women), clinical pregnancy from 11 studies (1701 women), and live birth from 8 studies (1265 women).

Miscarriage and clinical pregnancy trends

Studies were conducted across 14 countries on 5 continents. Nine trials enrolled women undergoing ovulation induction, 3 enrolled women undergoing assisted reproductive technology, and 2 enrolled mixed populations. Metformin doses ranged from 1000 to 2550 mg/day. In 9 studies including 1233 women, metformin was stopped after pregnancy confirmation. In 6 studies including 762 women, metformin was continued through the first trimester.

For miscarriage, continuation of metformin through the first trimester was associated with a lower odds ratio compared with placebo or no treatment (OR, 0.64; 95% CI, 0.32–1.25; I² = 0%; 4 studies; 544 women; low-quality evidence). In contrast, discontinuation of metformin after a positive pregnancy test was associated with a higher odds ratio for miscarriage compared with placebo or no treatment (OR, 1.46; 95% CI, 0.73–2.90; I² = 0%; 6 studies; 794 women; low-quality evidence).

Clinical pregnancy rates were greater among women who continued metformin through the first trimester compared with placebo or no treatment (OR, 1.57; 95% CI, 1.11–2.23; I² = 19%; 3 studies; 537 women; moderate-quality evidence). An increase in clinical pregnancy was also observed among women who discontinued metformin after pregnancy confirmation compared with placebo or no treatment (OR, 1.35; 95% CI, 1.01–1.80; I² = 27%; 8 studies; 1164 women; low-quality evidence).

Live birth outcomes showed a trend toward higher rates in women who continued metformin through the first trimester (OR, 1.24; 95% CI, 0.59–2.61; I² = 0%; 2 studies; 471 women; moderate-quality evidence). A smaller effect was observed in women who discontinued metformin after pregnancy confirmation (OR, 1.09; 95% CI, 0.55–2.18; I² = 0%; 6 studies; 794 women; low-quality evidence).

Clinical implications

Indirect comparisons were performed to evaluate the relative effects of continuation versus discontinuation of metformin. These analyses suggested a lower odds of miscarriage (OR, 0.44; 95% CI, 0.17–1.16) and greater odds of clinical pregnancy and live birth with continued therapy, although confidence intervals were wide.

Overall, this systematic review and meta-analysis found that the timing of metformin use in women with PCOS was associated with differences in pregnancy outcomes, with continuation of metformin through the first trimester linked to greater clinical pregnancy rates and a signal toward lower miscarriage risk, compared with placebo or no treatment.

"Future research could look at the benefit of continuing metformin until the end of the pregnancy. In addition, studies on specific PCOS phenotypes are required to better target PCOS subsets in which preconception and first-trimester metformin may be of most benefit," wrote investigators.

References

1. Cheshire J, Garg A, Smith P, Devall AJ, Coomarasamy A, Dhillon-Smith RK. Preconception and first-trimester metformin on pregnancy outcomes in women with polycystic ovary syndrome: a systematic review and meta-analysis. American Journal of Obstetrics & Gynecology. 2025;233(6):530-547. doi:10.1016/j.ajog.2025.05.038
2. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertility and Sterility. 2004;81(1):19-25. doi:10.1016/j.fertnstert.2003.10.004