The Effectiveness of Metformin in Reducing the Risk of Preeclampsia in Patients with Polycystic Ovary Syndrome (PCOS) : A Systematic Review
Keywords:
Metformin, Polycystic Ovary Syndrome (PCOS), Preeclampsia, Pregnancy, Randomized Controlled TrialAbstract
Introduction: Polycystic Ovary Syndrome (PCOS) affects a significant proportion of women of reproductive age and is associated with an elevated risk of adverse pregnancy outcomes, including preeclampsia (PE). Metformin, an insulin sensitizer, has been proposed as a potential intervention to reduce this risk. However, the evidence regarding its effectiveness in preventing PE specifically in pregnant women with PCOS remains inconsistent.
Methods: This study conducted a systematic synthesis of evidence from 41 sources, including major randomized controlled trials (RCTs) etc. The primary outcome was the incidence of preeclampsia. Secondary outcomes included early pregnancy loss, preterm delivery, gestational diabetes mellitus (GDM), and gestational weight gain. A methodological quality assessment was performed, distinguishing between evidence from RCTs and non-randomized studies.
Results: The findings were discordant. Non-randomized studies reported a significant reduction in PE risk with metformin (e.g., Zheng et al., 2013: OR 0.53; Zhao & He, 2022: RR 0.61). However, analyses restricted to high-quality RCTs found no significant benefit. In the PregMet trial (Vanky et al., 2010), PE rates were 7.4% in the metformin group vs. 3.7% in the placebo group (p=0.18). The PregMet2 trial (Løvvik et al., 2019) also found no significant reduction. A meta-analysis of PCOS-specific RCTs (Nascimento et al., 2018) produced a pooled RR of 1.96 (0.81–4.77), trending toward harm. Conversely, consistent benefits were observed for secondary outcomes, including reduced early pregnancy loss, preterm delivery, and gestational weight gain.
Discussion: The discrepancy between study designs highlights the risk of selection bias and confounding in non-randomized studies. Women who continue metformin throughout pregnancy may differ systematically from controls. While metformin improves metabolic parameters and reduces weight gain, the highest-quality evidence from placebo-controlled RCTs does not support its use for preeclampsia prevention in PCOS. The drug may reduce pregnancy-induced hypertension but not the specific pathophysiology of PE.
Conclusion: Current high-level evidence does not support a clinically meaningful reduction in preeclampsia risk with metformin in pregnant women with PCOS. However, metformin is beneficial for reducing other maternal complications, such as preterm delivery and miscarriage. Future research should focus on specific high-risk PCOS phenotypes.
References
Vanky E, Stridsklev S, Heimstad R, et al (2010) Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. Journal of Clinical Endocrinology and Metabolism. https://doi.org/10.1210/jc.2010-0853
Løvvik T, Carlsen S, Salvesen Ø, et al (2019) Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial. The Lancet Diabetes and Endocrinology. https://doi.org/10.1016/S2213-8587(19)30002-6
Nascimento IB, Dienstmann G, Souza MLR de, et al (2018) Evaluation of Preeclampsia Results after Use of Metformin in Gestation: Systematic Review and Meta-analysis. Gynecologie et obstetrique. https://doi.org/10.1055/s-0038-1675214
Alqudah A, McKinley MC, McNally R, et al (2018) Risk of pre‐eclampsia in women taking metformin: a systematic review and meta‐analysis. Diabetic Medicine. https://doi.org/10.1111/dme.13523
Zheng J, Shan P, Gu W (2013) The efficacy of metformin in pregnant women with polycystic ovary syndrome: A meta-analysis of clinical trials. Journal of Endocrinological Investigation. https://doi.org/10.3275/8932
Zhao Q, He J (2022) Efficacy and safety of metformin in pregnant women with polycystic ovary syndrome: a systematic review with meta-analysis of randomized and non-randomized controlled trials. Gynecological Endocrinology. https://doi.org/10.1080/09513590.2022.2080194
Ghazeeri G, Nassar A, Younes Z, Awwad J (2012) Pregnancy outcomes and the effect of metformin treatment in women with polycystic ovary syndrome: an overview. Acta Obstetricia et Gynecologica Scandinavica. https://doi.org/10.1111/j.1600-0412.2012.01385.x
Palomba S, Seminara G, Costanzi F, et al (2025) Is metformin effective and safe during pregnancy in women with PCOS? An overview of reviews. Expert Review of Endocrinology & Metabolism. https://doi.org/10.1080/17446651.2025.2574334
Zhu D, Chen Y, Huang J, et al (2022) Effects of metformin on pregnancy outcome, metabolic profile, and sex hormone levels in women with polycystic ovary syndrome and their offspring: a systematic review and meta-analysis. Annals of Translational Medicine. https://doi.org/10.21037/atm-22-909
Saadati S, Mason T, Godini R, et al (2025) Metformin use in women with polycystic ovary syndrome (PCOS): Opportunities, benefits, and clinical challenges. Diabetes, obesity and metabolism. https://doi.org/10.1111/dom.16422
Feng L, Lin X, Wan Z, et al (2015) Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: a meta-analysis. Gynecological Endocrinology. https://doi.org/10.3109/09513590.2015.1041906
Tan X, Li S, Chang Y-L, et al (2016) Effect of metformin treatment during pregnancy on women with PCOS: a systematic review and meta-analysis. Clinical and investigative medicine Medecine clinique et experimentale. https://doi.org/10.25011/CIM.V39I4.27091
Vanky E, Zegher F de, Díaz M, et al (2012) On the potential of metformin to prevent preterm delivery in women with polycystic ovary syndrome – an epi‐analysis. Acta Obstetricia et Gynecologica Scandinavica. https://doi.org/10.1111/aogs.12015
Kanda S, Chatha U, Odoma V, et al (2023) Effect of Metformin (MTF) Intervention During Pregnancy in Women With Polycystic Ovarian Syndrome (PCOS): A Systematic Review. Cureus. https://doi.org/10.7759/cureus.44166
Alimohammadi S, Ghasemi E, Mohsenpour Z, Mohsenpour F (2020) Investigating the Impact of Metformin Consumption on the Incidence of Gestational Diabetes and Preeclampsia in Pregnant Women Suffering Polycystic Ovary Syndrome: A Clinical Trial Study. International Journal of Pediatrics. https://doi.org/10.22038/IJP.2020.45710.3737
Hameed AA, Shreif HE, Mowafy HE (2011) The role of continuing metformin therapy during pregnancy in the reduction of gestational diabetes and improving pregnancy outcomes in women with polycystic ovary syndrome. Middle East Fertility Society Journal. https://doi.org/10.1016/J.MEFS.2011.04.002
Jamal A, Milani F, Al-Yasin A (2012) Evaluation of the effect of metformin and aspirin on utero placental circulation of pregnant women with PCOS. Iranian Journal of Reproductive Medicine
Tarry-Adkins J, Ozanne S, Aiken C (2020) Impact of metformin treatment during pregnancy on maternal outcomes: a systematic review/meta-analysis. Scientific Reports. https://doi.org/10.1038/s41598-021-88650-5
Stridsklev S, Carlsen S, Salvesen Ø, et al (2014) Midpregnancy Doppler ultrasound of the uterine artery in metformin- versus placebo-treated PCOS women: a randomized trial. Journal of Clinical Endocrinology and Metabolism. https://doi.org/10.1210/jc.2013-3227
Ujvari D, Trouva A, Hirschberg AL, Vanky E (2023) Maternal serum levels of prokineticin-1 related to pregnancy complications and metformin use in women with polycystic ovary syndrome: a post hoc analysis of two prospective, randomised, placebo-controlled trials. BMJ Open. https://doi.org/10.1136/bmjopen-2023-073619
Zeng X, Zhang Y, Tian Q, et al (2016) Effects of metformin on pregnancy outcomes in women with polycystic ovary syndrome. Medicine. https://doi.org/10.1097/MD.0000000000004526
Cao Q, Hu Y, Fu J, et al (2021) Gestational metformin administration in women with polycystic ovary syndrome: A systematic review and meta‐analysis of randomized control studies. The journal of obstetrics and gynaecology research. https://doi.org/10.1111/jog.15044
Glueck C, Goldenberg N, Pranikoff J, et al (2013) Effects of metformin-diet intervention before and throughout pregnancy on obstetric and neonatal outcomes in patients with polycystic ovary syndrome. Current Medical Research and Opinion. https://doi.org/10.1185/03007995.2012.755121
Tosti G, Barberio A, Tartaglione L, et al (2023) Lights and shadows on the use of metformin in pregnancy: from the preconception phase to breastfeeding and beyond. Frontiers in Endocrinology. https://doi.org/10.3389/fendo.2023.1176623
Raperport C, Chronopoulou E, Homburg R (2021) Effects of metformin treatment on pregnancy outcomes in patients with polycystic ovary syndrome. Expert Review of Endocrinology & Metabolism. https://doi.org/10.1080/17446651.2021.1889366
Leo V, Musacchio MC, Piomboni P, et al (2011) The administration of metformin during pregnancy reduces polycystic ovary syndrome related gestational complications. European Journal of Obstetrics, Gynecology, and Reproductive Biology. https://doi.org/10.1016/j.ejogrb.2011.03.024
Notaro ALG, Neto F (2022) The use of metformin in women with polycystic ovary syndrome: an updated review. Journal of Assisted Reproduction and Genetics. https://doi.org/10.1007/s10815-022-02429-9
Fan H (2013) Use of metformin during pregnancy for women with polycystic ovary syndrome. Open Journal of Obstetrics and Gynecology. https://doi.org/10.4236/OJOG.2013.31021
Lautatzis M, Goulis D, Vrontakis M (2013) Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: a systematic review. Metabolism: Clinical and Experimental. https://doi.org/10.1016/j.metabol.2013.06.006
González C, Alvariñas J, Bagnes MFG, Girolamo GD (2019) Metformin and Pregnancy Outcomes: Evidence Gaps and Unanswered Questions. Current Clinical Pharmacology. https://doi.org/10.2174/1574884714666181224151116
Zeng W, Luo Y, Ou J, et al (2025) Metformin in polycystic ovary syndrome: unraveling multi-stage therapeutic mechanisms from puberty to long-term health outcomes. Frontiers in Pharmacology. https://doi.org/10.3389/fphar.2025.1654372
Wang Y, Zhang L, Tan J, et al (2011) Effect of metformin during early pregnancy on pregnancy outcome of women with polycystic ovarian syndrome. Chinese Journal of Perinatal Medicine. https://doi.org/10.3760/CMA.J.ISSN.1007-9408.2011.10.004
Dube R (2016) Using Metformin in Pregnancy for Different Indications: Are We Any Wiser now? https://doi.org/10.2174/2213476X03666151221210516
Ryssdal M, Skage JE, Jarmund A, et al (2025) Metformin Treatment in PCOS Pregnancies Reduces Maternal Infections and Increases the Risk of Allergies and Eczema in the Offspring: Post Hoc Analyses of Two Randomised Controlled Trials and One Follow‐Up Study. BJOG: an International Journal of Obstetrics and Gynaecology. https://doi.org/10.1111/1471-0528.18320
Montplaisir P (2011) Is metformin a multifunctional medication for inducing ovulation and improving pregnancy outcomes in PCOS? Journal of the American Academy of Nurse Practitioners. https://doi.org/10.1111/j.1745-7599.2011.00651.x
Sivalingam VN, Myers J, Nicholas S, et al (2014) Metformin in reproductive health, pregnancy and gynaecological cancer: established and emerging indications. Human Reproduction Update. https://doi.org/10.1093/humupd/dmu037
Butalia S, Gutierrez L, Lodha A, et al (2017) Short‐ and long‐term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta‐analysis. Diabetic Medicine. https://doi.org/10.1111/dme.13150
Ijäs H, Vääräsmäki M, Morin-Papunen L, et al (2011) Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study. BJOG: an International Journal of Obstetrics and Gynaecology. https://doi.org/10.1111/j.1471-0528.2010.02763.x
Li X, Celotto S, Pizzol D, et al (2021) Metformin and health outcomes: An umbrella review of systematic reviews with meta‐analyses. European Journal of Clinical Investigation. https://doi.org/10.1111/eci.13536
Artini P, Obino M, Sergiampietri C, et al (2018) PCOS and pregnancy: a review of available therapies to improve the outcome of pregnancy in women with polycystic ovary syndrome. Expert Review of Endocrinology & Metabolism. https://doi.org/10.1080/17446651.2018.1431122
Abdalla M, Shah N, Deshmukh H, et al (2021) Impact of pharmacological interventions on insulin resistance in women with polycystic ovary syndrome: A systematic review and meta‐analysis of randomized controlled trials. Clinical Endocrinology. https://doi.org/10.1111/cen.14623
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