December 13, 2021
Metformin and Pregnancy Outcomes in Women with PCOS: A Review of Research
By Daniel Murphy
Editor’s Note: Polycystic ovarian syndrome (PCOS) is not only extremely common but it also has significant implications for a woman’s fertility and overall health. While on the FACTS elective as a fourth-year medical student, Daniel Murphy reviewed a 2012 article by Ghazeeri et al titled, “Pregnancy outcomes and the effect of metformin treatment in women with polycystic ovary syndrome: an overview.” Below is his summary of the research which, though not as conclusive as one would hope, highlights the complex nature of this condition and the need for ongoing research to improve diagnosis, treatment, and outcomes in PCOS.
Why It Matters
Polycystic ovarian syndrome is a disorder of ovarian dysfunction thought to be the leading cause of anovulatory infertility affecting women today (5-10% of women). Although the exact pathophysiology of PCOS and its effects on pregnancy-related outcomes has not been fully elucidated, numerous studies suggest associations between the presence of PCOS and higher rates of pregnancy complications. These include gestational diabetes mellitus (GDM), pregnancy-induced hypertension (HTN), preeclampsia, early pregnancy loss, and preterm birth. A more thorough understanding of the factors that may contribute to these outcomes as well as any potential treatments will be useful to ensure patients experience healthier and safer pregnancies.
MEDLINE and PubMed searches were performed to include studies from 1982 to 2011 evaluating pregnancy outcomes in women with PCOS, as well as studies assessing the effect of treatment with metformin on the same outcomes. Outcomes of interest included the relative risk of women with PCOS to develop GDM, gestational HTN or preeclampsia, preterm delivery, and early pregnancy loss.
A total of 5,114 women with PCOS and 87,805 control women were included in the studies selected for this review. Most of the studies were of retrospective design, with prospectively designed trials being the second most represented study type in the review. Overall, the preponderance of evidence suggests clinically significant associations between PCOS and increased incidence of GDM, gestational HTN, and preeclampsia compared to women without PCOS.
The associations of PCOS and preterm delivery or early pregnancy loss were less clear. PCOS was not found to be an independent risk factor for preterm delivery or early pregnancy loss. However, patients who had received ovulation induction treatments, which is common in PCOS due to the frequent presence of anovulation, were found to have higher risk for preterm delivery compared to women who did not undergo ovulation induction.
Several factors must be considered when assessing this study, beginning with the retrospective design of the majority of the studies included in the review. There was also a lack of standardization for PCOS definitions used in each trial, along with inconsistencies in control group matching for potential confounders.
Still, the preponderance of evidence suggests positive associations between a diagnosis of PCOS and increased perinatal complications, including GDM (partly due to obesity), gestational HTN, and preeclampsia, compared to women without PCOS.
Due to the same study limitations mentioned above, the data surrounding the effect of metformin treatment on the same target outcomes do not provide many robust conclusions. In this review, no mention is made of any harms associated with metformin use in pregnant women with PCOS. Numerous retrospective and prospective studies suggested reductions in pregnancy complications when metformin was used in the pre/perinatal period. However, a larger placebo-controlled, randomized, multicenter trial did not find any improvement in pregnancy complications with metformin use. A meta-analysis focused on the same outcomes also failed to show any benefit. The main arena where metformin has been shown to have significant benefit is in ovulation induction for clomiphene-resistant women with PCOS, showing improvements in ovulation by around 50%.
Various theories exist for the proposed mechanism of action for metformin’s potential benefits in perinatal outcomes. Among these are the potential for metformin to reduce early pregnancy loss by lowering serum androgen levels, or its insulin-like growth factor-1 effect that may improve ovulation in women with PCOS. Yet, it may seem that the true benefit of this research is not the conclusions made (or lack thereof) but punctuation of the complex syndrome that comprises the diagnosis of PCOS. As such, future research assessing PCOS-related perinatal outcomes may need to focus on individual modifiable factors of the syndrome (overweight/obesity, specific hormone/androgen imbalances, hyperinsulinemia/insulin resistance, cystic vs non-cystic ovaries, etc.) to evaluate the effect of modification of distinct components of this complex but very prevalent and, thus, important condition.
Editor’s Note: Since the publication of the 2012 research by Ghazeeri et al summarized above, PCOS remains a prevalent condition still being studied in depth. Among many other findings, at least four different phenotypes now appear to be at play in the diagnosis of PCOS, each potentially impacting management, prognosis, and pregnancy outcomes in unique ways. The need for an individualized approach in the care of these women is increasingly apparent. Follow the links below to learn more about PCOS from research reviews published in the FACTS blog.
 Ghazeeri GS, Nassar AH, Younes Z, Awwad JT. Pregnancy outcomes and the effect of metformin treatment in women with polycystic ovary syndrome: an overview. Acta Obstet Gynecol Scand. 2012;91(6):658-678. doi:10.1111/j.1600-0412.2012.01385.x.
 Ibáñez L, Díaz M, García-Beltrán C, et al. Toward a Treatment Normalizing Ovulation Rate in Adolescent Girls With Polycystic Ovary Syndrome. J Endocr Soc. 2020;4(5):bvaa032. Published 2020 Mar 14. doi:10.1210/jendso/bvaa032.
About the Author
Daniel Murphy wrote this review as a fourth-year medical student at Stritch School of Medicine in Chicago. He is pursuing residency training in family medicine. He hopes that the understanding of fertility awareness learned in the FACTS course and beyond will be a tool that will help him to provide holistic and thoughtful care for his future patients.