Immunomodulatory Effects of Metformin Treatment in Pregnant Women With PCOS

Abstract

Context Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with low-grade systemic inflammation and increased risk of pregnancy complications. Metformin treatment reduces the risk of late miscarriage and preterm birth in pregnant women with PCOS. Whether the protective effect of metformin involves immunological changes has not been determined. Objective To investigate the effect of metformin on the maternal immunological status in women with PCOS. Methods A post-hoc analysis was performed of two randomized controlled trials (RCTs), PregMet and PregMet2, including longitudinal maternal serum samples from 615 women with PCOS. Women were randomized to metformin or placebo from first trimester to delivery. Twenty-two cytokines and C-reactive protein (CRP) were measured in serum sampled at gestational weeks 5-12, 19, 32 and 36. Results Metformin treatment was associated with higher serum levels of several multifunctional cytokines throughout pregnancy, with the strongest effect on eotaxin (P < 0.001), interleukin (IL)-17 (P = 0.03) and basic fibroblast growth factor (FGF-b) (P = 0.04). Assessment of the combined cytokine development confirmed the impact of metformin on half of the 22 cytokines. The immunomodulating effect of metformin was more potent in normal weight and overweight women than in obese women. Moreover, normoandrogenic women had strongest effect of metformin in early pregnancy while hyperandrogenic women presented increasing effect throughout pregnancy. Conclusion It appears that metformin has immunomodulating rather than anti-inflammatory properties in pregnancy. Its effect on the serum levels of many multifunctional cytokines demonstrates robust, persisting, and BMI-dependent immune mobilization in pregnant women with PCOS.

Metformin use in pregnancy: What about long‐term effects in offspring?

“…Even though no teratogenic effects have been observed in offspring from maternal metformin use, there are increasing concerns about metformin's potential to affect fetal metabolic programming, which in turn might influence offspring long‐term cardiometabolic health 1 . Recently, data from the two randomized controlled trials PregMet and PregMet2, revealed that metformin use in pregnant women with PCOS induces a general systemic immune activation with a broad increase of maternal cytokine levels 18 . Interestingly, the authors suggest that metformin has immunomodulating, rather than anti‐inflammatory effects in pregnancy.…”

“… 1 Recently, data from the two randomized controlled trials PregMet and PregMet2, revealed that metformin use in pregnant women with PCOS induces a general systemic immune activation with a broad increase of maternal cytokine levels. 18 Interestingly, the authors suggest that metformin has immunomodulating, rather than anti‐inflammatory effects in pregnancy.…”