Current Researches, Rationale, Plausibility, and Evidence Gaps on Metformin for the Management of Hypertensive Disorders of Pregnancy

Abstract

Hypertensive disorders of pregnancy (HDP) are a group of morbid pregnancy complications, with preeclampsia (PE) being the most common subclassification among them. PE affects 2%–8% of pregnancies globally and threatens maternal and fetal health seriously. However, the only effective treatment of PE to date is the timely termination of pregnancy, albeit with increased perinatal risks. Hence, more emerging therapies for PE management are in urgent need. Originally introduced as the first-line therapy for type 2 diabetes mellitus, metformin (MET) has now been found in clinical trials to significantly reduce the incidence of gestational hypertension and PE in pregnant women with PE-related risks, including but not limited to pregestational diabetes mellitus, gestational diabetes mellitus, polycystic ovary syndrome, or obesity. Additionally, existing clinical data have preliminarily ensured the safety of taking MET during human pregnancies. Relevant lab studies have indicated that the underlying mechanism includes angiogenesis promotion, endothelial protection, anti-inflammatory effects, and particularly protective effects on trophoblast cells against the risk factors, which are beneficial to placental development. Together with its global availability, easy administration, and low cost, MET is expected to be a promising option for the prevention and treatment of PE. Nevertheless, there are still some limitations in current studies, and the design of the relevant research scheme is supposed to be further improved in the future. Herein, we summarize the relevant clinical and experimental researches to discuss the rationale, safety, and feasibility of MET for the management of HDP. At the end of the article, gaps in current researches are proposed. Concretely, experimental MET concentration and PE models should be chosen cautiously. Besides, the clinical trial protocol should be further optimized to evaluate the reduction in the prevalence of PE as a primary endpoint. All of those evidence gaps may be of guiding significance to improve the design of relevant experiments and clinical trials in the future.

Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome‐Induced Pyroptosis via Inhibiting the TLR4/NF‐κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

“…According to the MET pharmacokinetics in pregnancy [ 26 , 44 ], we carefully designed a pharmacological MET concentration gradient (10~40 μ M) in our study, which had no effects on trophoblastic viability or apoptosis through CCK-8 assays ( Figure 1(a) ) and flow cytometry analysis (Figures 1(b) and 1(c) ). Low-dose LPS has long been utilized to induce preeclamptic trophoblast models [ 39 , 40 ].…”

“…Furthermore, the clinical trial protocol should be further optimized to evaluate the reduction in the prevalence of PE as a primary endpoint. Therefore, we look forward to more high-quality randomized controlled trials and well-designed lab studies in the future to clarify the place of MET in the prevention and treatment of PE [ 26 ].…”

“…Up to now, there has been a clinical dilemma that current clinical therapies for PE are mainly symptomatic treatments, while, thus far, the only curative intervention for PE is the delivery of the fetus and placenta, albeit with raised consequent risks [ 26 ]. Hence, more possible therapeutic strategies remain to be further explored.…”

“…Moreover, the safety of taking MET during human pregnancies has been preliminarily ensured [ 36 ]. Thus, the therapeutic potential of MET in PE is worth in-depth study [ 26 ].…”

Current Therapeutic Use of Metformin During Pregnancy: Maternal Changes, Postnatal Effects and Safety

“…It is excreted by the kidney, so, proper renal function is required to prevent its retention. Therefore, such patients require monitoring of kidney function tests regularly [35].…”