(161) Metformin prevents miscarriage by reducing placental inflammation in a mouse model of preterm birth.

Intra-amniotic infection/inflammation is a trigger mechanism leading to preterm birth (PTB). Abnormal glucose tolerance may contribute to its etiopathogenesis by amplifying tissue inflammation and increasing susceptibility to infections. Metformin is largely used in glucose metabolism disorders of pregnancy for its insulin-sensitizing effect, but its anti-inflammatory properties have been poorly investigated. The aims of this study were to evaluate the effects of metformin in a mouse model of PTB in terms of: a) amniochorionic membranes, placental and serum inflammation; b) prevention of miscarriage and PTB.

Study Design:

Swiss CD1 pregnant mice were treated with intra-peritoneally injection of lipopolysaccharide (LPS) (14.5 days post coitum-dpc) with (group 1; n=15) or without (group 2: n=15) 200mg/Kg of metformin administered by oral gavages (8.5/10.5/12.5/14.5 dpc). Control groups were treated with PBS (n=15) or metformin (n=15) only. The expression of the inflammasome NLRP-3, IL-1β, IL-6, IFN-γ, TNF-α and insulin receptor (ISR) were quantified by ELISA and Western blot in amniochorionic membranes, placentas and maternal sera. 

Results:

Reduced miscarriage rate (b) and higher pups’ weight (d) were observed in group 1 compared to group 2 (p< 0.05 and p< 0.0001, respectively). Decreased placental expression of NLRP-3 (g, p< 0.05), IFN-γ (h, p< 0.0001) and TNF-α (i, p< 0.05) and reduced expression of NLRP-3 (l, p< 0.05), IL-1β (m, p< 0.05), IL-6 (n, p< 0.001), and TNF-α (o, p< 0.0001) in amniochorionic membranes were observed in group 1 compared to group 2. Metformin significantly increased ISR levels in amniotic membranes (p) and sera (k) (p< 0.0001 and p< 0.001, respectively) and decreased serum IL-6 levels (j, p< 0.01).


Conclusion:
Oral administration of metformin in a mouse model of PTB is able to: a) decrease systemic, amniochorionic and placental inflammation; b) reduce miscarriage rate and increase pups’ weight. This study highlights the anti-inflammatory properties of metformin and its potential clinical application in the prevention of miscarriage and PTB.