Clinical and pathogenetic rationale for two-stage prevention of preeclampsia in high-risk women using an insulin sensitizer for preconception preparation

Objective: To demonstrate the effectiveness of a two-step approach for the prevention of pre-eclampsia in high-risk women, consisting of pregestational use of the insulin sensitizer metformin (ISM) followed by low-dose acetylsalicylic acid (LDAA) during pregnancy.

Materials and methods: At the preconception stage, women at high risk of preeclampsia were divided into groups according to the prevention method: group 1, 77 patients who received two-stage prophylaxis (ISM at the preconception stage and LDAA during pregnancy); group 2, 75 patients who received LDAA monotherapy at the gestational stage; group 3, 72 patients who received metformin only preconceptionally; and group 4, 73 patients who refused prevention. Thirty women with physiological gestation served as the controls. At 11–14, 18–21, and 30–34 weeks, hormonal-metabolic, pro-inflammatory, and endothelial-hemostasiological patterns were assessed. Based on the primary outcome, the incidence of pre-eclampsia, the size of the effect of the preventive intervention was calculated.

Results: Clinical and laboratory parallels proved the advantage of a two-stage approach to the prevention of preeclampsia: the incidence of preeclampsia in group 1 was 3.8 times lower (RR 0.26 [0.14; 0.49], RRR 73.7% [50.9; 85.9], ARR 36.3% [22.6; 50.1], NNT 3 [2; 4], χ²=21.58, p<0.001), compared with the group without prevention, and with ISM or LDAA alone, only 2.7 (RR 0.37 [0.21; 0.63], RRR 63.4% [36.9; 78.8], ARR 31.3% [16, 8; 45.8], NNT 4 [2; 6], χ²=14.47, p<0.001) and 1.6 times (RR 0.62 [0.41; 0.94], RRR 37.8 % [6.0; 58.8], ARR 18.7% [3.1; 34.2], NNT 6 [3; 32], χ²=4.62, p=0.03), respectively. In group 1, the incidence of severe preeclampsia was reduced by 3.1 and 3.6 times, early preeclampsia by 1.6 and 1.6 times, relative to groups 2 and 3. The effectiveness of the staged approach was confirmed by the influence of preeclampsia prevention methods on the intensity of compensation for insulin resistance and the associated proinflammatory and prothrombogenic patterns, markers of alteration, and remodeling of the vascular endothelium. The lack of effectiveness of the standard use of LDAA is associated with the lack of a periconceptual influence on key events in early pregnancy.

Conclusion: A new strategy for the prevention of preeclampsia is represented by a staged approach that provides a reduction in cardiovascular risk by developing metabolic resistance in women at high risk of preeclampsia from the stage of pregnancy planning and is implemented as a promising, highly effective, pathogenetically substantiated method of prevention aimed at improving obstetric outcomes and stabilizing cardiovascular disease. the vascular continuum later in life.