The objective is to study effectiveness of prevention of severe preeclampsia development in planned pregnancy by endothelial dysfunction correction with use of L-arginine preconceptively and in the 1st trimester of pregnancy in women with severe preeclampsia in history.

Patients and methods. The effectiveness of endothelial dysfunction correction, the effect of it on prevention of preeclampsia, and on reduction of the target organ damages, in particular, expressed hypertension (use of two-component hypotensive therapy) was studied). Tivortin aspartate (manufactured by Yuria-Pharm) was used preconceptively and in the period of early gestation in women with severe preeclampsia during the previous pregnancy. Women were divided into two groups: 1st group (I) — 9 women who gave birth at 28-32 weeks of the previous pregnancy; 2nd group (II) — 18 women who gave birth at 32-34 weeks of the previous pregnancy.

Given that the risk of recurrent preeclampsia in the first group of women is 50% and in the second group — 25%, the endothelial dysfunction correction by using L-arginine to prevent preeclampsia is absolutely justified. Women received Tivortin aspartate (manufactured by Yuria-Pharm) orally 5 g (2.85 L-arginine) per day preconceptionally (3 months before the current pregnancy) and in early gestation period (up to 12 weeks). The effectiveness of therapy was assessed by the number of endothelial cell precursors and obstetric effects of the pregnancy. The prevention of preeclampsia in the second and the third trimesters of pregnancy has been conducted in accordance with the requirements of the current clinical guidelines.

Results. The achievement of arterial hypertension control as a result of combination of basic hypotensive therapy with effective therapy using Tivortin asparate (manufactured by Yuria-Pharm) contributes to reduction in obstetric complications incidence (iatrogenic preterm labor, detachment of placenta). The reduction in the incidence of hypertensive complications is proved by the duration of gestation in period of more than 37 weeks in 77.7% of women in group I, and in 94.4% of women in group ІІ, as well as by decrease in the use antihypertensive medicine for control of hypertension in both groups. This shows the effectiveness of hypertension control with one drug and helps to avoid polypharmacy. Proper correction of endothelial dysfunction with Tivortin asparate (manufactured by Yuria-Pharm) promotes adequate increase in endothelial cell precursor cells, which in its turn optimizes endothelial function in women with preeclampsia and high risk of its recurrence, and today is a reliable marker for the effectiveness of correction.

Conclusions. Non-invasive nature of Tivortin asparate (orally), its ease of use, high efficacy in pregnant women, and high safety profile make it possible to recommend the indicated treatment regimen for endothelial dysfunction correction in women at high risk for preeclampsia.

Key words: preeclampsia, pregnancy, endothelial dysfunction, prevention, L-arginine.

Background

The identification of the association between placental ischaemia/hypoxia and maternal cardiovascular disorders is still an important area of research, since preeclampsia, HELLP or eclampsia is a major cause of maternal and perinatal morbidity and mortality [1, 2, 4–7].

Today, history of preeclampsia is considered to be a factor that not only increases the incidence of obstetric and perinatal complications, but also causes the risk of cardiovascular disease (CVD) development hereafter. It is proved that women with history of severe hypertensive complications have an increased risk of hypertension, obesity, metabolic syndrome, ischaemic heart disease, in particular, in case of premature delivery, preterm labor. Considering the lack of tendency to reduce the rate of hypertensive complications worldwide, the prevention of preeclampsia plays a significant medical and social role, and the search for the latest preventive methods should be based on new pathophysiological approaches [1, 2, 4–7].

Over the past ten years, new hypotheses have emerged to study the potential mechanisms underlying the pathogenesis of hypertension and local endothelial dysfunction in preeclampsia development. Actually it has been proven that the pathophysiological processes that cause preeclampsia development are divided into two stages. The 1st stage is decreased placental perfusion, the 2nd stage is clinical maternal syndrome, and in the 1st stage placental ischaemia/hypoxia leads to the release of various factors that profoundly affect endothelial function, arterial circulation and blood pressure regulation, in the 2d stage the maternal body response and its compensatory potential play a significant role (Fig. 1) [1, 2, 6–8].

Maternal endothelial dysfunction worsens the invasion of the extravillous trophoblast into the coiled arteries, therefore it prevents the development of the uteroplacental complex, the vascular system of which is characterized by high fluidity, low resistance to provide adequate blood supply to the fetus. Furthermore, recent studies suggest that endothelial dysfunction occurs much earlier than the development of hypertensive complications during pregnancy, and the consequences of this dysfunction predispose newborns from mothers with preeclampsia to early occurrence of hypertension and CVD [6, 10, 11]. Since 2018, the Society of Obstetricians and Gynaecologists of Canada has introduced L-arginine as part of preventive measures in women at high risk of preeclampsia development [5].

Changes in the secretion of prostacyclin by endothelium, endothelial relaxing factor and increased production of thromboxane A2 and endothelin are leading factors in the pathogenesis of preeclampsia. Endothelial progenitor cells (EPCs), in turn, play an important role in maintaining endothelial integrity and postnatal neovascularization of tissues in adults [9–11].

The restoration of the endothelial monolayer by endothelial progenitor cells is crucial for the maintenance of unhindered endothelial integrity. The release of endothelial progenitor cells from the bone marrow is associated with the production of NO, and a reduction in their number leads to impaired arterial elasticity in patients with endothelial dysfunction (Fig. 2) [5, 9].

To date, there is a consensus that endothelial progenitor cells originate from the bone marrow, and CD133/VEGFR2 cells are a special population capable of becoming endothelial progenitor cells. However, increasing evidence suggests the existence of additional bone marrow-derived cell populations (e.g., myeloid cells, side population cells, and mesenchymal cells) and the existence of bone marrow-derived cells which can also cause the growth of endothelial cells [9].

Furthermore, the recruitment and incorporation of endothelial progenitor cells requires a coordinated sequence of multistep adhesive and signaling events, including adhesion and migration (e.g., under the control of integrins), chemoattraction (e.g., under the control of SDF-1/CXCR4), and finally, differentiation into endothelial cells, i.e., a balanced process of neovascularization and re-endothelialization regulation that is mediated by endothelial progenitor cells is required (Fig. 2) [5].

Previously the differentiation of mesodermal cells to angioblasts and their further endothelial differentiation was believed to occur exclusively during embryonic development. However, in 1997 [3] it was proved that purified CD34+ hematopoietic progenitor cells in adults can differentiate ex vivo to endothelial phenotype. These cells were called the “endothelial progenitor cells” (EPCs), they showed expression of various endothelial markers, and incorporated into neovessels at sites of ischaemia [9].

Circulating endothelial progenitor cells are a modern diagnostic and prognostic biomarker of CVD, and the dynamics of their number is a marker of the prevention and treatment effectiveness.

Given the risk of preeclampsia recurrence of 17-50%, it is advisable to include L-arginine (Tivortin aspartate, manufactured by Yuria-Pharm) as a NO donor to the preconception preparation regimen and in early pregnancy for women at high risk of preeclampsia to correct endothelial dysfunction and prevent the preeclampsia development.

The objective is to study effectiveness of prevention of severe preeclampsia development in planned pregnancy by endothelial dysfunction correction with L-arginine preconceptively and in the 1st trimester of pregnancy in women with severe preeclampsia in history.

Study materials and methods

The effectiveness of endothelial dysfunction correction, the effect of it on prevention of preeclampsia, and on reduction of the target organ damages, in particular, expressed hypertension (use of two-component hypotensive therapy) was studied). Tivortin aspartate (manufactured by Yuria-Pharm) was used preconceptively and in the period of early gestation in women with severe preeclampsia during the previous pregnancy. Women were divided into two groups: the 1st (I) — 9 women who gave birth at 28-32 weeks of the previous pregnancy; the second (II) — 18 women who gave birth at 32-34 weeks of the previous pregnancy.

Table 1. Effectiveness of endothelial dysfunction correction with L-arginine in women with severe preeclampsia during the previous pregnancy

Note: * — comparison of values before treatment and after 1.5 months (p<0.05)

Fig. 1. Role of endothelial dysfunction in the preeclampsia development

Given that the risk of recurrent preeclampsia in the first group of women is 50% and in the second group — 25%, the endothelial dysfunction correction by using L-arginine to prevent preeclampsia is absolutely justified. Women received Tivortin aspartate (manufactured by Yuria-Pharm) orally 5 g (2.85 L-arginine) per day preconceptionally (3 months before the current pregnancy) and in early gestation period (up to 12 weeks). The effectiveness of therapy was assessed by the number of endothelial cell precursors and obstetric effects of the pregnancy. The prevention of preeclampsia in the second and the third trimesters of pregnancy has been conducted in accordance with the requirements of the current clinical guidelines.

The study was carried out in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the Local Research Ethics Committee of the institution. Informed consent of women was obtained for the study.

Results of the study and discussion

There is a significantly low ascending level of endothelial progenitor cells in I and II groups of pregnant women, which indicates the presence of endothelial dysfunction in women before pregnancy (Table 1). After the use of L-arginine for 6 weeks, a significant increase in endothelial progenitor cells is observed in both groups of women. The number of endothelial progenitor cells remains almost invariably high in the 1st trimester of pregnancy under the condition of continuous use of L-arginine 2–3 months before pregnancy and during the 1st trimester of the current pregnancy.

It should be noted that the pathogenetic correction of endothelial dysfunction by NO donor before pregnancy allows preventing preeclampsia and prolong pregnancy to term birth in 77.7% of women in group I and 94.4% of pregnant women in group II. Absence of detachment of a normally situated placenta (placental syndrome caused by endothelial dysfunction) also proves the effectiveness of endothelial correction. It should be noted that in group II of pregnant women the need for two-component antihypertensive therapy was only in 27.7% of women, which indicates the effectiveness of this approach to prevent the fetus and maternal genesis of preeclampsia.

Discussion

According to the study results, endothelial dysfunction correction before the onset and in early pregnancy period can prevent obstetric complications arising from placental disorders and result in hypertensive complications during the next pregnancy, and ultimately lead to early onset of CVD in later life. The study [8] showed that in patients with endothelial dysfunction detected before the onset or at the beginning of pregnancy, the reproductive outcome is significantly improved with the use of L-arginine during pregnancy. However, in patients with repeated pregnancy losses, preterm labor, birth of children with low weight for the gestational age, and, of course, with preeclampsia, it is advisable to continue the study on the prevention of defective placentation due to the vascular component.

Fig. 2 Formation of a new vessel with the presence of endothelial progenitor cells

Conclusions

Endothelial dysfunction is a factor that determines the clinical manifestations of pregnancy pathology and center-tapped circuit of preeclampsia pathogenesis. It is known that women with preeclampsia and their descendants are at risk of early ischaemic heart disease, hypertension, type 2 diabetes mellitus. Therefore, the endothelial dysfunction correction by prescription of medicines with endotheliosis protective effect, in particular L-arginine, has not only medical but also social significance.

The achievement of arterial hypertension control as a result of combination of basic hypotensive therapy with effective therapy using Tivortin asparate (manufactured by Yuria-Pharm) contributes to reduction in obstetric complications rate (iatrogenic preterm labor, detachment of placenta). The reduction in the incidence of hypertensive complications is proved by the duration of gestation for more than 37 weeks in 77.7% of women in group I, and in 94.4% of women in group ІІ, as well as by decrease in the use antihypertensive medicine for control of hypertension in both groups.

This shows the effectiveness of hypertension control with one drug and helps to avoid polypharmacy. Proper correction of endothelial dysfunction with Tivortin asparate (manufactured by Yuria-Pharm) promotes adequate increase in endothelial cell precursor cells, which in its turn optimizes endothelial function in women with preeclampsia and high risk of its recurrence, and today  is a reliable marker for the effectiveness of correction.

Non-invasive nature of Tivortin asparate (orally), its ease of use, high efficacy in pregnant women, and high safety profile make it possible to recommend the indicated treatment regimen for endothelial dysfunction correction in women at high risk for preeclampsia.

The authors declare that there is no conflict of interest.

Authors

Y.V. Davydova, A.Y. Lymanska, A.O. Ohorodnyk, L.P. Butenko, Associate Professor of the Medical Sciences, Professor, the Master of Public Administration, the Head of obstetrical problems of an extragenital pathology department SI «Institute of Pediatrics, Obstetrics and Gynecology NAMS of Ukraine» Kyiv, Ukraine.

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