A novel approach to the therapy of placental dysfunction using L-arginine


Lugansk State Medical University, Ukraine
Lugansk Oblast Clinical Hospital, Ukraine

The article presents the authors’ own data on assessment of L-arginine as a therapy of placental dysfunction in pregnant women. According to the results of this study, Tivortin® was highly effective and safe at Week 24–27 and Week 32–34 of gestation.
Furthermore, the incidence of preterm delivery has decreased 2.3 times, the incidence of foetoplacental dysfunction has decreased 4.6 times, the incidence of intrauterine growth restriction has decreased 4 times, and the incidence of foetal distress has decreased by 9.6%, whereas the blood flow in the maternal-placental-foetal circulation system has grown by 37.7%.

Key words: placental dysfunction, L-arginine, intrauterine growth restriction, endothelium, therapy, Tivortin®.

The placental dysfunction has been included in the International Statistical Classification of Diseases and Related Health Problems as a primary diagnosis of foetal and neonatal abnormalities. Virtually all complications of pregnancy are accompanied by the emergence and the build-up of placental dysfunction (PD). Thus, the incidence of the latter abnormality is 50-77% in habitual miscarriage, 32% in toxaemia of pregnancy and up to 45% in extragenital disease. The foetus developing under insufficient placental perfusion is considerably more susceptible to hypoxic damage of vital organs in course of in utero development and more prone to in labour injury [8].

In course of normal uneventful pregnancy, there is an increase in endothelium-dependent vasodilation, which returns to baseline after delivery. This process involves such mediators as nitric oxide (NO), prostacyclin and endothelium-derived hyperpolarizing factor [5]. The endothelium participates in regulation of vascular tone, vascular permeability, leukocyte and platelet adhesion, angiogenesis, thromboresistance, immune response, the synthesis of inflammatory mediators and their respective inhibitors and barrier functions [6]. The literature data [6] indicate that NO synthesis is an important function of the endothelium, since NO maintains baseline vascular tone and participates in vasodilation in response to various stimuli. When dysfunction occurs, the endothelium acquires atherogenic properties with a tendency to vasoconstrictor responses and thrombophilia; adhesion molecules and growth factors rush into the bloodstream; the inflammatory and oxidative activity of the serum increases. Endothelial dysfunction is an imbalance between the mediators normally responsible for normal ratios between all endothelium-dependent processes.

This primarily applies to production of vasodilators, angioprotectors and anti-proliferative substances, on the one hand, and the levels of vasoconstrictors and pro-thrombotic/proliferative factors, on the other hand [7, 12]. Endothelial dysfunction accompanies the complications of pregnancy and delivery, which are to different extents related to the placental factor and the impaired vascular adaptation in pregnancy [8].

Endothelial damage is facilitated by such factors as smoking, toxic exposures, hypertension, obesity, hyperhomocysteinaemia, dyslipidaemia, insulin resistance, activation of the cytokine cascade in systemic inflammation, oxidative stress, the effects of endogenous blockers of the endothelial NO-synthase, vasoactive peptides (angiotensin II, endothelin-1), accumulation of asymmetric dimethyl arginine, changes in uric acid levels, etc. [8].

The impact of the damaging factors in endothelial cells include destruction of the cells, accelerated apoptosis, reduced NO synthesis and reduced production of hyperpolarizing factors. Consequently, the increased functional activity of adhesion molecules and chemokines activates inflammatory responses and vasoconstriction and changes homeostatic parameters.

Numerous studies have demonstrated the participation of NO in the maintenance of baseline vascular tone, stabilisation of blood rheology, prevention of aggregation of blood corpuscles, reduction of vascular wall permeability and elimination of the consequences of metabolic acidosis [2].

With every year there are more reports dedicated to practical obstetric use of various treatment protocols and correction of impaired utero-placental blood flow, the latter performed using several modalities. However, the pharmacological ‘aggression’ or obstetrical polypharmacy has increased the incidence of both maternal and foetal adverse effects, has caused neonatal sensitisation, and delayed complications of drug therapy [8]. From this perspective, it is reasonable to employ pharmacological therapy with endogenous metabolites, which produce a multidimensional effect in several pathogenetic links of PD while exerting minimal adverse effects in the foetus.

Today, owing to the expanded diagnostic options to detect impaired placental functions, as well as in view of novel data on the mechanisms of regulation of placental blood flow in both physiological pregnancy and aggravated pregnancy, there is a new possibility to append the PD therapeutic protocols with NO donor substances (L-arginine). Tivortin®, being a gravidoprotector, fully meets all of the above expectations.

In a normally functioning endothelium, low levels of NO are continuously released to keep blood vessels dilated and provide for non-adhesion of blood corpuscles to the endothelium. When exposed to various damaging factors (mechanical, infectious, metabolic, related to immune complexes, etc), endothelial cells diminish their ability to release relaxing factors, whereas the formation of vasoconstriction factors is either intact or increased; this condition is defined as endothelial dysfunction [1, 3, 11].

It is known that in human body NO is synthesized from the L-arginine amino acid with NO-synthase (NOS) enzymes. Thus, this essential amino acid is a substrate for NO synthesis [12]; the use of L-arginine has a positive impact on the function of vascular endothelium and improves endothelium- dependent vasodilation. In Ukraine, L-arginine is authorised as a 4.2% solution for infusions, known under the Tivortin® brand (manufactured by Yuria-Pharm, Ukraine). This product provides the body with the building material for NO synthesis.

Much attention is given to the influence of the L-arginine/NO bioregulatory system on the utero-placental blood flow and to the intrauterine foetal development. Increased production and release of NO, mediated by L-arginine, may act as an antioxidant and facilitate improvements of endothelial function in pregnant women.

The aim of this research was to evaluate the efficacy of using L-arginine in the therapy of foetoplacental dysfunction in pregnant women.