According to some recent data, PI accompanies practically all pregnancy complications [18]. Despite modern techniques of complex treatment and preventive maintenance of PI, the risk of PI in PM remained high and varied between 47.6 and 77.3% [1]. The delicate relation between mother and placenta/fetus operates during progression of the pregnancy. Former spontaneous abortions and endometritis could provoke receptor abnormalities in the endometrium, including hormone receptors, and thus initiate unfavorable hormonal and metabolic shifts as a prerequisite of PI at the present pregnancy [19].

Some authors classify PI as a display of "disadaption disease" [3]. The modern concept of physiological adaptation of the maternal organism and her fetus during pregnancy formulated by Wallenburg [20]. To a great extent, the favorable outcome of pregnancy in the case of PI depends on adequate adaptation of various components of cardiovascular systems of the mother and fetus. Recent investigations have shown that endothelial dysfunction in mother, in fetoplacental complex and in arteries of the umbilical cord is one of the leading factors in pathogenesis of PM and PI [6]. Angiotensin-converting enzyme, as a basic component of the renin-angiotensin system, is responsible for conversion of angiotensin I into angiotensin II and for inactivation of bradykinin, and plays a key role in the origin and progression of endothelial dysfunction and vasoconstriction [21]. Changes in vascular metabolites affect the functions of the fetoplacental complex and may induce abnormalities of blood circulation in the placenta [7-10]. The I/D polymorphism of the ACE gene is functionally significant as it may influence the whole renin-angiotensin system that participates in regulation of vascular tone [13]. The I allele is associated with decreased ACE production compared to the D allele. An association of the D allele of with cardiovascular disease, in particular, with hypertension [22,23] and with some kinds of preeclampsia [24], has been reported. Since ACE is responsible for processes of vasoconstriction and vasodilatation in placental tissue, it is logical to assume an association between its allelic variants and development of PI. The results of the present study demonstrate the association between allelic variants of the ACE gene and PI development, and indicate that the D allele may be a risk factor for PI in women without PM in the anamnesis, whereas the I allele may be a risk factor for development of PI on a PM background.

At first sight, these results are rather inconsistent. However, the causes of PI in women without PM– and with PM in their obstetric history could be quite different. Placental insufficiency is mostly primary in patients with PM. Placental insufficiency during early pregnancy develops on a background of hormone abnormalities, inflammatory processes and changes in ednometrium receptors. Patients without PM have secondary PI, which occurs on the background of a pregnancy complicated by nephropathy, premature placental separation and extragenital pathology. Thus, we were dealing with rather different groups of patients.

In a case of ‘pure’ PI (group 3), it’s clear-cut correlation with the D/D genotype of the ACE gene was assessed. The same allele is known to be associated with risk of myocardial infarction at a young age, ischemic heart disease, etc. [10,23]. It can be suggested that the D/D genotype in placentae results in an increase of placental infarctions and partial detachment of the placenta, and thus it could contribute to abnormalities of blood circulation in the placenta and to development of PI.

The pathogenesis of PI in conjunction with a PM case history could be quite different. Hormonal insufficiency, abnormalities of vascularization and endometrium reception owing to previous curettages, genital infantilism, and the presence of inflammatory and vascular reactions, thrombophilic complications at autoimmune processes are the most important causes of PI [25]. In PM cases, morphological and functional changes result in abnormalities of placenta maturation, involutive-dystrophic and inflammatory abnormalities of placental tissue [1,2,4]. Owing to this pathogenic background,PI in patients with PM should be treated as a primary character. Homozygosity for the I allele could decrease ACE concentration in plasma, and thus decrease the rate of bradykinin inactivation in the placenta. Reduction of bradykinin level may increase vessel permeability, and modulate inflammatory reaction, provoking premature interruption of pregnancy.

The differences in frequencies of the ACE alleles between groups 3 and 4 with PI could mainly be due to the complexity of the PI syndrome including pathological changes in the fetus and placenta joined by similar clinical manifestations, but varied in the cause of complications and in a number of development pathways.

Determining which genetic factors influence development of PI is of great importance for understanding the pathophysiological mechanisms of this disorder. Identification of candidate genes that participate in PM and PI has great practical value for prevention of this frequent obstetric pathology. Our data show that products of the ACE gene in placenta participate in PI development. The D/D genotype is associated with a 3-fold increased risk of PI development in women without PM. The I/I genotype increases by 2.6-fold the risk of PI development in patients positive for PM in obstetric history. Testing for the I/D polymorphism of the ACE gene in chorionic villus cells in the first trimester of pregnancy could be very important for prediction of PI. However, it is still unknown whether the maternal I/D polymorphism may influence development of PM and PI. Identification of genetic markers of PI is still in its infancy but could provide new insight into molecular mechanisms of pathology in obstetrics, gynecology, and clinical medicine as a whole.