Prognostic factors determining the course of pregnancy and perinatal outcomes in patients with chronic arterial hypertension

The dissertation is devoted to the study of prognostic factors that influence the course of pregnancy and perinatal outcomes in patients with chronic arterial hypertension. The research covers an evaluation of the functional state of the sympathoadrenal system by the value of β-adrenoreception of erythrocyte membranes, an analysis of the parameters of twenty-four-hour blood pressure monitoring, and the structural and functional state of the left ventricular myocardium in different trimesters of pregnancy, as well as a comparison of these indicators with data from practically healthy pregnant women.

Special attention is paid to the clinical efficacy and safety of antihypertensive therapy with the β-adrenoblocker bisoprolol and the dihydropyridine calcium antagonist nifedipine SR/GITS, as well as to the study of the association of the polymorphic marker C1846A of the CYP2B6 gene with individual sensitivity to the administered therapy. The data obtained are aimed at substantiating criteria for the individual selection of antihypertensive therapy and for predicting the complicated course of pregnancy and adverse perinatal outcomes in this category of patients.

Arterial hypertension is the most common extragenital pathology and, according to various authors, occurs in 5–40% of pregnant women [25, 83]. The presence of arterial hypertension is associated with a high rate of pregnancy complications: in 36–86% of cases, gestosis develops against the background of chronic arterial hypertension, and the frequency of births of children with intrauterine growth retardation increases 2.5-fold compared with a normally proceeding pregnancy [21, 43, 44, 62]. High blood pressure is one of the main causes of maternal mortality, accounting for 20–30% of its structure according to WHO data.

The identification and assessment of risk factors for the development of various complications, primarily gestosis, and of possible adverse outcomes in these women remains relevant at present.

The sympathoadrenal system plays an important role in the adaptation of the cardiovascular system during a physiologically proceeding pregnancy, and disorders in its functioning underlie various pathogenetic mechanisms of the development of hypertensive disease [36, 45, 63]. In this regard, the assessment of its activity may have not only diagnostic but also prognostic significance for predicting the risk of complications during pregnancy and adverse perinatal outcomes.

The literature contains data on the adverse role of a number of parameters of the circadian blood pressure profile in the development of complicated pregnancy course; however, their significance has not been fully established [51].

Antihypertensive therapy occupies an important place in the management of patients with arterial hypertension during pregnancy; its selection and assessment of efficacy are carried out under blood pressure control and with account taken of gestational age. The drugs of choice are adrenoblockers and dihydropyridine calcium antagonists, which in most cases are sufficiently effective in the treatment of chronic arterial hypertension during pregnancy [21, 123]. However, it has recently been established that adverse pharmacological responses depend not only on the choice of a particular drug but also on the genetic characteristics of the patient [32]; therefore, the search for new criteria for the individual selection of antihypertensive therapy in pregnant women is relevant.

Aim of the study: to identify prognostically unfavorable factors that determine the course of pregnancy and perinatal outcomes and to determine the criteria for the individual selection of antihypertensive therapy in patients with chronic arterial hypertension.

Tasks of the study:

1. To study the characteristics of the parameters of twenty-four-hour blood pressure monitoring in pregnant women with chronic arterial hypertension in different trimesters of pregnancy and to compare them with the results of twenty-four-hour blood pressure monitoring of practically healthy pregnant women.

2. To investigate the parameters of the structural and functional state of the left ventricular myocardium in pregnant women with chronic arterial hypertension and in the control group.

3. To study the functional state of the sympathoadrenal system by the value of β-adrenoreception of erythrocyte membranes and to compare these data with the parameters of the structural and functional state of the left ventricular myocardium and twenty-four-hour blood pressure monitoring in the groups of pregnant women.

4. To evaluate the clinical efficacy of the β-adrenoblocker bisoprolol and the long-acting dihydropyridine calcium antagonist nifedipine SR/GITS in pregnant women with chronic arterial hypertension.

5. To study the association of the polymorphic marker C1846A of the CYP2B6 gene with the efficacy and safety of bisoprolol therapy in patients with chronic arterial hypertension.

6. To analyze the perinatal outcomes in the examined patients.

Scientific novelty of the work:

For the first time, the state of the sympathoadrenal system was studied by the value of β-adrenoreception of erythrocyte membranes (β-ARM) in practically healthy pregnant women and in pregnant women with arterial hypertension. It was shown that a physiologically proceeding pregnancy is characterized by moderate hypersympathicotonia (β-ARM up to 25–35 conventional units).

It has been established that excessive hypersympathicotonia (β-ARM > 50 conventional units) is a prognostically unfavorable factor that determines the complicated course of pregnancy and a high rate of adverse perinatal outcomes.

It has been shown that such a parameter of twenty-four-hour blood pressure monitoring as the circadian blood pressure rhythm can be considered as a marker of the development of gestosis in women with arterial hypertension.

It has been established that β-ARM values of less than 50 conventional units may serve as one of the criteria for the effectiveness of monotherapy with the cardioselective β-adrenoblocker bisoprolol in pregnant women with arterial hypertension.

For the first time, genetic testing was performed in pregnant women to identify a possible association of the polymorphic marker C1846A of the CYP2B6 gene with the efficacy and safety of antihypertensive therapy with the β-adrenoblocker bisoprolol, and no such association was shown.

Practical significance:

The work substantiates the need for repeated twenty-four-hour blood pressure monitoring to assess the blood pressure level, the circadian profile, and to monitor the effectiveness of antihypertensive therapy.

It is advisable to include in the comprehensive examination of pregnant women with arterial hypertension a method for assessing body adrenoreactivity by the value of β-ARM, which makes it possible to predict adverse events of the gestational period, a high rate of perinatal complications, and the individual sensitivity of patients with arterial hypertension to β-adrenoblockers.

The absence of an association between the polymorphic marker C1846A of the CYP2B6 gene and the efficacy and safety of antihypertensive therapy with the β-adrenoblocker bisoprolol necessitates the search for other genetic factors.

Main propositions of the thesis submitted for defense:

1. In practically healthy pregnant women and in patients with chronic arterial hypertension, an increase in the functional activity of the sympathoadrenal system is observed, as reflected by β-ARM values exceeding 30 conventional units.

2. Pronounced hypersympathicotonia and the presence of pathological types of the circadian blood pressure profile are unfavorable factors for the complicated course of pregnancy and perinatal outcomes in women with arterial hypertension.

3. The individual effectiveness of therapy with β-adrenoblockers and dihydropyridine calcium antagonists is determined by the level of body adrenoreactivity and is not associated with the polymorphic marker C1846A of the CYP2B6 gene.

Implementation of the results

The obtained research results and the main recommendations are used in the practical work of the specialized cardiology department for pregnant women with diseases of the cardiovascular system of City Clinical Hospital No. 67 of the Moscow Department of Health, the specialized maternity hospital for pregnant women with diseases of the cardiovascular system of City Clinical Hospital No. 67 of the Moscow Department of Health, and in the work of the women's consultation clinic of City Clinical Hospital No. 71 of the Moscow Department of Health.

The dissertation was discussed and approved at a joint meeting of the staff of the Department of Internal Diseases of the Dental Faculty of MGMSU, the Department of Therapy No. 1 of FPDO MGMSU, the Institute of Clinical Pharmacology of the Federal State Institution BD ESMP of Roszdravnadzor, and the physicians of City Clinical Hospital No. 67 of Moscow on 5 November 2008 (Protocol No. 10).

The materials of the dissertation were reported and discussed at the XXX Jubilee Final Conference of Young Scientists of MGMSU in 2008, the I All-Russian Conference "Problems of Women's Health and Ways to Solve Them" in 2007, the Russian National Congress of Cardiologists in 2007, the All-Russian Conference "Problems of Women's Health and Ways to Solve Them" in 2008, and the VI Conference with International Participation "Problems of Quality of Life in Healthcare" in 2008.

Publications

Based on the presented work, 10 scientific papers have been published, including 2 in journals recommended by the Higher Attestation Commission of the Russian Federation.

Personal contribution of the applicant

It is confirmed by the provided act of verification of primary material; the journal of clinical studies of 160 patients; and the report on the conduct of the study. The author personally performed the clinical examination of patients for the scientific research, assessed the activity of the sympathoadrenal system by the value of β-adrenoreception of erythrocyte membranes, performed twenty-four-hour blood pressure monitoring, Holter ECG monitoring, ultrasound examination of the fetus with Doppler measurement of uteroplacental and fetal blood flow, collected material for genetic testing, actively participated in their comprehensive laboratory and instrumental examination, and performed the statistical processing of the results. Overall, the personal contribution is estimated to exceed 80%.

Volume and structure of the work

The dissertation consists of an introduction, a literature review, chapters of original research, conclusions, practical recommendations, and a list of references. The work is presented on 149 pages of typewritten text, illustrated with 18 figures and 38 tables. The bibliographic index includes 201 literature sources, of which 86 are domestic and 115 are foreign.