Features of prevention of fetal growth retardation in pregnant women with chronic hypertension

The lack of effective methods to prevent the development of fetal growth retardation in highrisk pregnant women remains a significant problem of modern obstetrics, which determines the relevance of the study. The aim of the study was to examine the effectiveness of monoprophylaxis of fetal growth retardation using aspirin at a dose of 150 mg, starting at 12-13 weeks of gestation, pregnant women with chronic hypertension. In order to apply and implement the proposed prevention of fetal growth retardation, all pregnant women with chronic hypertension were divided into two groups. The patients were divided into groups randomly. To prevent the development of fetal growth retardation, patients in group A received acetylsalicylic acid at 150 mg/day, patients in group B received acetylsalicylic acid at 100 mg/day. Primary examination of pregnant women in a prospective study was performed during pregnancy 11-12 weeks in all groups, which included: history taking, general clinical examination, blood pressure measurement, obstetric and gynecological examination according to clinical protocols of the Ministry of Health of Ukraine No 417 from 15.07.2011, No 676 dated 31.12.2004. Clinical and instrumental examination was performed: blood pressure and ECG monitoring, Doppler examination. Childbirth and initial assessment of the condition of newborns were performed in accordance with the current orders of the Ministry of Health of Ukraine with the assessment of the condition on the Apgar scale and the result of anthropometry (determination of mass and growth rate). It was found that the age characteristics of the group of pregnant women did not differ statistically significantly: the average age of patients in group A reached 27.3±1.6 years, group B 28.1±1.8 years. According to the obstetric and gynecological history, the women did not differ. It should be noted that statistically significant differences between the main group and the comparison group by the degree of chronic hypertension (grade 1 and 2) were not detected: 30 % of women in group A and 35 % of group B had chronic hypertension grade 1, 70 % and 65 %, respectively chronic arterial hypertension of 2 degrees. Among the concomitant lesions in pregnant women were determined: obesity 8 women of group A (26.7 %), 8 people (25.8 %) of group B; varicose veins in 3 women (10.0 %) of group A, 4 people (12.9 %) of group B; pathology of the urinary system in 2 cases (6.6 %) in group A and in 2 people (6.45 %) of group B; pathology of the thyroid gland 2 women (6.6 %) of group A, and 1 person (3.22 %) of group B, anemia of pregnant women in 4 women (13.3%) of group A, and 4 people (12.9 %) of group B; chronic viral hepatitis C in remission in 1 woman of group B (3.22 %). As a result of the analysis of pregnancies and complications of childbirth, we found that the appointment of acetylsalicylic acid in addition to standard treatment of chronic arterial hypertension in accordance with clinical protocols at a dose of 150 mg/day helped reduce the incidence of disorders of uteroplacental and fetal circulation by 2.7 times, fetal growth retardation by 8,8 times and small to gestational age fetus 4.8 times compared with the results of patients who received acetylsalicylic acid at a dose of 100 mg/day.


Introduction
In the structure of causes of perinatal morbidity and mortality, cardiovascular pathology ranks first among extragenital diseases [10,11]. Among these cardiovascular diseases, chronic hypertension occupies a leading place.

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The results of studies have shown that even moderate chronic hypertension, starting from the first trimester, poses an increased risk of cerebrovascular disorders and complications of normal pregnancy [7,14,16,20]. The basis of insufficiency in the mother-placenta-fetus system are changes in fetal and uterine-placental complexes with a violation of adaptive-compensatory mechanisms at the molecular, cellular and tissue levels, which contributes to the violation of transport, trophic, endocrine, metabolic and antitoxic function of the placenta. in the future -to fetal growth retardation [13].
Disorders of uteroplacental circulation are characterized by: impaired arterial blood flow and difficulty of venous outflow from the intervillous space, changes in the rheological and coagulation properties of maternal and fetal blood (hypercoagulation, hyperaggregation and increased viscosity); decreased capillary blood flow in the chorionic villi [1,13,15]. Nowadays, due to the lack of effective methods of prevention of fetal growth retardation, this problem remains relevant. This is due to the fact that the treatment of fetal growth retardation at a late stage of diagnosis, especially in severe cases of fetal growth retardation, is ineffective and does not solve the problem. Early diagnosis and early initiation of preventive measures are important [2,5,6,10,18].
The aim of the research was to study the effectiveness of monoprophylaxis of fetal growth retardation using aspirin at a dose of 150 mg, starting from 12-13 weeks of pregnancy for pregnant women with chronic hypertension.

Materials and methods
In order to apply and implement the proposed comprehensive prevention of fetal growth retardation, all pregnant women with chronic hypertension were divided into two groups. The distribution of patients with chronic hypertension into groups A and B was performed randomly: each patient with odd laboratory values was assigned to group A (main group -30 pregnant women with diagnosed chronic hypertension of 1-2 degrees), with even -to group B (comparison group -31 pregnant women with diagnosed chronic arterial hypertension of 1-2 degrees), all patients received therapy according to the clinical protocol of the Ministry of Health of Ukraine.
To prevent the development of fetal growth retardation, patients in group A received acetylsalicylic acid at 150 mg/ day, patients in group B received acetylsalicylic acid at 100 mg/day.
Criteria for inclusion in the study: pregnant women with diagnosed chronic arterial hypertension of the 1st degree; pregnant women with diagnosed chronic arterial hypertension of the 2nd degree.
Criteria for exclusion of pregnant women from the study: diagnosed chronic stage III hypertension; diabetes; multiple pregnancy; the presence of chronic diseases in the pregnant woman in the stage of decompensation; severe infectious diseases (HIV infection, tuberculosis, syphilis, progressive viral hepatitis B and C); chromosomal and genetic disorders; thrombophilia; perinatal infections; systemic connective tissue diseases; heart disease (defects, myocarditis); moderate or severe anemia; lung disease; oncological diseases; pregnancy that occurred with the help of assisted reproductive technologies.
The diagnosis of "chronic hypertension" was established in accordance with the recommendations of the Ukrainian Association of Cardiologists and the European Society of Cardiology for the treatment of hypertension, according to the current clinical protocol of the Ministry of Health of Ukraine № 676 from 31.12.2004. All pregnant women were examined by a physician, cardiologist. None of the study participants had contraindications to the appointment of the proposed drug prophylaxis.
Comprehensive clinical examination of patients included the study of obstetric and gynecological and somatic history, assessment of pregnancy, childbirth and the condition of the newborn, evaluation of clinical, laboratory and instrumental research methods.
Primary examination of pregnant women in a prospective study was performed during pregnancy 11-12 weeks in all groups, which included: history taking, general clinical examination, blood pressure measurement, obstetric and gynecological examination according to clinical protocols of the Ministry of Health of Ukraine № 417 from 15.07.2011, № 676 dated 31.12.2004. On the basis of "Regional perinatal center", Zaporizhzhia maternity hospital № 1 conducted clinical and instrumental examination: blood pressure monitoring and electrocardiography, Doppler examination.
Childbirth and initial assessment of the condition of newborns were performed in accordance with the current orders of the Ministry of Health of Ukraine with the assessment of the condition on the Apgar scale and the result of anthropometry (determination of mass and growth rate).
Chronic hypertension and fetal growth retardation were diagnosed according to the current clinical protocols of the Ministry of Health of Ukraine № 676 from 31.12.2004, № 782 from 29.12.2005. All pregnant women were examined by a physician, cardiologist.
Data on the results of examination and treatment of pregnant women were stored, processed and calculated by modern methods of analysis using the statistical package of the licensed program STATISTICA®13 ("StatSoft", USA, № of license AXXR712D833214FAN5). The statistical significance of differences in groups in the assessment of qualitative indicators was determined using the criterion Chi-square (χ 2 ) using the Yates correction.

Results
The age characteristics of the group of pregnant women did not differ statistically significantly: the average age of patients in group A reached 27.3±1.6 years, group B -28.1±1.8 years (p>0.05). According to the obstetric and gynecological history, women did not differ (Table 1). It should be noted that statistically significant differences between the main group and the comparison group by the degree of chronic hypertension (1st and 2nd degree) were not detected: 30 % of women in group A and 35 % in group B had chronic arterial hypertension of the 1st degree, 70 % and 65 %, respectively -chronic arterial hypertension of the 2nd degree (p>0.05).
In pregnant women with chronic arterial hypertension of the 1st and 2nd degrees, preeclampsia was detected in about a third of women in both group A and group B, but disorders of uteroplacental and fetal circulation were significantly less common in pregnant women in group A ( Table 2).
Fetal growth retardation was also statistically significantly less common in patients of group A ( Table 3).
The fetus was small before gestational age in 2 women of group A and 10 in group B (p<0.05). Other complications of childbirth did not differ in frequency in both groups of pregnant women (p>0.05) ( Table 4).

Discussion
In the presence of extragenital pathology, in particular chronic arterial hypertension in pregnant women, treatment must include antihypertensive drugs. Clinical protocol of the Ministry of Health of Ukraine № 676 dated 31. 12.2004 in the group of high-risk pregnant women regulates the use of methyldopa (central α2-blocker), clonidine (affects the neurogenic regulation of vascular tone), calcium channel blockers, selective β2-adrenergic antagonist, calcium and use of aspirin in doses of 60-100 mg/day from 20 weeks of pregnancy and before childbirth (improves the depth of placentation and blood circulation in the spiral arteries) [4,12,17,18].
Despite the action of appropriate antihypertensive drugs, to reduce the risk of fetal growth retardation in pregnant women with chronic hypertension, such treatment is often insufficient due to a number of complications, including fetal growth retardation [3,8,9,19]. Thus, currently the search for effective methods to prevent the development of fetal growth retardation remains an urgent problem of modern obstetrics. The use of aspirin at a dose of 150 mg up to 16 weeks of pregnancy is promising for women at increased risk, which reduces the likelihood of developing early preeclampsia and fetal growth retardation by 60-80 %, according to the recommendations of FIGO (2016).
As a result of the research, we did not find significant differences between the groups of patients of both groups by age, obstetric and gynecological history and the structure of the disease. It was found that daily use of aspirin 150 mg/day, started at 12-13 weeks of pregnancy, significantly reduces the incidence of uteroplacental and fetal circulation, fetal growth retardation and small to gestational age in pregnant women with chronic hypertension. The use of aspirin 150 mg/day, reduced the incidence of preeclampsia, reduced the risk of sub-and decompensated placental insufficiency, which increased the frequency and timing of full-term pregnancy and made  Table 3. Frequency of fetal growth retardation in groups of patients.  it possible to significantly reduce perinatal effects. The earlier the start of prophylaxis with aspirin at a dosage of 150 mg/day, the more effective the prevention of preeclampsia and the development of fetal growth retardation in pregnant women with chronic hypertension. It should be noted that these studies conducted at 12-13 weeks of gestation had small groups, and we believe that large randomized controlled trials are needed to confirm our results. With the development of a method for predicting the high risk of fetal growth retardation, it will be possible to perform randomized trials to monitor groups at high risk of fetal growth retardation from early pregnancy and timely aspirin prevention. It remains unknown whether there is a gestational age at which aspirin prophylaxis becomes ineffective, which is the subject of our further research.

Conclusions
As a result of analysis of pregnancies and complications of childbirth, we found that the appointment of acetylsalicylic acid in addition to standard treatment of chronic hypertension in accordance with clinical protocols at a dose of 150 mg/day helped reduce the incidence of disorders of uteroplacental and fetal circulation by 2.7 times, fetal growth retardation -8.8 times and small to gestational age fetus -4.8 times compared with the results of patients receiving acetylsalicylic acid at a dose of 100 mg/day. значною проблемою сучасного акушерства, що визначає актуальність дослідження. Метою дослідження було вивчення