No 11 (2023)

Objective: To summarize the current data on optimal thromboprophylaxis in thrombophilic women undergoing in vitro fertilization (IVF) and embryo transfer, primarily with a focus on strategies for preventing venous thromboembolism (VTE); to discuss the possibility of preventing pregnancy complications in pregnant women with thrombophilia.

Materials and methods: The databases and services, namely PubMed, Wiley, Scopus and Google scholar, have been searched for articles on thrombophilia and assisted reproductive technology-related pregnancy over the past 10 years. No restrictions were imposed on the design of the study. The search was carried out using MESH keywords.

Results: Hereditary thrombophilia is a genetic condition that increases the risk of thromboembolic diseases, especially during pregnancy. However, it is not recommended to have routine screening for hereditary thrombophilia in asymptomatic patients. Pregnant women with a previous history of VTE or with first-line relatives with this disease should be screened for thrombophilia genes. Low molecular weight heparins and acetylsalicylic acid are effective methods of thromboprophylaxis; anticoagulant therapy should start in the first trimester and continue in the postpartum period. The patients with antiphospholipid syndrome may have a high antibody titer, these patients should refrain from IVF until the antibody titer decreases. Immunosuppressive therapy is an effective method of reducing antibodies.

Conclusion: The history of repeated IVF failures and habitual miscarriage is not an indication for examination for thrombophilia genes; however, these women should be examined for the presence of antiphospholipid syndrome.

The article presents the analysis of the data of modern literature on the actual aspects of fetal growth retardation (FGR) verification in terms of molecular genetic diagnostic methods. The review includes the data of foreign and Russian scientists published in PubMed and eLibrary. The problem of the FGR diagnosis remains relevant, despite the “golden standard” of diagnosis meeting the criteria adopted by the international consensus of Delphi which was introduced into the practice of obstetricians, gynecologists and ultrasound specialists. The article presents the results of the analysis of the literature data on the role of molecular genetic markers in the FGR pathogenesis, various mechanisms of the FGR development in terms of genomics, transcriptomics, as well as the analysis of their combination with the factors of the hemostasis system. Special attention is paid to the mechanisms of the FGR development due to the changes in immune processes, inflammatory reactions, as well as the changes in the processes of angiogenesis in the placenta. This study also examines the possibility of diagnosing a fetus with FGR using the assessment of the level of extracellular fetal DNA, the processes of methylation of genes-regulators of metabolic pathways and a number of immune processes. The literature data on the epigenetic regulation of gene expression in FGR are of particular interest; microRNAs isolated from the placenta and circulating in the blood of pregnant women are studied. The search for specific minimally invasive markers currently continues as they have already allowed the clinicians to improve the existing criteria for diagnosis.

Stress is an important factor that influences the work of many systems, and it can cause an imbalance in the human body. The issue of stress and its consequences is extremely important, since there is a rapid increase in behavior disorders caused by stress and stress-associated diseases all over the world (various forms of neuroses and depressions) which affect from 25 to 35% of the population. The impact of stress on the female reproductive system is of particular interest. Stress can be considered to be one of the most common and underestimated factors which contribute to the female infertility. The main aspect of scientific research is the study of the work and interaction of the nervous, immune and endocrine systems under the influence of external stimuli, namely stress factors. The analysis of the literature data indicates the adverse impact of stress factors on the outcomes of assisted reproductive technology programs, the processes of oogenesis and embryogenesis. Our literature review systematizes the data on the close relationship between the central nervous system, immune and endocrine systems; each of these systems contributes to the female reproductive health at various levels.

Conclusion: The optimal functioning of the female reproductive system under stress directly depends on the function of the central nervous system, endocrine and immune systems, as well as their direct interaction. It is necessary to search and develop new personalized approaches to the prevention and treatment of stress-related conditions. Further studies devoted to this problem can be beneficial not only for scientific researchers, but they can also have a high practical significance for clinicians.

Objective: To evaluate the clinical and laboratory efficacy and safety of nifuratel for women with diseases accompanied by pathological discharge from the genital tract.

Materials and methods: This systematic review was conducted according to the PRISMA checklist. The analysis included controlled clinical studies for the period 1972–2023 which evaluated the efficacy and safety of oral and/or vaginal administration of nifuratel in women over the age of 18 with bacterial vaginosis, aerobic vaginitis, candidiasis vulvovaginitis, mixed vaginitis and trichomoniasis.

Results: After selecting the proper publications and excluding duplicates, the qualitative analysis included 14 studies (5 randomized and 9 non-randomized); totally, there were 3,337 patients including 544 pregnant women. The quantitative synthesis and meta-analysis included 9 clinical studies. According to received data, a statistically significant difference in clinical and microbiological efficacy was determined in favor of nifuratel in comparison with other drugs (odds ratio (OR)=1.03, 95% CI [1.00, 1.07], p=0.03 and OR=1.15, 95% CI [1.04, 1.27], p=0.005, respectively). There was a statistically significant difference in the frequency of relapses after a course of therapy in favor of nifuratel in comparison with other drugs (OR=0.36, 95% CI [0.19, 0.68], p=0.001). None of the included studies showed any serious side effects after the treatment with the drug.

Conclusion: The use of nifuratel both as monotherapy and in combination with nystatin surpasses other drugs in clinical and microbiological efficacy in the treatment of diseases accompanied by pathological discharge from the genital tract in women; it also shows a lower frequency of relapses. Nevertheless, additional well-planned studies with standardized criteria for evaluating results and long-term follow-up periods can allow the women with vaginitis and bacterial vaginosis to make a better choice among antimicrobial therapy options.

The central-acting antihypertensive drug Dopegyt and the calcium channel blocker Cordaflex are commonly used in obstetric practice for managing hypertensive disorders during pregnancy. However, in early-onset preeclampsia (ePE), their efficacy is notably diminished because of its limited impact on endogenous nitric oxide (NO) production, a critical vasodilator.

Objective: 1) Investigate NO production and factors influencing vascular tone regulation in ePE patients undergoing different antihypertensive therapy regimens: Dopegyt monotherapy and two-drug therapy (Dopegyt+Cordaflex), and 2) examine the relationship between NO, maternal hemodynamic parameters, the fetal-placental unit, and factors affecting vascular tone regulation.

Materials and methods: This study included 49 patients at up to 340 weeks of gestation. The control group consisted of 16 pregnant women with healthy pregnancies. The study group included 33 pregnant women with PE, with 16 receiving antihypertensive monotherapy (Group 1) and 17 receiving two-drug antihypertensive therapy (Group 2). All pregnant women underwent: 1) 24-hour blood pressure monitoring to assess hemodynamic status and determine parameters characterizing changes in central aortic pressure, intracardiac hemodynamics, and arterial stiffness; 2) Doppler assessment of fetoplacental and uteroplacental blood flow; and 3) determination of blood factors regulating vascular tone, thrombosis, and markers of cardiovascular insufficiency using ELISA.

Results: Patients in the study group exhibited significant disruption in endogenous NO production, coupled with vasodilator/vasoconstrictor imbalance, as well as impaired maternal and fetal-placental unit hemodynamics, which were more pronounced with two-drug therapy. There was an association between NO levels and maternal hemodynamic parameters and concentrations of factors regulating vascular tone.

Conclusions: The findings of this study indicate that the lack of a NO-stimulating effect on the endothelium of Dopegyt monotherapy and Dopegyt in combination with Cordaflex in patients with ePE leads to significant hemodynamic disturbances, justifying the early delivery of these patients.

Objective: This study aimed to estimate the influence of maternal pregestational and gestational diabetes mellitus on the risk of congenital anomalies in newborns.

Materials and methods: We conducted a cohort study using data from the Murmansk and Arkhangelsk County birth registries, which contain information on the health of pregnant women and neonatal diaseses in newborns of 134,884 pregnancies.

Results: From 2006 to 2017, 4862 newborns with congenital anomalies were identified, resulting in a prevalence of 36.2 per 1,000 births. Pregnant women with pregestational diabetes mellitus had a higher risk of giving birth to babies with anomalies of the eye, ear, face, and neck, circulatory system, and other congenital anomalies (Q80-Q89), including multiple anomalies. Pregnant women with gestational diabetes mellitus had a higher risk of having children with respiratory system anomalies.

Conclusion: Diabetes mellitus in women increases the risk of congenital anomalies in their children. Prognostic models developed to determine the risk of congenital anomalies should include information regarding the presence of maternal diabetes.

Objective: To define the characteristics of the contents of macro- and microelements in blood serum before labor and in first stage of labor in women with weak contractions.

Materials and methods: The study included 86 women with full-term pregnancy, who were divided into 2 groups after delivery depending on the characteristics of the course of labor: the main group included the patients with weak contractions (n=46), the comparison group included the women, in whom labor and delivery happened without without anomalies labor contractions (n=40). Serum potassium, sodium, ionized calcium, total calcium, magnesium, inorganic phosphorus, and iron levels were analyzed before labor and in the first stage of labor.

Results: The women with weak contractions before labor have higher serum levels of potassium, iron, potassium-to-magnesium ratio and lower sodium-to-potassium ratio versus women with normal physiologic birth. In women with hypotonic uterine contractions in labor, magnesium levels are low and calcium to magnesium ratio and potassium to magnesium ratio is higher versus the comparison group.

Conclusion: In women with weak labor contractions, there are changes of macro- and microelement contents in blood serum. The obtained results may indicate the reasons for inadequate excitability and contractility of the myometrium in these patients.

Objective: To identify piwiRNAs in the culture medium of a blastocyst associated with cell ploidy and the implanting ability of an embryo after transfer into the uterine cavity.

Materials and methods: The study included 73 couples whose culture medium of 93 embryos was analyzed; among them there were 53 euploid blastocysts (according to the results of PGT-A) with implantation (27 embryos) and without implantation (26 embryos) after transfer of cryopreserved embryos into the uterine cavity in ART programs using cyclic hormone therapy; 40 blastocysts were aneuploid. piwiRNAs were isolated from 20 µl of the culture medium with the miRNeasy Serum/Plasma Kit (Qiagen) and analyzed using deep sequencing on the NextSeq 500/550 platform (Illumina, USA). The obtained data were subsequently validated by quantitative polymerase chain reaction in real time with the miScript II RT Kit and miScript SYBR Green PCR Kit (Qiagen, Hilden, Germany).

Results: Two logistic regression models were built after quantification of hsa_piR_020497 and hsa_piR_020829, or hsa_piR_016677 and hsa_piR_020829, which have 93% and 100% specificity, respectively, in identifying euploid blastocysts with high implantation potential. The miRanda algorithm was used to analyze potential target genes of piwiRNAs associated with aneuploidy, which are involved in the formation of the spindle apparatus, the development and functioning of kinetochore, and cytokinesis.

Conclusion: A noninvasive method of selecting euploid embryo with a high implantation potential for transfer into the uterine cavity in ART programs was developed. At this stage of the study, this method is additional but not alternative to the PGT-A method.

Objective: This study aimed to compare the distribution of different human papillomavirus (HPV) genotypes in various cervical lesions and estimate the prevalence of low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL) when one or more HPV genotypes are detected.

Materials and methods: We conducted an analysis of HPV testing using the Quantum-21 test system in 19236 women aged 18–81 years who visited the V.I. Kulakov NMRC for OG&P between November 2011 and April 2022. Among these women, 5700 tested positive for HPV and were included in this analysis. We retrospectively examined the laboratory findings used to confirm this diagnosis. The patients were divided into three groups based on the histological verification of the diagnosis. Group 1 included 186 patients with chronic cervicitis, Group 2 included 341 patients with LSIL, and Group 3 included 292 patients with HSIL.

Results: Analysis of HPV genotype distribution revealed that HPV type 16 was the most prevalent (23.6%), followed by genotypes 44 (12.3%), and 31 (12.3%). The evaluation of HPV genotype prevalence showed that in 66.6% of cases, only one HPV type was detected, whereas in 20.8% of cases, two types were detected. Three types were found in 7.4% of cases and four or more types were detected in 5.2% of cases. Examination of the ratio between single and multiple HPV types revealed that the detection of multiple genotypes was significantly more frequently associated with LSIL than with HSIL (24.9% vs. 5.5%, respectively).

Conclusion: The results of this study demonstrated that the distribution and representation of HPV genotypes in cervical pathology in our sample differed from global trends. Furthermore, the study showed that the detection rate of multiple HPV types decreased with increasing grades of cervical lesions.

Objective: To analyze the clinical efficacy of combined therapy of vulvovaginal candidiasis in pregnancy.

Materials and methods: The study included 40 women who were pregnant from 13 to 34 weeks with a confirmed diagnosis of vulvovaginal candidiasis. The patients were divided into two equal groups: the main group included the patients who received therapy for vulvovaginal candidiasis with an antifungal drug in combination with the immunomodulatory drug Superlymph and restoration of vaginal flora with probiotics; the control group included the patients who received only antifungal therapy. Efficacy was evaluated on the basis of the analysis of clinical manifestations, microbiological and microscopic examination of vaginal discharge, pro-inflammatory cytokines.

Results: Clinical manifestations were reduced in both groups after receiving the therapy, but four patients from the control group complained of itching and discharge from the genital tract. The frequency of relapses significantly decreased and the duration of remission increased in the main group. After treatment microscopic examination showed a statistically significant decrease in the number of fungi in both groups, and the number of leukocytes and epithelial cells was decreased in the main group. Bacteriological examination revealed complete elimination of the pathogen in the main group, Candida species were isolated in 15% of patients (n=3) in the control group.

Conclusion: Complex therapy of recurrent vulvovaginal candidiasis in pregnant women with antifungal drugs in combination with the immunomodulatory drug Superlymph and probiotics normalized the vaginal microecology, reduced the number of relapses, and did not have a negative impact on maternal and perinatal outcomes.

Objective: To evaluate the clinical and laboratory parameters of women with bacterial vaginosis before and after two-stage therapy with prebiotic vaginal gel.

Materials and methods: Twenty patients with bacterial vaginosis aged 28–46 years (median 37±9) were examined and treated in two stages. Vapigel was prescribed at the second stage of treatment for bacterial vaginosis (after antibiotic therapy) at a dose of one tube once a day (before bedtime) for seven days intravaginally. Clinical and laboratory parameters were evaluated before treatment (Visit 0), on days 8+2 from the beginning of the course of treatment with Vapigel (Visit 1) and on days 30+2 after the end of the second stage of treatment (Visit 2).

Results: There was a positive dynamics of clinical symptoms immediately after the end of therapy (Visit 1) and after 30 days (Visit 2). After the patients received the two-stage therapy with Vapigel prebiotic, the frequency of detection of Lactobacillus spp. in the concentration of 106 CFU/ml increased to 60% by Visit 1 and to 90% by Visit 2. The proportion of patients with clinically significant amounts of facultative and obligate anaerobic microorganisms tended to decrease immediately after the end of two-stage treatment and a month later. During the month after the end of the course of therapy, there were no clinical signs of a recurrence of bacterial vaginosis in 19/20 (95%) women; normal flora was confirmed 30 days after the end of treatment in 18/20 (90%) women.

Conclusion: The use of the Vapigel prebiotic intravaginally is beneficial for restoring the microbiocenosis of the vaginal microflora at the second stage of therapy of bacterial vaginosis. It is necessary to study the possibility of using Vapigel as a monotherapy for bacterial vaginosis as an important component in the system of measures aimed at reducing the use of antimicrobial drugs in routine clinical practice.

Currently, import substitution of medications is one of the priorities of the state policy in the field of healthcare. One of the main criteria for evaluating a generic medication is confirmation of its bioequivalence to the relevant original drug.

Objective: To study the comparative pharmacokinetics and evaluate the bioequivalence of the generic contraceptive drugs PlanyGens in healthy female volunteers after a single oral intake of the drugs on an empty stomach.

Materials and methods: It is an open comparative randomized cross-sectional study with two stages and two subsequent studies. The pharmacokinetic parameters of levonorgestrel, etonogestrel (the active metabolite of desogestrel), nomegestrol, ethinylestradiol and estradiol were determined in the blood plasma of healthy volunteers after a single oral intake of the compared drugs on an empty stomach. The following pharmacological parameters were calculated for the analyzed drugs: AUC0–72, AUC0–∞, Cmax, Tmax, T½, kel, f’, f’’, Cmax/AUC, MRT.

Results: The research presents the results of bioequivalence studies on contraceptives PlanyGens levo, PlanyGens dezo 20, PlanyGens dezo 30, PlanyGens nome produced by “Pharmasyntez-Tyumen” LLC, Russia and relevant original (reference) drugs Microgynon (Bayer Pharma AG, Germany), Mercilon (N.V. Organon, Netherlands), Marvelon (N.V. Organon, Netherlands), and Zoely (N.V. Organon, Netherlands). The 90% confidence intervals for the ratio of the geometric mean AUC0–72 and Cmax parameters lay in the range of 80.00–125.00% in bioequivalence studies of drugs. The safety profiles of all the studied drugs are comparable to the safety profiles of the relevant original drugs.

Conclusion: The bioequivalence of the studied generic contraceptive drugs PlanyGens to the relevant original drugs was confirmed.

Thanatophoric dysplasia is an autosomal dominant congenital disorder associated with primary bone dysplasia. Thanatophoric dysplasia is caused by mutation of the gene that encodes fibroblast growth factor 3 (FGFR3).

Case report: The paper presents two clinical observations of thanatophoric dysplasia. In both cases, pregnant women were referred for invasive prenatal diagnosis which identified the normal male karyotype of the fetus.

In the first case, a number of markers of chromosomal abnormalities were detected in the first trimester using ultrasound. There were no markers allowing to suspect skeletal dysplasia. The ultrasound examination performed at 19–20 weeks’ gestation revealed multiple congenital malformations including shortening and bowing of the limbs. The boy who was born at 36–37 weeks’ gestation after surgical delivery had the following congenital malformations: shortening of limb bones, hypoplasia of the chest, anomalies of the ribs and spine, secondary hypoplasia of the lungs. The child died in the neonatal period.

In the second case, there were the following abnormalities of the musculoskeletal system in the fetus at 14–15 weeks’ gestation: shortening and deformation of the tubular bones of the arms and legs, hypoplasia of the chest, clover-shaped skull. The patient provided the consent for termination of pregnancy.

Pathogenic variants in the FGFR3 gene were identified during a subsequent study of DNA which was isolated from chorionic villi. In the first case, the c.1948 A>G variant was identified, while the c.742 C>T was revealed in the second one; both variants were previously described as pathogenic.

Conclusion: It is necessary to confirm the diagnosis of thanatophoric dysplasia using molecular genetic research methods and ultrasound assessment showing the signs of fetal skeletal pathology in order to clarify the medical indications for termination of pregnancy and to determine the prognosis for future offspring in the family.

Background: Pregnancy in patients with uterine malformations such as complete intrauterine septum with duplicated cervix is rare and it is associated with the risk of complications. There is no unified guidance on the management and delivery.

Case report: A 35-year-old female patient with a complete intrauterine septum and duplicated cervix had her third twin pregnancy (in each uterus) with the help of assisted reproductive technologies (ART). The woman had a previous history of two miscarriages and secondary infertility. There was a threat of miscarriage at 14–15 weeks gestation, the pregnancy was prolonged to 34 weeks 4 days. A cesarean section was performed after premature rupture of the membranes. The woman gave birth to live premature babies: a female with a weight of 2172 g and height of 46 cm long, and a male with a weight of 2416 g and height of 50 cm; they were both in a satisfactory condition.

Conclusion: This is an extremely rare clinical case when a woman with a complete intrauterine septum, duplicated cervix, and a history of habitual miscarriage becomes pregnant with twins after ART. The favorable outcome of this pregnancy is determined by accurate interpretation of the ultrasound image and the correct sequence of actions during pregnancy for prolongation and delivery.