No 12 (2022)

The review analyzes Russian and foreign literature sources on the pathogenesis of preeclampsia. The latter is considered to be an urgent and unsolved problem in modern obstetrics. The wide prevalence, the complexity of etiopathogenesis, the lack of accurate and highly informative methods for prediction and diagnosis, as well as the insufficient effectiveness of therapeutic and preventive measures are a cause of higher global maternal and perinatal morbidity and mortality rates of preeclampsia. Understanding the pathogenetic mechanisms implicated in the development and progression of preeclampsia is of fundamental importance and plays an important role in specifying the causes of this pregnancy complication, which should be treated. Conclusion: Based on the analysis of the data available in the literature, the authors summarize the current aspects of the development and progression of preeclampsia.

Uterine inversion is a puerperal complication, the incidence of which ranges from 1:1700 to 1:20 000, according to some reports. This complication is frequently accompanied by postpartum hemorrhage and hypovolemic shock, which, if not properly managed, can cause hysterectomy and even maternal death. This is a situation that is exigent and needs emergency obstetric care. Surgical treatment requires rapid recognition, intensive care, and immediate uterine repositioning either manually or surgically. An analysis of the data available in the literature, as well as the results of previous studies have shown that there is a need to develop Russian clinical practice guidelines on the organization of emergency care for puerperas with uterine inversion, the introduction of which will be able to facilitate the decision-making process when choosing obstetric tactics, as well as to reduce the frequency of surgical interventions, hysterectomies, and maternal complications. Conclusion: Puerperal uterine inversion can lead to massive blood loss and even cause maternal death. The inverted uterus should be repositioned as soon as possible, therefore, it is important to quickly implement treatment and diagnostic measures and to commit the practiced team actions of obstetricians//gynecologists and anesthesiologists, as well as midwives and operating nurses. Each obstetrician/gynecologist should be able to diagnose this rare but severe puerperal complication and to eliminate it in a timely manner.

Part 2 of the review considers various purposes of exome (targeted) sequencing to f ind the causes of reproductive losses, as well as the difficulties of using NGS in reproduction. The authors present their own data and literature ones on the use of NGS to identify lethal fetal phenotypes caused by autosomal recessive monogenic disorders (α-thalassemia; multiple pterygium syndrome, galactosialidosis; mucopolysaccharidosis type VII), autosomal dominant ones (thanatophoric dysplasia; type 2 osteogenesis imperfecta; achondroplasia; tuberous sclerosis 1) and X-linked diseases (incontinentia pigmenti, Goltz syndrome, Rett syndrome, immune dysregulation, polyendocrinopathy, and enteropathy). They thoroughly consider the use of NGS for preconception screening that allows optimization of algorithms to manage a future pregnancy: the choice of diagnostic procedures; recommendations for therapeutic abortion; counseling, pregnancy planning, donation, and prenatal genetic testing. The paper presents the features of and prospects for the introduction of NGS in practical reproductology. Conclusion: It is necessary to introduce exome sequencing in accordance with the concept of a clinical genetic reproduction passport, especially at the preconception stage, along with the already expanding neonatal screening, which will be able to increase birth rates, to ensure a safe pregnancy, and to enhance the reproductive potential of the Russian population.

As the body grows old, the risk of cancers increases. Aging is one of the most significant risk factors for cancer. The peak (65%) incidence rate of cancers is noticed at the age of 63 years. However, at a younger age of30-59years, a third (33%) of all neoplasias is detected in women. Young people are most often diagnosed with hereditary cancer syndromes that result from genetic defects. Early diagnosis and the latest advances in anticancer therapy form the basis for increasing survival and reducing cancer death rate. After the successful completion of therapy for a malignant neoplasm, some patients need effective contraception, because the onset of pregnancy may be associated with a high risk for progression or recurrence of the neoplastic process. To date, there have been no clearly formulated recommendations or protocols for prescribing contraception in patients with a family history of cancer. This paper gives the results of the work of the European Society of Contraception Expert Group that has attempted to identify the most common types of cancers in women who are likely to need this or that contraception methods to be prescribed after their cure. Information on the characteristics of treatment, its impact on fertility, efficiency/ risks to health, possible benefits and contraindications to the available contraception methods is analyzed for each type of cancer. The obtained information (of studies and reviews) is summarized in the guidelines for contraception for each type of cancer. Due to a large amount of information, the results are presented in two parts. Part 1 includes the contraception methods used after breast and reproductive organ cancers. Part 2 summarizes results and recommendations regarding contraception in women with a history of skin, gastrointestinal, hematological, and endocrine cancers. Conclusion. Patients with a family history of cancer should be informed about the level of safety and efficiency of this and that contraception method. Most experts hold to the idea that non-hormonal contraception methods should be a priority. However, emergency contraception is permitted in any case.

Female poor responders to ovarian stimulation (OS) are a large portion (9-24%) of patients in the in vitro fertilization (IVF) programs. In accordance with the POSEIDON classification, the patients with a poor response to OS are stratified into 4 groups by age, the number of antral follicles (AF), and the level of anti-Mullerian hormone (AMH). Particular emphasis is placed on patients with an unexpected poor response to gonadotropic stimulation with the normal parameters of the ovarian reserve (POSEIDON Group 1) that is associated with reduced ovarian sensitivity to gonadotropins due to individual genetic variability. The review considers the contribution of single nucleotide polymorphisms (SNPs) of the genes of gonadotropins, steroid hormones and their receptors, AMH, P450 aromatase, and growth differentiation factor 9 (GDF9) to the genesis of an unpredictable poor and suboptimal response to OS. It discusses whether it is expedient to apply a pharmacogenetic approach to OS in this group of patients in order to select the optimal gonadotropins and to adjust their doses to increase the effectiveness of the IVF program. Conclusion: A priori understanding of individual genetic variability in a patient population with an unpredictable poor ovarian response and preserved ovarian reserve parameters along with known clinical and laboratory markers will assist in developing personalized OS protocols in the IVF program.

Objective: To analyze the course and outcomes of pregnancy in patients with severe preeclampsia concurrent in some cases with a history of fetal growth restriction and/or Hemolysis, Elevated Liver enzymes and Low Platelets (HELLP) syndrome according to different regimens for the prevention of these complications (acetylsalicylic acid (ASA) or ASA and low-molecular-weight heparin (LMWH)) during subsequent pregnancy. Materials and methods: An investigation conducted in the V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology in 2016 and 2022 included 48 pregnant women with a family obstetric history (severe preeclampsia, HELLP syndrome, fetal growth restriction), who were divided into 2 groups: 1) 20 pregnant women who took only ASA for prophylactic purposes; 2) 28 pregnant women who were treated with ASA and LMWH. Clinical, laboratory, and instrumental examinations were made. Results: The incidence of preeclampsia in the ASA groups was 50%, that of fetal growth restriction was 30%; combination (ASA and LMWH) therapy caused a 1.75-fold decrease in the incidence of preeclampsia from 50 to 28.6% (p=0.113) and a 4.43-fold reduction in that of fetal growth restriction (p=0.045). The incidence of early-onset severe preeclampsia was slightly lower in Group 2; however, there were no statistically significant results. It was also noted that there was no case of recurrent antenatal fetal death in this pregnancy during anticoagulant therapy started no later than 16 weeks’ gestation in women with a history of antenatal fetal death. Conclusion: The investigation revealed a positive trend in reducing the incidence of early-onset severe preeclampsia and fetal growth restriction and showed the effectiveness of preventing antenatal fetal death with the combined prophylactic use of ASA and LMWH. The findings may suggest that it is expedient to add LMWH at a prophylactic dose to ASA in the first trimester of pregnancy. Clearly, further studies are needed to recruit more patients.

Objective: To investigate the characteristic features of late postpartum hemorrhage that required endovascular intervention. Materials and methods: This is a retrospective analysis of medical records of 31 patients who were treated between 2006 to 2022. Inclusion criteria were late postpartum hemorrhage (24 h-42 days after delivery) and the use of uterine artery embolization (UAE). Results: Bleeding started on day 8 (6;14) postpartum, including 20/31 (64.5%) on days 2-10, 9/31 (29%) on days 12-21, and 2/31 (6.5%) on days 35-38. Twenty-three of the 31 (74.2%) patients (subgroup I) underwent uterine vacuum aspiration. Continued blood loss of1000 (600;1350) ml after vacuum aspiration was an indication for UAE. Surgical hemostasis was performed in 1/23 (4.3%) patients after UAE. A complicated course of the postoperative period was observed in 4/23(17.4%) patients. In 8/31 (25.8%) patients (subgroup II), UAE was performed in the first stage with an initial blood loss of650 (400;2000) ml. The postpartum period was uneventful and the patients were discharged on the fourth day. Conclusion: Massive late postpartum hemorrhage is rare. UAE is effective in stopping late postpartum hemorrhage in the absence of residual placental tissue in the uterine cavity established by echography.

Aim: To conduct a pilot study of whole exome sequencing in couples with unexplained infertility. Materials and methods: Whole exome sequencing was performed using DNA from peripheral blood samples obtained from six married couples (women and men). The samples were purposefully selected in the group of unexplained infertility on the basis of clinical and anamnestic findings, laboratory and instrumental parameters, and the results of using assisted reproductive technologies. Assessment of clinical significance (pathogenicity) of the identified variants was based on the American College of Medical Genetics and Genomics (ACMG) guidance for the interpretation of sequence variants and the recommendations of the Russian Society of Medical Geneticists for interpretation of the obtained data using next-generation sequencing. Results: Whole exome sequencing in 6 married couples with unexplained infertility showed no pathogenic/likely pathogenic variants related to patients phenotype, as well as incidental (secondary) findings according to ACMG list of genes. Conclusion: Whole exome sequencing in the most typical patients with unexplained infertility found no variants, which are known to be associated with infertility.

Objective: To study specific features of cervicovaginal fluid lipidome in patients with vulvovaginal atrophy (VVA) in postmenopause under exposure to dynamic quadripolar radiofrequency (DQRF). Materials and methods: The study included 60patients aged 46- 65 years (the mean age 54.8 (5.1) years) with the symptoms of VVA. All patients underwent treatment: dynamic quadripolar radiofrequency was used in the area of vulva and vagina in group 1 (4 procedures with 2-week intervals); DQRF with radioporation technique with application of cream containing 0.5 mg estriol was used in group 2 (4 procedures with 2-week intervals); and local hormonal treatment with cream containing 0.5 mg estriol was used in group 3 (8 weeks of treatment). Lipid extraction from cervicovaginal fluid was performed using modified Folch method at two-time points - before and 1 month after treatment. Results: Lipidome analysis compared 3 groups of samples of cervicovaginal fluid- in 40 patients before and after exposure to DQRF and in 20 patients before and after treatment with local estrogens according to treatment regimen. 6 compounds were isolated. Their levels were statistically significantly higher in the group of patients who were exposed only to radiofrequency - Anandamide (18:2, n-6), DG 18:0/18:0/0:0, DG 18:0/16: 0/0:0, LTB4-dimethylamide, N-hydroxy arachidonoilamine, Virodhamin. The levels of Anandamide (18:2, n-6), LTB4-dimethylamide, N-hydroxy arachidonoilamine and Virodhamin were statistically significantly lower in patients who were exposed to radiofrequency in combination with estrogens for treatment of VVA in postmenopause. Conclusion: This article describes an innovative approach to alternative treatment of women with VVA in postmenopause using DQRF. The results of lipidome analysis of cervicovaginal fluid after exposture to DQRF are published for the first time. Further study and research in the field of high energy methods for VVA treatment are necessary to assess the effectiveness and safety of long term radio wave exposure.

Background: Topical hormonal therapy with estriol is the treatment standard for women with genitourinary syndrome of menopause. The appropriate dosages of estriol to treat its symptoms and to minimize a risk to the patient continue to be debated. Objective: To compare the efficacy and safety of vaginal agents containing estriol 50 pg/g (gel) and 500pg/0.5 g (cream) in the treatment of postmenopausal atrophic vaginitis. Materials and methods: Design: this was an active controlled Phase III multicenter, open-label, prospective, randomized comparative parallel group clinical trial. It was conducted in 8 Russian research centers in 2016 to 2018. The trial included 120 postmenopausal patients with a history of vulvovaginal atrophy (VVA) lasting for at least one year, who were randomized to 2 groups; 1) 60 patients received vaginal estriol gel 50 pg and 2) 60 received vaginal estriol cream 500pg according to the regimens (the patients used the agents on their own at night every day once daily for 3 weeks; then maintenance therapy was performed, by reducing the dose twice a week for 9 weeks). The total therapy duration was 12 weeks. The main outcome criterion was an increase in the vaginal epithelium maturation value (VEMV). The relief or disappearance rate of VVA symptoms and clinical signs, vaginal pH value, and safety were also calculated. Results. The increase in VEMV relative to the baseline was 21.4 (SD 21.1) and 18.9 (SD 21.6) points in Groups 1 and 2, respectively; A=2.47(95% CI: -4.07; 9.01 points; p=0.27), which did not exceed the upper CI limit of 10% and suggested that there was no difference in VEMV between both drugs after 12 weeks of therapy. There was relief or disappearance of VVA symptoms and a vaginal pH decrease that was comparable between the groups. The drugs compared were well tolerated, there were a total of15 adverse events (AEs): 5 (33.3%) AEs in Group I and 10 (66.7%) in Group 2, no serious AEs were registered. The established AEs were consistent with the known safety information; the number of reported cases was comparable in both groups. Conclusion: The eff icacy of ultra-low dose (50pg/day) vaginal estriol gel in improving the symptoms and clinical signs of VVA is similar to that of standard dose vaginal cream (500pg/day). The safety of both agents is comparable.

Objective: To evaluate the efficacy of follitropin delta versus follitropin alfa used in IVF programs in terms of the number of obtained oocytes, metaphase II (MII) oocytes, the rate of fertilization, high-quality blastocyst yield, the proportion of euploid embryos, as evidenced by preimplantation genetic testing for aneuploidy (PGT-A), and pregnancy rate. To evaluate the safety, usability, and patient compliance to the application of follitropin delta. Materials and methods: The investigation included 35 patients undergoing IVF treatment at 22 to 36 years of age. Controlled ovarian hyperstimulation (OHS) was done using the individualized doses of follitropin delta. The daily dose of the drug was 5 to 12 ig in accordance with its instructions. The follitropin alfa group consisted of 35 patients aged 21 to 36 years. The starting daily dose of the drug was 100 to 225IU. Results: Among the patients who underwent ovarian stimulation with follitropin delta, (42.8%) (15/35) of cases were observed to have a normal ovarian response (10-19 oocytes), none of the patients had a poor response (1-3 oocytes), 28.6% (10/35) of cases had a suboptimal response (4-9 oocytes), and 28.6% (10/35) had a hyperergic response (20 or more oocytes). In the follitropin alpha group, there was a normal ovarian response (10-19 oocytes) in 51.4% (18/35) of cases, poor and suboptimal responses (1-3 and 4-9 oocytes, respectively) in 17.1% (6/35) and 22.9% (8/35) of patients, respectively, and a hyperergic response (20 or more oocytes) in 8.6% (3/35) of cases. In the follitropin delta group, the mean number of oocytes retrieved was 15.4; of them, MII oocytes were 76% (11.7/15.4). In the follitropin alfa group, there was an average of10.9 obtained oocytes; of them MII oocytes were 74% (8.1/10.9). The fertilization rate was 76.9% (9.0/11.7) in the follitropin delta group and 80.2% (6.5/8.1) in the follitropin alfa group. At the same time, the high-quality embryos among the MII oocytes were 43.6% (5.1/11.7) and 47% (3.8/8.1) in the follitropin delta and follitropin alpha groups, respectively. The pregnancy rate after embryo transfer in the cycle with follitropin delta and follitropin alfa was 43.8% (7/16) and 40.9% (9/22), respectively. The risk of OHS syndrome (OHSS) was noted in 14.3% (5/35) of patients in the follitropin delta group and 11.4% (4/35) in the follitropin alfa group. Mild OHSS was observed in all cases. Conclusion: The individualized gonadotropin dose in IVF programs based on initial patient characteristics (body weight and AMH level) ensures an adequate ovarian response, by maintaining a high stimulation efficiency and pregnancy rate. At the same time, it is noteworthy that, when using follitropin delta, there was no poor response to OHS, but there was a low suboptimal response rate. In addition, the starting follitropin alfa dose required upward correction in 11.4% (4/35) of cases. Both examined group showed a comparable risk of OHSS.

The term lichen ruber planus (LRP) is understood as a chronic inflammatory disease of the skin and mucous membranes, including the genitals, which is caused by CD8+ cytotoxic T lymphocytes. Despite the fact that the dermatosis was described more than 100 years ago, the exact causes of its development have not been identified to date. There is an increase in the number of cases of genital LRP concurrent with lichen sclerosus, focal neurodermatitis, atrophic vulvovaginitis, genitourinary syndrome, vulvar candidiasis, desquamative vaginitis, herpetic and papillomavirus infections. The review summarizes an update on the dinical presentations of genital LRP, diagnosis, treatment approaches, drug dosage regimens, and its duration. Taking into account the fact that the pathogenesis of LRP is based on the formation of an inflammatory infiltrate, topical glucocorticosteroids are the drugs of choice for the treatment of LRP in the anogenital area. Conclusion: Genital LRP is a disease associated with a large number of causes and precipitating factors. Numerous studies have shown the efficiency of topical glucocorticosteroid therapy in combination with moisturizing and emollient agents. When properly administered and used, current topical corticosteroids are safe for patients with genital LRP.

Background: The steady increase in the number of patients with a history of even one caesarean section leads to a rise in the frequency of such form of ectopic pregnancy, as pregnancy in the scar. The choice of the optimal organ-sparing treatment option for this category of patients depends on timely diagnosis. The formation of retrochorial hematoma that accompanies non-developing pregnancy in the scar in the early stages significantly complicates the diagnosis. Case report: The paper describes a clinical case of a reproductive-aged patient, in whom a long episode of menometrorrhagia ended with the formation of a round mass up to 8 cm in diameter in the area of the scar after cesarean section at the uterine isthmus. Erroneously diagnosed incomplete abortion during uterine pregnancy and uterine fibroids served as a reason for uterine curettage complicated by massive blood loss. The final diagnosis was established after pathological mass excision and metroplasty. Conclusion: A pathological uterine mass localized in the scar area after cesarean section, which is suddenly detected during abnormal uterine bleeding, requires the exclusion of pregnancy in this area. Correct diagnosis of non-developing pregnancy in the scar is the key to successful organ-sparing surgery.