RU2741621C1 - Method for treatment of intrauterine synechia - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates namely to obstetrics and gynecology and can be used for treatment and prevention of recurrence of intrauterine synechia. For its purpose dissection of intrauterine synechiae is performed by means of surgical hysteroscopy, followed by intraoperative intrauterine subendometrial injection of platelet-rich autoplasm using a semi-rigid needle for surgical channel of hysteroscope at several points of injection, namely 2 points in bottom area, lateral walls of uterus, 4 points in anterior area and posterior walls of uterus in amount of 0.2 ml for each injection to the depth of 5 mm. Uterine cavity is irrigated with platelet-rich autoplasma in a volume of 15 ml using a catheter for intrauterine insemination on the 2nd and 3rd days after the operation.

EFFECT: method enables activating regenerative processes in endometrium due to local and systemic action of growth factors and cytokines contained in platelets.

1 cl, 2 ex

Description

The invention relates to medicine, namely to obstetrics and gynecology, and can be used for the treatment and prevention of recurrence of intrauterine synechia.

Intrauterine synechiae (IV) occupy one of the important places in the structure of endometrial pathology due to the high frequency of menstrual irregularities in the form of hypomenorrhea, amenorrhea, as well as reproductive disorders such as miscarriage and infertility. One of the main etiological factors of the occurrence of VS is considered iatrogenic - trauma of the endometrium as a result of curettage in the postpartum period or during abortion, as well as during operations accompanied by opening the uterine cavity.

At the present stage of development of reproductive surgery, hysteroscopic adhesiolysis (dissection of adhesions) is rightfully considered the main stage in the treatment of intrauterine synechia. At the same time, in recent years, preference has been given to the use of mechanical energy in order to minimize thermal damage to the endometrium. Despite the significant success of minimally invasive surgical methods, the rate of recurrence of the disease, especially with significant damage to the uterine cavity, remains high. So, with moderate severity of VS, the recurrence rate reaches 23.5%, and with severe - 62.5%. This necessitates the development and application of effective schemes for complex treatment.

Despite the large number of proposed treatment options, there is no consensus regarding the management of the postoperative period after surgical dissection of intrauterine synechiae. Most authors agree on the need for hormone therapy, with preference given to the appointment of higher doses of estrogens in combination with gestagens. There are reports of the use of sildenafil citrate, the mechanism of action of which is based on a positive effect on nitric oxide synthase isoforms in the uterus and an increase in the vasodilator effect. For the same purpose, various options for physiotherapy are used. Intrauterine devices and balloons, anti-adhesion gels based on hyaluronic acid and carboxymethyl cellulose are used as methods for preventing the re-formation of the sun. Attempts are being made to use implants made from the amniotic membrane in order to reduce the risk of VS formation. However, the use of these methods does not give the desired effect, and the use of drugs and allogeneic materials has a number of side effects, including allergic reactions. In this regard, the use of platelet-rich plasma (PRP) in the treatment of patients with VS seems to be quite promising.

The pathogenetic mechanism of action of PRP is primarily associated with growth factors and cytokines contained in platelet alpha granules - platelet growth factor, transforming growth factor β, insulin-like growth factor, vascular endothelial growth factor, etc., participating in the processes of mitogenic activity, proliferation and migration. cells. In addition, there are reports of the ability of platelets to activate peripheral blood mononuclear cells, which produce anti-inflammatory interleukin-10, which is involved in tissue regeneration.

PRP has a number of undeniable advantages: the absence of immune responses in the recipient due to the use of autologous plasma, good tolerance, both intracavitary and parenteral administration. In addition, it should be noted the high reproducibility of methods for obtaining OTP and their low cost.

In this regard, the aim of the present invention was to increase the effectiveness of complex treatment of women with intrauterine synechiae using platelet-rich autoplasma.

The closest analogs to the claimed are several methods with intrauterine administration of drugs.

A method is proposed for the treatment of intrauterine synechiae (patent RU 2 716 143 C1, published 2020.03.06) using intrauterine irrigation with a bovgialuronidase solution with cavitated ultrasound at a frequency of 25 kHz for 6 minutes, followed by peloid therapy (the introduction of a tampon with therapeutic mud at a temperature of 38-41 ° C in rectum and the simultaneous application of mud on the lower abdomen for 20 minutes). The procedures are carried out from the 5th to the 10th day of three consecutive menstrual cycles. The disadvantage of this method is the absence of a surgical stage of treatment, which excludes its use in cases of moderate and severe lesions of the uterine cavity.

Also proposed is a method for the treatment of chronic endometritis and synechiae of the uterine cavity (patent RU 2 581 912 C1, published on 2016.04.20.), In which the drug of recombinant biodegradable hyaluronic acid "Revie reform" is injected intrauterinely three times in an amount of 2 ml, and the first time is injected for 5 -7 day of the menstrual cycle immediately after the hysteroscopy, and then the injections are carried out on the 3-4th and 7-8th day of the next menstrual cycle. The disadvantage of this method is its low efficiency with an average and high severity of the adhesive process in the uterine cavity, the absence of adhesiolysis before re-administration of the drug.

Also proposed is a method for the treatment and prevention of recurrence of intrauterine synechiae through intrauterine administration of drugs (patent RU 2 582 226 C1, published 2016.04.20.). For this, hysteroscopy is carried out, followed by the installation of medicinal substances against the background of hormonal therapy. Using a pediatric Foley catheter, which is inserted into the uterine cavity and through the holes in the distal end of the catheter, a pre-prepared mixture of 100 mg filgrastim and 1.5 ml of mesogel is injected. The mixture is administered daily for 6 days. The invention helps to activate the regenerative processes of the endometrium due to local prolonged immunostimulation, to increase the efficiency of the implementation of in vitro fertilization programs, to ensure rapid relief of the inflammatory process and restoration of the endometrium.

Disadvantages of the method: relatively fast flow of filgrastim solution from the uterine cavity to the outside and, accordingly, shortening of the period of active exposure to endometrial cells.

A method for the prevention of intrauterine synechiae after intrauterine surgical interventions (patent RU 2 722 261 C1, published 2020.05.28) by means of intrauterine administration of antiadhesion gel antiadhesin 3 ml followed by tamponade of the cervical canal lumen for 24 hours by introducing a stepped plug into the uterine cavity and cervix is also proposed. ... The disadvantage of this method is the introduction of only anti-adhesion gel, which creates a film barrier, and the absence of a biostimulating effect on the endometrium.

The use of platelet-rich autoplasma has been proposed to increase the effectiveness of assisted reproductive technologies in patients with repeated ineffective attempts at implantation (Patent RU 2 669 726 C1, published 2018.10.15). The preparation of the patient's endometrium is carried out according to a standardized protocol of hormone replacement therapy against the background of monitoring the growth of the endometrium, from 3/4 day of the cycle, estradiol valerate 2 mg is prescribed 2 times a day and a transdermal form of estradiol at a starting dose of 1.25 g 2 times a day, and as support of the luteal phase, micronized progesterone is used vaginally in a daily dose of 90 mg and an oily solution of progesterone 1% - 1 ml intramuscularly once a day, and the transfer of viable embryos is performed on the 6th day of progesterone administration, and on the 10/11 day of the cycle after ultrasound assessment of endometrial thickness intrauterine perfusion of 1.0-1.5 ml of autologous platelet-rich blood plasma is performed using a catheter for intrauterine insemination. The method increases the expression of growth factors in the endometrium, which leads to an increase in the thickness of the endometrium and an increase in the likelihood of a successful result of assisted reproductive technology.

The closest to the claimed is a method of treating a thin endometrium (RU 2 646 508 C1, published 2018.03.05), which consists in a single irrigation of the uterine cavity with platelet-rich autoplasma in an amount of 0.5-1 ml as pregravid preparation or against the background of hormone replacement therapy in the late phase of the menstrual cycle proliferation, with the simultaneous introduction of platelet-rich autoplasma, paracervically at the border of the anterior and lateral parts of the vaginal fornix to a depth of 0.5 cm with a volume of 1.5 ml on one side and on the other at 17 and 19 hours. The method allows to stimulate the growth of the endometrium by increasing the blood supply in the mucous membrane of the uterus in the absence of complications and a low degree of pain.

Until now, in modern medical practice, there is no data on the treatment of women with intrauterine synechiae by using platelet-rich autoplasma.

The proposed method is carried out as follows:

1. Technique for obtaining OTP:

On the day before surgery, after signing an informed consent, 400 ± 50.0 ml of whole blood was taken from the patient in a blood component collection unit in a blood bag (JMS Singapure) with an anticoagulant CPDA - 63 ml. Then the container with the collected blood was centrifuged for 10 minutes in a soft G 1900 mode. After centrifugation using a plasma extractor, the platelet-rich plasma (upper and middle layers) was transferred to the second container. The container with autoerythrocytes was detached and reinfused to the patient. The second container with platelet-rich plasma was further centrifuged in a G 5100 rigid mode for 15 minutes to concentrate the platelets. After that, using a plasma extractor, the upper layer was removed into the third container - this is native plasma, and the lower layer - concentrated platelets, suspended and concentrated in plasma, were transferred to a special container for storing platelets (JMS, Singapure) in the Climatic Chamber 100 LMB Technologie GmbH (Germany) at a temperature of +22 - 24 ° С for 5 days. The cell concentration was 0.55-0.70 × 10 ¹¹ in a volume of 50.0 ml. The container was labeled. On the day of surgical treatment, 50.0 ml of PRP, under aseptic conditions, were divided into three doses of 15 ml in labeled containers for storing platelets: the first container was issued on the day of surgery, the subsequent ones were stored in a chamber at a temperature of +22 - 24 and were issued for 2 and 3 days after surgery.

2. Dissection of intrauterine synechiae is performed using a standardized method by means of surgical hysteroscopy.

3. After performing the main surgical stage, intraoperative intrauterine subendometrial injection of platelet-rich autoplasma is performed using a semi-rigid needle for the surgical channel of the hysteroscope at several points of injection (2 points in the area of the bottom, lateral walls of the uterus, and 4 points in the anterior and posterior walls of the uterus) 0.2 ml for each injection to a depth of 5 mm.

4. On the 2nd and 3rd days after the operation, the uterine cavity is irrigated with platelet-rich autoplasma in a volume of 15 ml using a catheter for intrauterine insemination.

Clinical examples

1. Patient B., 28 years old. Complaints: scanty menstruation. History of 2 pregnancies: 1 - childbirth, 2 pregnancy - two years ago, cervical. After termination of a cervical pregnancy, hypomenorrhea developed. According to ultrasound, on the 7th day of the menstrual cycle, the endometrium is intermittent, the thickness of the endometrium is from 3 to 4 mm.

Hysteroscopy revealed grade 3 intrauterine synechiae (according to the classification of the American Fertility Society), more than 2/3 of the volume of the uterine cavity is occupied by synechiae, the orifices of the fallopian tubes are not visualized. Dissection of synechia with microscissors was performed. Intraoperatively introduced platelet-rich autoplasma according to the proposed method. On the 2nd and 3rd days after the operating period, the uterine cavity was perfused with platelet-rich autoplasma. In the postoperative period, antibiotic therapy was carried out. She received cyclic hormonal therapy for 3 months.

At control hysteroscopy after 3 months: the uterine cavity increased in volume three times compared to the previous operation, the endometrium is pink thin, there are single parietal intrauterine synechiae - dissected. The postoperative period was carried out in a similar way. When observed 6 months after treatment, the menstrual cycle recovered, there are no signs of hypomenorrhea, according to ultrasound on the 7th day of the menstrual cycle, the endometrium is uniform, the thickness of the endometrium is 6 mm.

2. Patient F., 35 years old. Complaints about scanty menstruation, no pregnancy within 2 years of regular sex life without contraception. A history of 3 non-developing pregnancies, ending with curettage at a period of 8-7-6 weeks. 2 laparoscopic operations: 1 - drugs, coagulation of endometriosis foci, 2 - LS, retrograde hysteroscopy, dissection of intrauterine synechiae, resectoscopy, dissection of the intrauterine septum, coagulation of foci of endometriosis of the pelvic peritoneum (2 years ago). According to ultrasound on the 7th day of the menstrual cycle: echo signs of chronic endometritis. The thickness of the endometrium is 4 mm. Intrauterine synechiae cannot be ruled out.

Hysteroscopy revealed a 2 degree intrauterine synechiae (according to the classification of the American Fertility Society): the mucous membrane of the cervical canal is folded, in the area of the internal os there is dense intrauterine synechia, immediately behind the internal pharynx, intrauterine synechiae are determined, occupying the entire middle part of the uterine cavity, dense, rough with symptoms of fibrosis, a cavity in the form of 2 narrow passages to the mouth of the fallopian tubes. Synechium dissected with microscissors; the uterine cavity of the correct shape is formed. The mouth of the fallopian tubes from 2 sides are accessible for inspection. The endometrium in the preserved areas is thin, pale pink in color. The vascular pattern is not enhanced. Intraoperatively introduced platelet-rich autoplasma according to the proposed method. On the 2nd and 3rd days after the operating period, the uterine cavity was perfused with platelet-rich autoplasma. In the postoperative period, antibiotic therapy was carried out. Within 3 months she received cyclic hormonal therapy, physiotherapy.

With control hysteroscopy after 3 months: immediately behind the internal pharynx on the left, a single thin synechia is determined, on the left lateral wall of the uterus, single parietal synechia is dissected. The tubular corners are rendered free. Endometrium of uniform thickness, pale pink color. The uterine cavity is of normal size. The postoperative period was carried out in a similar way. When observed 6 months after treatment, the menstrual cycle recovered, there are no signs of hypomenorrhea, according to ultrasound on the 7th day of the menstrual cycle, the uterine cavity is normal in size, the endometrium is uniform, the endometrial thickness is 7 mm. After 9 months after the treatment, an independent pregnancy began and is progressing.

Thus, the proposed method for the treatment of intrauterine synechiae has significant clinical efficacy even with moderate and high severity of the adhesive process in the uterine cavity, safety and the absence of adverse reactions. The economic feasibility of the method is associated with its low cost and high reproducibility.

LITERATURE

1. Akhmerov R.R. Regenerative medicine based on autologous plasma. PlasmoliftingTM technology. - M .: Litterra, 2014.-149 p.

2. Obidnyak D.M., Gzgzyan A.M., Niauri D.A., Chkhaidze I.Z. Prospects for the use of autologous platelet-rich blood plasma in patients with repeated ineffective implantation attempts. Reproduction problems. 2017; five; S.84-88.

3. Khirieva P.M., Martynov S.A., Bystritskiy A.A., Adamyan L.V. Genetic risk factors for the formation of intrauterine synechia. Reproduction problems. 2017; T.23; # 6; 39-44.

4. Khirieva P.M., Adamyan L.V., Martynov S.A. Modern methods of prevention and treatment of intrauterine synechia. Gynecology. 2016; T. 18; # 5; 32-36.

5. Khirieva P.M., Martynov S.A., Ezhova L.S., Adamyan L.V. Clinical and morphological features of the endometrium in intrauterine synechiae: assessment of the expression of estrogen and progesterone receptors. Obstetrics and gynecology. 2018; No. 9; 48-54.

6. AAGL Advancing Minimally Invasive Gynecology Worldwide. AAGL practice report: practice guidelines for management of intrauterine synechiae. J Minim Invasive Gynecol. 2010; 206: 181-185.

7. Bougie O., Lortie K., Shenassa H., Chen L, Singh S.S. Treatment of Asherman's syndrome in an outpatient hysteroscopy setting. J. Minim. Invasive Gynecol. 2015; 22: 446-450.

8. Chang Y, et al. Autologous platelet-rich plasma promotes endometrial growth and improves pregnancy outcome during in vitro fertilization. Int J Clin Exp Med. 2015; 8: 1: 1286-1290.

9. Chen X., Sun J., Li X. et al. Antifibrotic Effects of Decellularized and LyophilizedH uman Amniotic Membrane Transplant on the Formation of Intrauterine Adhesion. Experimental and Clinical Transplantation (2019) 2: 236-242.

10. da Silva RT, Heidrich F. Therapy with use of platelet-rich plasma in orthopedics and sports traumatology: literature review, evidence and personal experience. Springer Berlin Heidelberg. 2014; 153-170.

11. Dreisler E., Kjer J.J. Asherman's syndrome: current perspectives on diagnosis and management. Int J Womens Health 2019; 11: 191-198.

12. Farimani M, Bahmanzadeh M, Poorolajal J. A new approach using autologous platelet-rich plasma (PRP) to treat infertility and to improve population replacement rate. J Res Health Sci. 2016; 16: 3: 172-173.

13. Hanstede M.M., van der Meij E., Goedemans L., Emanuel M.H. Results of centralized Asherman surgery. Fertil. Steril. 2015; 69: 860-864.

14. Kim H., Shin J., Koo H et al. Effect of Autologous Platelet-Rich Plasma Treatment on Refractory Thin Endometrium During the Frozen Embryo Transfer Cycle: A Pilot Study. Front. Endocrinol. 14 February 2019. vol. 10, p 1-9.

15. Lu H, Hu Y2, Cui Z, Jia H. Human menstrual blood: a renewable and sustainable source of stem cells for regenerative medicine. Stem Cell Res Ther. 2018 Nov 21; 9 (1): 325.

16. Nazari L, et al. Effects of autologous platelet-rich plasma on implantation and pregnancy in repeated implantation failure: a pilot study. Int J Reprod Biomed (Yazd, Iran). 2016; 14: 10: 625-628.

17. Oz M, Cetinkaya N, Bas S, Korkmaz E, et al. A randomized controlled experimental study of the efficacy of platelet-rich plasma and hyaluronic acid for the prevention of adhesion formation in a rat uterine horn model. Arch Gynecol Obstet. 2016 Sep; 294 (3): 533-40.

18. Reghini MFS, et al. Inflammatory response in chronic degenerative endometritis mares treated with platelet-rich plasma. Theriogenology. 2016; 86: 2: 516-522.

19. Zhang S, Li P, Yuan Z, Tan J. Platelet-rich plasma improves therapeutic effects of menstrual blood-derived stromal cells in rat model of intrauterine adhesion. Stem Cell Res Ther. 2019 Feb 15; 10 (1): 61.

List of cited patents

1. Method for the treatment and prevention of recurrence of intrauterine synechiae, Likhacheva Victoria Vasilievna RU 2 582 226 C1, Published: 2016.04.20.

2. A method for increasing the effectiveness of assisted reproductive technologies in patients with repeated ineffective attempts at implantation Diana Malkhazovna Obidnyak RU 2 669 726 C1, Published: 2018.10.15.

3. Method for the treatment of chronic endometritis and synechiae of the uterine cavity, Malinina Olga Yurievna, RU 2581 912 C1, Published: 2016.04.20.

4. Method for the treatment of thin endometrium, Kravchenko Elena Nikolaevna, RU 2 646 508 C1, Published: 2018.03.05.

5. Method for the prevention of intrauterine synechiae after intrauterine surgery, Dobrokhotova Yulia Eduardovna, RU 2 722 261 C1, Published: 2020.05.28.

6. Method for the treatment of synechiae of the uterine cavity, Omarpashaeva Madina Isaevna, RU 2 716 143 C1, Published: 2020.03.06.

Claims (1)

A method of treating intrauterine synechiae, characterized in that after hysteroscopic dissection of intrauterine synechiae, intraoperative intrauterine subendometrial injection of platelet-rich autoplasma is performed using a semi-rigid needle for the surgical channel of the hysteroscope at several injection points, 2 points each in the region of the bottom, lateral uterine walls, 4 in the area of the anterior and posterior walls of the uterus, 0.2 ml for each injection to a depth of 5 mm, followed by irrigation of the uterine cavity with platelet-rich autoplasma in a volume of 15 ml on the 2nd and 3rd days after surgery using an intrauterine catheter insemination.