RU2525533C1 - Method of treatment and prevention of recurrences of intrauterine synechiae - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: for treatment and prevention of recurrences of the intrauterine synechiae within the range of pre-implantation preparation of the endometrium, heteroscopy with further installation of the child's Foley catheter into the uterine cavity is performed. The catheter balloon is filled with 2 ml of the physiological solution. The catheter is installed for 7 days, on which instillagel in a dose of 2.5 ml is introduced into the uterine cavity through holes in the distal end of the catheter on 1, 3, 5, 7 day alternating it with introduction of filgrastim in a dose of 100 mcg on 2, 4, 6 days. Instillation is realised at the background of performed hormonal therapy.

EFFECT: effective treatment and prevention of recurrences of the intrauterine synechiae due to activisation of regenerative processes of the endometrium and performing an immunomodulating impact on it with taking into account the terms of ending of a risk of possible adhesion formation.

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Description

The invention relates to medicine, namely to obstetrics and gynecology, and can be used for the treatment and prevention of relapse of intrauterine synechia as part of preimplantation preparation of the endometrium.

One of the reasons for infertility and the inefficiency of using assisted reproduction methods is the pathology of the endometrium, which is manifested in the formation of fibrous adhesions in the uterine cavity (synechia), which prevents optimal implantation of the embryo. The frequency of this pathology in infertility reaches 5-7%. The causes of the formation of synechia can be trauma to the basal layer and / or inflammation of the uterine mucosa. Endometrial trauma occurs during curettage of the uterine cavity: abortion, diagnostic curettage; surgical interventions on the uterus, removal of submucosal nodes, surgery for malformations, cesarean section, intrauterine contraception (intrauterine device). Also, the formation of adhesions in the uterine cavity can lead to a chronic inflammatory process in the endometrium. Various microorganisms can cause inflammation after complicated births, abortions, and surgical operations. Very often a combination of factors is observed - mechanical trauma with joining inflammation.

The clinical manifestations of the adhesive process in the uterine cavity are very diverse, and depend on the severity of the lesion. In mild cases, the woman does not complain, and synechiae are detected as a find during ultrasound. With gross and numerous synechiae, menstrual irregularities occur in the form of a decrease in menstrual blood loss, a delay in menstruation until its complete cessation - amenorrhea.

At the first stage of treatment, the majority of patients with intrauterine synechia use the surgical method. A modern method for eliminating synechia is “intrauterine” surgery using hysterectomy.

Before surgery, it is advisable to conduct an examination to exclude an infectious factor, to conduct antibiotic therapy, taking into account the sensitivity of the selected microflora. It must be remembered that the formation of synechia in the uterine cavity in patients with primary infertility without an indication of any intrauterine interventions in the anamnesis occurs only with tuberculous endometritis and requires examination by a TB doctor and appropriate treatment.

After the surgical manipulations and obtaining the results of a histological examination of the removed material, it is necessary to conduct the second stage of treatment using physical and medical methods. The purpose of this stage is to prevent the re-formation of adhesions in the uterine cavity, increasing the sensitivity of the endometrial receptor apparatus to the effects of hormonal substances and optimizing the condition of the endometrium. Physiotherapeutic effect improves healing processes, improves local immunity.

There is a method when, for the prevention of relapse of intrauterine synechia, the introduction of intrauterine devices during hysteroresectoscopy is recommended (medical medical portal medichelp.ru edited by G. M. Savelyeva, V. G. Brusenko).

However, the effectiveness of the method remains quite low, possibly due to the fact that the IUD in this case is a foreign body that provokes the development of an adhesion process in the endometrium and its area is insufficient to completely distinguish between the anterior and posterior walls of the uterus and does not prevent them from “sticking together”.

A known method of treating infertility due to endometriosis. (Patent No. 2237490, IPC A61K 38/19, A61K 31/56, A61P 5/24, published on 10/10/2004). The proposed method is carried out by conducting complex therapy of endometriosis using Reaferon-EU (human recombinant interferon-alpha-2b protein synthesized by a bacterial strain of Escherichia coli) according to the developed scheme: reaferon 1 million units intramuscularly at 5, 6, 8, 10, 12 , Day 14 of the menstrual cycle, then dyufaston 10 mg per os in a cyclic mode from 15 to 25 days of the menstrual cycle. Duphaston was used for hormone therapy, since this drug does not affect ovulation; and the onset of pregnancy is possible against the background of ongoing therapy. The proposed scheme is used for three to six menstrual cycles with an estimate of the frequency of pregnancy.

The disadvantage of this method is its inefficiency in the presence of chronic endometritis and intrauterine synechia.

Closest to the claimed is a method of treating tubal-peritoneal infertility in women with chronic endometritis (Patent No. 2281108, IPC A61K 35/48, A61K 31/67, A61K 31/7036, publ. 10.08.2006), which consists in conducting hysteroscopy with subsequent instillation of the drug composition according to the following scheme: on the first and third days of treatment, prednisone 30 mg, dioxidine 0.5% solution in an amount of 50 ml, metrogil 5.0 ml, lidase 32 units, antibiotic taking into account the sensitivity of microflora, as local therapy at night vaginally injected candles M kmimor morning spend douching vagina chamomile solution; on the second and fourth days of treatment, prednisone 30 mg, Instillagel 6-11 ml are intrauterine administered, a tampon containing Vishnevsky ointment in the amount of 20 ml at night is injected locally into the posterior vaginal vault; on the fifth, seventh and ninth days, intrauterine administration of dioxidine 0.5% solution in an amount of 50 ml, metrogil 5.0 ml, cycloferon 0.5 ml, lidase 32 units, antibiotic taking into account the sensitivity of microflora, McMimore candles are administered vaginally at night, in the morning douching of the vagina with a solution of chamomile; on the sixth, eighth and tenth days, Instillagel 6 ml, dimexide 5 ml are administered intrauterine, a tampon containing Vishnevsky ointment in the amount of 20 ml at night is administered into the posterior vaginal vault, immunomodulating therapy and systemic enzyme therapy are simultaneously carried out; course of treatment 10 procedures.

The disadvantages of the prototype: massive pharmacological load (9 drugs), the inconvenience of use, in the presence of intrauterine synechia does not exclude their recurrence, taking into account the use of glucocorticoid and antimicrobial drugs, the effect on the endometrium is bacteriological and cytostatic rather than regenerative.

The objective of this invention is to improve the quality of treatment by preventing the re-formation of intrauterine synechiae, activating the regenerative processes of the endometrium, increasing the efficiency of the implementation of the program of in vitro fertilization (IVF).

The problem is achieved by the method of treatment and prevention of recurrence of intrauterine synechia, including hysteroscopy with subsequent instillation of drugs against the background of hormonal therapy. The instillation is carried out using a Foley pediatric catheter, which is inserted into the uterine cavity, a balloon is filled with 2 ml of physiological saline. The catheter is installed for 7 days, during which 2.5 ml are inserted into the uterine cavity through the holes in the distal end of the Instillagel catheter on days 1, 3, 5, 7, alternating with the introduction of filgrastim 100 μg for 2, 4, 6 days.

The novelty of the invention:

- The instillation is carried out using the Foley's pediatric catheter. A catheter is inserted into the uterine cavity, a balloon is filled with 2 ml of physiological saline. The balloon mechanically separates the walls of the uterus and prevents them from sticking together for 7 days. The small outer diameter of the catheter allows atraumatic insertion into the uterine cavity. Mechanical differentiation of the walls of the uterus prevents the fusion of synechiae, which prevents the formation of adhesions. Double sterile packaging provides aseptic catheterization and allows the catheter to be inserted directly from the bag without touching it. The duration of the catheter installation is due to the fact that the process of adhesion ends at 6-7 days from the start of the operation. The small outer diameter of the catheter and the presence of a conductor in it make it possible to atraumatically introduce it into the uterine cavity.

- Into the uterine cavity we introduce aseptic and regenerating substance. From the first day of treatment, 2.5 ml instillagel is introduced into the uterine cavity through openings in the distal end of the catheter on days 1, 3, 5, 7, alternating with the introduction of filgrastim 100 μg for 2, 4, 6 days. Instillagel has a local aseptic and analgesic effect. Filgrastim has a regenerative effect on the endometrium, contributes to an increase in its thickness, and also additionally has an immunomodulatory effect by increasing the number of immunocompetent cells in the endometrium.

In the literature available to us there is no data on the use of the Foley pediatric catheter for the introduction of instillagel and filgrastim in obstetric and gynecological practice for the treatment of intrauterine synechia.

The set of essential features of the invention allows to obtain a new technical result, namely to improve the quality of treatment by preventing the formation of synechiae and increasing the activity of regenerative processes of the endometrium. The method provides a quick relief of the inflammatory process and restoration of the endometrium. Conducted rehabilitation treatment can increase the effectiveness of the implementation of in vitro fertilization programs.

Preparations for the implementation of this method are selected based on the following. The composition of the Instillagel preparation includes 2.0 g of lidocaine, 0.05 g of chlorhexidine, 0.06 g of methyl 4-hydroxybenzoate, and contains hydroxyethyl cellulose and propylene glycol as a gel base. The therapeutic effect of Instillagel is based on the fact that the drug has a lubricating, disinfecting and local anesthetic effect. It has a bactericidal effect on a wide range of gram-positive and gram-negative flora, as well as on fungi of the genus Candida, genital mycoplasmas and Trichomonas vaginalis (A. M. Savicheva, M. A. Bashmakova, S. L. Zatsiorskaya. Antimicrobial effect of the drug Instillagel on microorganisms of the genital tract // Journal of obstetric and female diseases., No. 3, 2004, pp. 23-27.). The bactericidal effect occurs 5-10 minutes after administration of the drug. Instillagel does not have the side effects characteristic of antibiotics (dysbiosis, allergic reactions).

Filgrastim is a hematopoietic growth factor. Used in oncology and hematology. The mechanism of action is based on the activation of receptors on the surface of hematopoietic cells, the stimulation of cell proliferation, differentiation and functional activation. Human granulocyte colony stimulating factor (G-CSF) is produced by monocytes, fibroblasts and endothelial cells. G-CSF regulates the production of neutrophils and the release of functionally active neutrophils from the bone marrow into the blood. G-CSF is not a specific factor only for neutrophils; in vivo and in vitro studies have shown its minimal direct effect on the production of other hematopoietic cells. In Phase I of clinical trials with the inclusion of 96 patients with various non-myeloid malignancies in the study, it was shown that filgrastim when administered in various ways - in / in (1-70 μg / kg 2 times a day), s / c (1-3 μg / kg once a day) or by prolonged s / c infusion (3-11 μg / kg / day) - dose-dependently increases the number of neutrophils circulating in the blood with normal functional activity (shown in the study of chemotaxis and phagocytosis). After completion of filgrastim therapy, the number of leukocytes returned to the initial level in most cases within 4 days. An increase in the number of lymphocytes on the background of filgrastim was recorded in healthy patients and in patients with cancer. In clinical trials, it was noted that when calculating the number of leukocytes differentially, the formula shifts to the left with the appearance of granulocyte progenitor cells, including promyelocytes and myeloblasts. In addition, the appearance of Dohle-bodies, an increase in granulation of granulocytes, and hyper-segmentation of neutrophils were noted. These changes were transient. The use of filgrastim is effective in patients with neutropenia, in patients preparing for bone marrow transplantation; with persistent neutropenia in patients with advanced stage of HIV infection (the absolute number of neutrophils is 1000 cells / μl or less); for mobilization of peripheral stem cells (including after myelosuppressive therapy), as well as for severe or recurrent infections (history) in the last 12 months.

The use of filgrastim locally by introducing into the uterine cavity can have both a regenerative effect on the endometrium, contributing to an increase in its thickness, and an additional immunomodulating effect due to an increase in the number of immunocompetent cells in the endometrium.

The figure shows a diagram of a Foley pediatric catheter. The Foley catheter has a balloon balloon 1, a closed end with two side holes 2, a drain funnel 3, a balloon inflation hole 4, an anti-return valve 5.

The method is as follows. After hysteroresectoscopy and separation of intrauterine synechiae, a Foley catheter is placed in the uterine cavity. The small outer diameter of the catheter and the presence of a conductor in it enable its atraumatic insertion into the uterine cavity without the use of bullet forceps and a probe even in nulliparous patients. After the Foley catheter is inserted through the cervical canal into the uterine cavity, the balloon 1 is filled through the inflation hole 4 and the non-return valve 5 with physiological saline in an amount of 2 ml, thereby achieving mechanical separation of the uterine walls and preventing them from sticking together. Subsequently, the plastic conductor is removed, drugs are introduced through the drainage funnel 3, which has an outlet into the uterine cavity through openings 2. The catheter is installed for 7 days, during which 2.5 ml instillagel is administered into the uterine cavity for 1, 3, 5, 7 days in alternation with filgrastim 100 μg for 2, 4, 6 days. This treatment is carried out on the background of hormone replacement therapy with natural estrogens: drugs containing 17B-estradiol or estradiol valerate and drugs of natural progesterone or its derivatives. The introduction of estrogen begins from the first day of the postoperative period and lasts until the 25th day of the menstrual cycle. Over the past 10 days, gestagen is added to estrogens. The proposed scheme allows, if necessary, to increase the dose of the estrogen component. In the next two cycles, hormone therapy is prescribed for 21 days (from 5 to 25 days) by any two-phase preparations convenient for the patient, recommended for HRT. Currently, preference is given to transdermal forms of estrogen. In our work, we use Divigel on the skin for 1-2 g per day as an estrogen component and Duphaston 20-40 mg per day as a progestogen. Of the two-phase preparations for HRT, we use Femoston 1/10 or 2/10 with the addition of duphaston 10-20 mg per day from 16 to 25 days of the cycle.

The proposed method treated 7 patients. After the treatment, one of the patients became pregnant spontaneously, three out of 4 patients participating in the IVF program got pregnant within six months and two patients are preparing for the IVF program. As part of the pre-implantation preparation of the endometrium, all patients underwent control hysteroscopy 3 months after resectoscopy, and no recurrence of intrauterine synechia was detected.

Clinical example: Patient Ch., 36 years old, complained of a lack of pregnancy for 1 year of regular sexual activity without contraception. A history of 1 pregnancy ended in urgent delivery 13 years ago. The survey was conducted: according to the results of her husband’s spermogram, normospermia, sperm survival is high, the MAR test is negative; contrast ultrasonic echosalpingoscopy - fallopian tubes are passable; ultrasonic folliculometry - chronic anovulation against the background of a latent form of congenital dysfunction of the adrenal cortex (VCD). According to the results of PCR of the separated cervical canal, ureaplasma parvum and gardnerella vaginalis were detected, treated with her husband, control smears were negative. According to the results of smears for oncocytology of the cervix, mild dysplasia was detected. Ultrasound examination of the pelvic organs revealed echographic signs of chronic endometritis in the form of small hyperechoic inclusions in the basal layer of the endometrium. After a course of antibacterial, anti-inflammatory, resorbable, immunomodulating therapy, surgical sanitation of the cervix by the radio wave method in the form of conization of the cervical tissue, diagnostic curettage of the cervical canal followed by histological examination of the tissue was performed. The histological conclusion is stationary endocervicosis, focal chronic cervicitis, focal proliferation of basal squamous cells. After complete epithelialization of the mucous membrane of the cervix, artificial insemination with the husband’s sperm was performed twice on the background of stimulation of ovulation with urinary gonadotropins, glucocorticoid therapy without effect. Given the lack of effect of the treatment, an attempt was made to in vitro fertilization (IVF). After stimulation of superovulation according to the “long” protocol, 17 oocytes were obtained; on day 5, two embryos were transferred at the blastocyst stage of quality grade 1 (4aa) with an endometrial thickness of 13 mm. Implantation did not happen.

After an unsuccessful IVF attempt for diagnostic purposes, hysteroscopy, a biopsy with histological examination, and a cultural examination of endometrial tissue were performed. According to the results of hysteroscopy, signs of chronic endometritis, intrauterine synechia were revealed, a resectoscopy of intrauterine synechia was performed, a Foley pediatric catheter was installed to prevent relapse of intrauterine synechia and instillation of therapeutic drugs. The diagnosis of chronic endometritis is morphologically confirmed. According to the results of a cultural study of endometrial tissue, candida albicans was revealed. A course of treatment of chronic endometritis and intrauterine synechia according to the proposed method, anti-candidiasis therapy taking into account the sensitivity of the selected microflora.

1 month after the therapy, a spontaneous uterine pregnancy occurred, which ended with a caesarean section at the full term of pregnancy. A newborn weighing 3600 g, 52 cm, 9 points according to Apgar.

Claims (1)

A method for the treatment and prevention of relapse of intrauterine synechia, including hysteroscopy followed by instillation of drugs against hormonal therapy, characterized in that the instillation is carried out using a Foley catheter, which is inserted into the uterine cavity, a balloon of 2 ml of physiological solution is filled, a catheter is installed for 7 days, during which 2.5 ml instillagel is introduced into the uterine cavity through holes in the distal end of the catheter on days 1, 3, 5, 7, alternating with the introduction of filgrass ima 100 mg at 2, 4 and 6 days.

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