Late pregnancy losses—late miscarriage (LM) and preterm birth (PL)—remain one of the pressing medical problems throughout the world, the significance of which is determined not only by the loss of a desired pregnancy, but also by the birth of a premature baby. Prematurity is associated with the majority of perinatal deaths and morbidities in newborns, subsequently leading to serious physical and mental disorders, as well as economic costs [1].
The etiology of late pregnancy losses is multifactorial and often unknown, so there is no clear algorithm for their prevention [2]. Treatment methods for the onset of PV/PR are also not effective enough. β-mimetics, calcium channel blockers, prostaglandin synthesis inhibitors, and oxytocin receptor antagonists used for acute tocolysis often only prolong the latent period before delivery by 2–7 days, but do not affect the rate of birth control and perinatal outcomes [3–5]. Long-term prophylactic administration of any form of tocolytics also does not reduce the risk of late pregnancy loss [6, 7].
Symptoms of threatening PT/PR are regular uterine contractions and shortening of the cervix. With an isolated increase in uterine activity, the risk of preterm birth is less than 2%, while in combination with a short uterine cervix, most pregnancies end prematurely [8]. Asymptomatic shortening of the cervix is also considered an extremely unfavorable prognostic factor for pregnancy outcome [8–11]. With a length of the cervix ≤25 mm in the second trimester of pregnancy, according to ultrasound cervicometry, the risk of pregnancy loss is 20%, and with a length of ≤ 15 mm - 50%, while with a length of more than 25 mm, 96% of women have a favorable prognosis [12, 13].
The cervix consists of smooth muscle fibers, fibroblasts, epithelial cells and blood vessels, surrounded by an extracellular matrix of collagen with elastin and proteoglycans. Maturation and shortening of the cervix occur as a result of complex biochemical processes of reorganization of the collagen structure and “loosening” of the extracellular matrix and do not depend on uterine activity [14]. The reasons for premature maturation of the cervix are not fully understood [13], but the key mechanism is considered to be insufficient action of progesterone [15-17], which also causes an increase in uterine contractile activity. Being the main hormone of pregnancy, progesterone reduces the sensitivity of the myometrium to oxytocin, blocks adrenergic receptors, prevents the synthesis of prostaglandins [17, 18], and also stimulates lymphocytes to synthesize progesterone-induced blocking factor (PIBF), ensuring the safety of the cervix, uterine relaxation and immune tolerance throughout pregnancy [19].
A systematic review published in 2013 [9] of 36 randomized controlled trials involving 8523 women and 12,515 newborns showed that prophylactic use of progesterone preparations (intramuscular injections of 17-hydroxyprogesterone caproate - 17-OPC) increased vaginal progesterone (VP) from 20 to 36 weeks in pregnant women with a short cervical period significantly reduces the incidence of pregnancy loss (RR—0.64; 95% CI—0.45–0.90), as well as the rate of perinatal mortality, neonatal morbidity and the risk of having low birth weight children (RR—0 .55, 0.74 and 0.92, respectively) compared with placebo. The effectiveness of vaginal progesterone in the prevention of pregnancy loss in pregnant women with a short cervical period was also confirmed by R. Romero et al. [20] after a meta-analysis of randomized trials involving 974 women. Risk P.R. was 18.1% compared to that in the placebo group - 27.5% (RR - 0.66 (95% CI - 0.52-0.83); p
=0.0005).
The effectiveness of micronized progesterone for oral (PO) and vaginal (VP) use in the complex treatment of threatening birth defects has been shown [21]. According to in vitro
, progesterone not only independently inhibits the contractile activity of the myometrium, but also significantly increases the tocolytic effect of indomethacin and nifedipine (
p
<0.05) [22]. Prolonged administration of VP after successful tocolysis has also been shown to be effective in the prevention of PR in comparison with placebo or no treatment [23, 24]. At the same time, data on the effect of other gestagens (dydrogesterone, 17-OPA) on the contractile activity of the uterus and the condition of the cervix are not so clear. It was found that injections of 17-OPA not only do not prevent premature maturation of the cervix [25] and do not reduce uterine contractile activity [26], but can increase the frequency of PT, very early PR and perinatal mortality [27, 28]. A randomized, double-blind, placebo-controlled study of pregnant women with impending birth defects published in 2021 found no effect of dydrogesterone on contraction frequency, latency to delivery, or perinatal outcomes [29].
As is known, the largest number of late pregnancy losses (25-40%) is caused by intrauterine infection and inflammation [11], resulting from disorders of the vaginal microbiocenosis - bacterial vaginosis (BV) [30]. But, despite the obvious connection between ascending infection and pregnancy loss, differences in the composition of the vaginal microbiotope during pregnancy in women who gave birth at term and prematurely were not identified [31], while preventive antibiotic therapy for BV does not prevent late pregnancy losses [30]. At the same time, the available data show the high informativeness of predicting CR using biochemical markers of microbial metabolic activity [32, 33], as well as a significant reduction in the risk of PT/CR (by 80 and 40%, respectively) when identifying and treating BV in the first weeks pregnancy [34] indicate that the risk of miscarriage is not limited only to the microbial composition of the vagina, but is also due to their activity and the duration of the damaging effect on the structures of the cervix and fetal membranes. As a result of ascending colonization of the cervix and fetal membranes by vaginal microflora, an inflammatory response occurs. Leukocyte infiltration, activation of lipopolysaccharides, peptidoglycans, pro-inflammatory cytokines and chemokines [35] trigger a cascade of reactions in the synthesis of matrix metalloproteinases [36] and prostaglandins [16], which leads to the maturation of the cervix, rupture of the membranes, increased contractile activity of the uterus and pregnancy loss [31, 36].
Taking into account the above, the purpose of our study was to evaluate the effectiveness of an integrated approach to the treatment and prevention of threatening PV or PR in pregnant women with short cervical cancer, including the use of progesterone drugs, tocolytic agents and correction of vaginal microbiocenosis.
A clinical study of the effectiveness of the use of dydrogesterone, 17-OPA and micronized progesterone for oral (PO) and vaginal (VP) use in the prevention of late pregnancy losses in women with short cervix was carried out in 2 stages.
Stage 1 of the study Material and methods
The first stage of the study was carried out at the Scientific Center for Obstetrics, Gynecology and Perinatology in Moscow in 2005-2007. 146 women with a singleton pregnancy and a diagnosis of isthmic-cervical insufficiency (ICI) at 15-24 weeks were examined, 52 of them with a cervical cervical length ≤ 25 mm according to transvaginal ultrasound cervicometry were included in the study after obtaining informed consent. The initial diagnosis of ICI, in accordance with the international classification, was replaced by the diagnosis of “short cervical cancer”. In 25 of 52 women, shortening of the cervix was asymptomatic, and in 27 pregnant women it was combined with clinical signs of threatening PV/PR: cramping pain in the lower abdomen and increased uterine contractile activity (3-5 contractions per hour). Pregnant women with a cervical cervix length >25 mm, the onset of PV/PR (more than 5 uterine contractions within an hour) and/or smoothing and opening of the cervical cervix were not included in the study.
After transvaginal cervicometry, pregnant women were prescribed various progesterone preparations: 15 patients received dydrogesterone 30 mg/day (dydrogesterone group), 10 received weekly intramuscular injections of 2 ml of a 12.5% solution of 17-OPK (17-OPK group), 12 received micronized PP in capsules 400 mg/day (PP group) and 15 - VP in capsules 400 mg/day (VP group). In case of threatening PT/CR, a solution of drotaverine 6 ml/day intramuscularly and suppositories with papaverine 40 mg/day rectally were additionally prescribed.
The average age of the examined women was 29±4.76 years (23-43 years), with the number of pregnancies per woman being 2.1±0.8 (0-6). There were no significant differences in the obstetric and gynecological history data, as well as the frequency of somatic diseases between the groups ( p
>0,05).
All pregnant women with a short cervical period complained of pathological discharge from the genital tract. Based on the Amsel criteria (at least 3), BV was diagnosed, and after excluding sexually transmitted infections (STIs) by polymerase chain reaction (PCR), local treatment was carried out according to the standard method: at the 1st stage, clindamycin 100 mg was prescribed for 3 days , at the 2nd stage - probiotics for 5-7 days. 14 women with curdled discharge and elements of mushrooms on microscopy of vaginal smears were supplemented with therapy with sertaconazole 300 mg once. In the group with VP, the above drugs were prescribed no earlier than an hour after the use of VP, ensuring its maximum absorption into the systemic circulation [37].
After 7 days of therapy, the length of the cervix, the course of pregnancy were re-assessed, and then the women in each group were randomly distributed into the following subgroups:
— 15 patients (12 with asymptomatic shortening of the cervix and 3 with threatening PV/PR) underwent surgical correction of the cervical tumor by applying two U-shaped sutures in combination with intravenous tocolysis with hexoprenaline for 2-5 days according to the standard method (subgroup “Sutures on ShM");
— 13 patients with asymptomatic shortening of the cervix continued taking progesterone drugs (subgroup A);
— 6 patients with threatening PV/PR continued to take dydrogesterone, 17-OPK or PP against the background of additional intravenous tocolysis with hexoprenaline for 2-5 days (subgroup B);
— 18 pregnant women with threatening PV/PR (subgroup C) began to receive VP 600 mg/day (400 mg once and then 200 mg 3 times a day for a week) and additionally they received tocolysis with a prostaglandin synthesis inhibitor, indomethacin. According to the latest data [16], excessive synthesis of prostaglandins is the main trigger for premature shortening of the cervix, in contrast to the mechanism of maturation of the cervix during full-term pregnancy. At the same time, indomethacin, as shown by a meta-analysis of randomized trials involving 3263 women with threatening birth defects [5], is significantly more effective than β-mimetics in stopping preterm labor (OR of delaying labor for 48 hours compared with placebo - 5.39, 2.14-12 .34 and 2.41, 1.27-4.55, respectively) with a significantly lower incidence of side effects (OR compared with placebo - 1.63, 0.40-6.85 and 22.68, 7.51-73 ,67 respectively). Indomethacin was prescribed according to the regimen of V.M. Sidelnikova [38] in a course dose of 1000 mg rectally: days 1-3 - 200 mg/day (1 suppository 100 mg 2 times a day), days 4-7 - 100 mg/day. Over the next week, pregnant women took only VP 400 mg/day and then 200 mg/day until 36 weeks of pregnancy.
When PT/PR began, progesterone medications were discontinued. Considering the data from numerous studies on the lack of effectiveness of acute tocolysis in cases of
PR [3, 4], we used tocolytics (β-mimetics, prostaglandin synthesis inhibitors) only at the stage of threatening PR/CR.
Follow-up included repeated ultrasound cervicometry and assessment of the course of pregnancy after a week, 1 and 2 months, as well as the date of delivery and the condition of the newborn.
Statistical analysis
The obtained results were carried out using the application package Microsoft Office Excel 2003 (license agreement 74017−640−0000106−57177) and StatSoft Statistica 6.1 (license agreement BXXR006D092218FAN11).
Influence
17-OPA or hydroxyprogesterone is naturally produced by the adrenal cortex. This substance is necessary for the normal synthesis of cortisol and testosterone. Indirectly, this substance normalizes the menstrual cycle and promotes early pregnancy.
The lack of this substance in the body leads to changes in appearance. Sometimes women or men have elevated levels of OPC, which means that the ability to synthesize cortisol is impaired. With a significant release of cortisol, an emergency mobilization of all the body’s forces occurs.
Thanks to this, many human capabilities are enhanced. He can act faster and becomes stronger. Such opportunities are provided due to a sharp rush of blood to the main organs and systems, namely the heart and muscles. This mechanism has not changed over the long period of existence of the human species.
These improvements act for a short time and only in critical situations for the body. A slight increase in the level of the hormone occurs with the onset of pregnancy, with disturbances in the functioning of the adrenal glands, with a malfunction of the ovaries, with any manifestations of fear or stress.
Complete mobilization of the body does not pass without leaving a trace, which is why it continues for a short time. A huge release of energy occurs due to the internal reserves of the body, which begins to burn itself. Constant work of organs and systems under wear and tear, for example, with prolonged stress, leads to illness. The OPC level can be determined by taking a blood test.
A similar examination is prescribed to all women who have hair growth in areas more characteristic of men. Usually in this case problems with the adrenal glands are identified. A similar examination is carried out on the fifth day from the arrival of menstruation.
If the numbers are high, then you should expect high testosterone levels. It is because of this chain of relationships that a woman cannot conceive a child for a long time. Under the influence of an excess of testosterone, the entire process responsible for conception fails. In this case, the woman is prescribed treatment aimed at increasing progesterone, a “female” hormone that is a testosterone antagonist.
results
Dydrogesterone group.
15 pregnant women with a cervix length of 15-25 mm were prescribed dydrogesterone 30 mg/day (Table 1), including 6 who were already taking 20 mg/day, and a two-stage correction of vaginal microbiocenosis was carried out.
In 7 patients with asymptomatic shortening of the cervix after a week of treatment, its length did not change, while in 8 with threatening PV/PR it decreased by another 3-13 mm, and the contractile activity of the uterus, despite antispasmodic therapy with drotaverine and papaverine, did not change or increased . In all women who continued taking dydrogesterone, including with additional tocolysis with hexoprenaline, pregnancy ended prematurely: with initially asymptomatic shortening of the cervix - at 31-34 weeks (subgroup A), with a threatening PB - at 19-20 weeks (subgroup B). After sutures were placed on the cervical incision (subgroup “Sutures on the cervical incision”), in 4 pregnant women with asymptomatic shortening of the cervical incision and 2 with threatening PV/PR, five births occurred at term and one at 35 weeks. In subgroup C, as a result of replacing dydrogesterone with antispasmodics with VP with indomethacin, in 4 women with threatening PV/PR and progressive shortening of the cervix, the contractile activity of the uterus was stopped within a week, and the length of the cervix increased by 2-6 mm. With subsequent maintenance therapy with VP 200 mg/day up to 36 weeks, ultrasound cervicometry data remained unchanged ( p
>0.05), and delivery occurred at term.
Table 1. Length of the cervix, contractile activity of the uterus and pregnancy outcome in patients of the examined groups
Group 17-OPK.
10 pregnant women with a cervical tumor 20–25 mm long received weekly intramuscular injections of 17-OPA before inclusion in the study. Additionally, a two-stage correction of vaginal microbiocenosis was carried out, and in the presence of contractile activity of the uterus, antispasmodics (drotaverine and papaverine) were prescribed. In 6 pregnant women with asymptomatic shortening of the cervix, after a week of treatment its length did not change, while in 4 women with complaints of pain in the lower abdomen, it decreased by another 2-13 mm and, despite antispasmodic therapy, the increased tone of the uterus remained. Continuation of 17-OPK injections, including intravenous tocolysis with hexoprenaline, prevented birth birth in only 1 out of 4 women (subgroups A and B), while after surgical correction of cervical insufficiency, on the contrary, 3 out of 4 births occurred in a timely manner (subgroup “Sutures” on ShM").
In two pregnant women with threatening PV/PR (subgroup C), 17-OPK with antispasmodics was replaced by VP with indomethacin. A week later, their condition returned to normal, and after progesterone support until the 36th week, term birth occurred. Ultrasound cervicometry showed an increase in the length of the cervix by 2-7 mm after a week of treatment and its stabilization subsequently.
PP group.
12 pregnant women with a cervical tumor length of 18–25 mm were prescribed micronized progesterone in capsules 400 mg/day orally, including four who took 200–400 mg/day before inclusion in the study.
In all women ( n
= 7) with complaints about uterine contractility, the length of the cervix after a week decreased by another 3-8 mm and, despite antispasmodic therapy with drotaverine and papaverine, the threat of PT/PR remained. In 5 pregnant women with asymptomatic shortening of the cervix, cervicometric data did not change after a week of treatment.
Subsequently, 1 patient with asymptomatic shortening of the cervical spine and 2 patients with threatening PV/PR continued to take PP, and PR occurred in all of them (subgroups A and B). After suturing the cervix with tocolysis with hexoprenaline (group “Sutures on the cervix”), 4 patients’ pregnancies ended in delivery at term, and 1 at 36 weeks. Four pregnant women with threatening PV/PR and negative dynamics of cervical length were prescribed VP with indomethacin (subgroup C). In 3 of them, the threatening PV/PR was stopped, and after maintenance therapy with PV until the 36th week, full-term delivery occurred. Repeated ultrasound cervicometry showed an increase in the length of the cervix by 3-7 mm after a week of treatment and stabilization of its condition in the future. In one pregnant woman, treatment of VP with indomethacin, carried out without correction of vaginal microbiocenosis, did not lead to an increase in the length of the cervix, the excitability of the uterus remained, and as a result, after 2 weeks, amniotic fluid was discharged, and pregnancy loss occurred.
VP Group.
15 pregnant women with a cervical tumor length of 15-25 mm were prescribed VP 400 mg/day, including five who had previously taken VP 200 mg/day. After a week of treatment, the length of the cervix in 7 patients with asymptomatic shortening of the cervix increased by 2-13 mm and, with maintenance therapy with VP 200 mg/day, remained unchanged for up to 36 weeks. All pregnancies proceeded without complications and ended in the birth of full-term children (subgroup A).
In 8 pregnant women with threatened PV/PR (subgroup C), after a week of treatment with PV with antispasmodics, the length of the cervix did not change or decreased by 5-10 mm and the contractile activity of the uterus remained. In 5 of them, after increasing the dose of VP to 600 mg/day (400 mg once, then 200 mg 3 times a day), tocolysis with indomethacin and correction of the vaginal infection, the condition returned to normal within a week, while the length of the cervix increased by 3-9 mm. Subsequently, VP was prescribed at a dose of 200 mg/day until 36 weeks of pregnancy, the results of repeated ultrasound cervicometry after 1 and 2 months did not change, and delivery occurred at term. In 3 pregnant women, despite increasing the dose of VP and the use of tocolytics, but without treatment for BV, ICI progressed, amniotic fluid was leaked, and PT occurred at 21 and PR at 22 and 24 weeks of pregnancy.
The use of VP at a dose of 600 mg/day in combination with tocolysis with indomethacin (subgroup C) stopped the majority (14 out of 18) of threatening PT/CR in women with short cervical cancer. During the subsequent prolonged administration of VP 200 mg/day up to 36 weeks, all pregnancies proceeded without complications and ended in the birth of full-term children.
Correlation analysis of the dynamics of the length of the cervix and pregnancy outcomes after the administration of dydrogesterone, 17-OPK, PP and VP in women with a short cervix within 15-24 weeks.
Dynamic control of the length of the cervix showed that in pregnant women with asymptomatic shortening of the cervix (Table 2, Fig. 1, a) in the first week of treatment with VP, the length of the cervix increased (
p
<0.05) by several (3-13) mm and then remained stable throughout the entire period of VP maintenance therapy, all pregnancies (7) ended in timely births.
When treated with dydrogesterone, 17-OPA and PP (18), the length of the cervix initially remained stable ( p
>0.05), but subsequently PR occurred in 5 of 6 who continued taking them. After surgical correction of the cervical tumor, 11 out of 12 pregnant women gave birth to full-term children.
Table 2. Length Sh.M. initially and after 1 week of taking dydrogesterone, 17-OPK, PP and VP (n=52)
Rice.
1. Dynamics of the length of the cervix after 1 week of taking dydrogesterone (1), 17-OPK (2), PP (3) and VP (4) with asymptomatic shortening of the cervix (a) and threatening PV/PR (b). In pregnant women with symptoms of threatening PV/PR (Table 2, see Fig. 1, b), despite conservative treatment, the length of the cervix continued to shorten (in the groups of dydrogesterone, 17-OPK and PP - in 100% (19 out of 19 ), in the VP group - in 5 out of 8, and the contractile activity of the uterus increased. Antispasmodics, such as drotaverine and papaverine, were also not effective in suppressing uterine contractions (27 out of 27). Subsequently, in all women ( n
=6), who continued taking dydrogesterone, 17-OPK or PP, despite additional acute tocolysis with hexoprenaline, PT/CR occurred within 1-5 weeks. Threatening PV/PR were stopped only by complex therapy, including acute tocolysis with β-mimetics/indomethacin in combination with cervical sutures (3 of 3) or the use of an increased dose of VP (14 of 18). Subsequently, in 1 out of 3 women with surgical correction of cervical cancer and in the absolute majority (14 out of 18) who took VP, pregnancy ended in timely birth. In 4 pregnant women who were not treated for vaginal infection, the use of VP with indomethacin turned out to be ineffective, ICI progressed, amniotic fluid was released and PR occurred, while three-component therapy, consisting of indomethacin, VP and correction of BV, stopped all threatening PV/PR.
The study showed varying effectiveness of progesterone preparations in the prevention of perinatal and obstetric complications in pregnant women with short cervical cancer. In the group of pregnant women with asymptomatic shortening of the cervix (Table 3), who took dydrogesterone, 17-OPK and PP, compared with the indicators in the group with sutures on the cervix, it was significant ( p
<0.05) the gestational age at delivery was lower (34.2±2.3 and 39.0±0.5 weeks), the latent period before delivery (14.5±3.9 and 18.4±5.6 weeks) and body weight of the newborn (2506.7±479.2 and 3320±340 g, respectively). At the same time, the risk of birth control significantly increased (<37 weeks RR 21.0; 95% CI 1.48–67.56, <34 weeks (RR 8.0; 95% CI 1.13–56.79 and the risk of having a child with low body weight (<2500 g) (RR 8.0; 95% CI 1.13–56.79) Differences in the incidence of obstetric and perinatal complications with VP, except for the absence of any side effects, compared with these indicators were not noted when applying sutures to the cervix.
Table 3. Pregnancy outcomes in women with asymptomatic shortening of the cervix after taking dydrogesterone, 17-OPK, PP, VP and cervical sutures (n=35) Note.
Here and in the table. 4: * - comparison of indicators with those in the group “Sutures on CMM”; nd - differences are not significant. A comparative analysis of pregnancy outcomes in women with threatened PV/PR and short cervical cancer (Table 4), who received tocolytic therapy with hexoprenaline/indomethacin with progesterone drugs or who underwent cervical sutures, also showed the high effectiveness of the use of VP (Table 4 shows generalized results 1st and 2nd - see below - stages of the study). Thus, the date of delivery, the latent period before delivery and the body weight of the newborn are significantly ( p
<0.05) exceeded similar indicators not only when using other forms of progesterone, but also in the group with cervical sutures.
Table 4. Pregnancy outcomes after the use of dydrogesterone, 17-OPK, PP, VP and suturing the cervix together with tocolysis with hexoprenaline/indomethacin in women with threatening PT/PR and short cervical cancer (n=60)
Study of the effectiveness of VP in the prevention of pregnancy loss in pregnant women with short CMM
Name:
Oxyprogesterone capronate / 17-OPK
Latin name:
Oksiprogesterona kapronat 17-OPK
Tags: Medicine, For urogenital organs and sex hormones
Description
Instructions for use of Oxyprogesterone capronate / 17-OPK
International name:
Pharmacological group:
List of drug analogues:
International name:
Hydroxyprogesterone caproate
Pharmacological group:
Gestagen*
Does not belong to VED
Does not contain narcotic drugs, psychotropic substances and their precursors
By doctor's prescription
List of drug analogues:
Depo-Provera Norkolut
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| Astrakhan | Master's degree, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 975 rub. |
| Barnaul | Pharmacy Brusnika | ampoules 12.5%-1.0 No. 10 | 511 rub. |
| Blagoveshchensk | GOSAPTEKA | ampoules 12.5%-1.0 No. 10 | 622 rub. |
| Blagoveshchensk | Social Pharmacy | ampoules 12.5%-1.0 No. 10 | 666 rub. |
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| Vladivostok | Monastyrev.rf, pharmacy | ampoules 12.5%-1.0 No. 10 | 655 rub. |
| Volgograd | Pharmacy on Yeletskaya | ampoules 12.5%-1.0 No. 10 | 488 rub. |
| Volgograd | Vita-express, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 916 rub. |
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| Ekaterinburg | SLAVIA, pharmacy | ampoules 12.5%-1.0 No. 10 | 676 rub. |
| Ekaterinburg | On Bauman, pharmacy | ampoules 12.5%-1.0 No. 10 | 743 rub. |
| Ekaterinburg | Planet Health, pharmacies | ampoules 12.5%-1.0 No. 10 | 915 rub. |
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| Kazan | Planet Health, pharmacies | ampoules 12.5%-1.0 No. 10 | 760 rub. |
| Kazan | Vita, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 807 rub. |
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| Kemerovo | Pharmacies of Kuzbass, OJSC, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 733 rub. |
| Krasnodar | Kubanfarmmed, LLC, on-duty pharmacy | ampoules 12.5%-1.0 No. 10 | 720 rub. |
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| Krasnodar | Kvarta, LLC, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 1015 rub. |
| Krasnodar | Pharmacy world, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 1036 rub. |
| Krasnoyarsk | Pion-pharma, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 874 rub. |
| Moscow | GoodMedical, LLC, pharmacy | injection solution 12.5%-1.0 No. 10 | 358 rub. |
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| Moscow | Avicenna Pharma on Proletarsky, pharmacy chain | injection solution 12.5%-1.0 No. 10 | 999 rub. |
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| Moscow | GorPharma, LLC, pharmacy chain | 1003 rub. | |
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| Moscow | Neopharm, pharmacy chain | 1060 rub. | |
| Moscow | Neopharm, pharmacy chain | injection solution 12.5%-1.0 No. 10 | 1060 rub. |
| Nizhny Novgorod | Dobrynya, LLC, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 471 rub. |
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| Nizhny Novgorod | Vita Express, pharmacy | ampoules 12.5%-1.0 No. 10 | 853 rub. |
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| Nizhny Novgorod | Farmani, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 994 rub. |
| Novosibirsk | White Pharmacy, a group of 24-hour pharmacies | ampoules 12.5%-1.0 No. 10 | 853 rub. |
| Novosibirsk | Monastyrev.rf, pharmacy | ampoules 12.5%-1.0 No. 10 | 854 rub. |
| Omsk | VitaMin, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 724 rub. |
| Omsk | GOSAPTEKA, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 739 rub. |
| Rostov-on-Don | Primula+, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 621 rub. |
| Rostov-on-Don | Your Pharmacy, LLC, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 640 rub. |
| Rostov-on-Don | PHARMACY on Volkova | ampoules 12.5%-1.0 No. 10 | 656 rub. |
| Rostov-on-Don | Pharmacy on Budennovsky | ampoules 12.5%-1.0 No. 10 | 774 rub. |
| Rostov-on-Don | WORLD OF HEALTH, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 859 rub. |
| Rostov-on-Don | Aibolitmedservis, LLC, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 920 rub. |
| Rostov-on-Don | Sport, LLC, pharmacy | ampoules 12.5%-1.0 No. 10 | 1027 rub. |
| Samara | On Maslennikova, pharmacy | ampoules 12.5%-1.0 No. 10 | 644 rub. |
| Samara | Vita Central | ampoules 12.5%-1.0 No. 10 | 724 rub. |
| Samara | Altey, LLC, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 731 rub. |
| Samara | Aliya (Pharmacy 121 - Discounter), pharmacy chain | ampoules 12.5%-1.0 No. 10 | 775 rub. |
| Samara | Vita-Express | ampoules 12.5%-1.0 No. 10 | 862 rub. |
| Saint Petersburg | Apteka, LLC | ampoules 12.5%-1.0 No. 10 | 373 rub. |
| Saint Petersburg | People's pharmacy, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 690 rub. |
| Saint Petersburg | NeoBazis, LLC, pharmacy | ampoules 12.5%-1.0 No. 10 | 720 rub. |
| Saint Petersburg | Poem of health, pharmacy | ampoules 12.5%-1.0 No. 10 | 800 rub. |
| Saint Petersburg | Pharmacy Vitamin on Svetlanovsky Prospekt, 66 | ampoules 12.5%-1.0 No. 10 | 830 rub. |
| Saint Petersburg | Pharmacy Vitamin on Svetlanovsky Prospekt, 66 | ampoules 12.5%-1.0 No. 10 | 856 rub. |
| Saint Petersburg | Pharmacy Vitamin on Nauki Avenue, 24 | ampoules 12.5%-1.0 No. 10 | 859 rub. |
| Saint Petersburg | Life, pharmacy | ampoules 12.5%-1.0 No. 10 | 860 rub. |
| Saint Petersburg | Healthy People Airports | ampoules 12.5%-1.0 No. 10 | 899 rub. |
| Saint Petersburg | Planet Health, pharmacies | ampoules 12.5%-1.0 No. 10 | 920 rub. |
| Saint Petersburg | OlTaPharm, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 955 rub. |
| Saint Petersburg | Aloe, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 960 rub. |
| Saint Petersburg | Pharmacy Vitamin on Thorez Avenue, 9 | ampoules 12.5%-1.0 No. 10 | 964 rub. |
| Saint Petersburg | Pharmacy Vitamin on Thorez Avenue, 9 | ampoules 12.5%-1.0 No. 10 | 964 rub. |
| Saint Petersburg | Petropharm, JSC, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 975 rub. |
| Saint Petersburg | Petropharm, JSC, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 975 rub. |
| Saint Petersburg | Neboleyka, pharmacy | ampoules 12.5%-1.0 No. 10 | 1055 rub. |
| Saint Petersburg | Vita, pharmacy | ampoules 12.5%-1.0 No. 10 | 1099 rub. |
| Saint Petersburg | Health, LLC, pharmacy | ampoules 12.5%-1.0 No. 10 | 1150 rub. |
| Saint Petersburg | Ecopharm, pharmacy | ampoules 12.5%-1.0 No. 10 | 1156 rub. |
| Saint Petersburg | Organic Neva, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 1159 rub. |
| Saint Petersburg | Ava-Peter Pharm, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 1160 rub. |
| Saint Petersburg | NGC, pharmacy | ampoules 12.5%-1.0 No. 10 | 1180 rub. |
| Saratov | Pharmacy on Moskovskaya | ampoules 12.5%-1.0 No. 10 | 750 rub. |
| Saratov | Aibolit-A, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 944 rub. |
| Surgut | Central Pharmacy, JSC | ampoules 12.5%-1.0 No. 10 | 1015 rub. |
| Tolyatti | Pharmacy | ampoules 12.5%-1.0 No. 10 | 587 rub. |
| Tolyatti | 63+, pharmacy | ampoules 12.5%-1.0 No. 10 | 686 rub. |
| Tolyatti | VITA | ampoules 12.5%-1.0 No. 10 | 823 rub. |
| Tolyatti | Pharmacy 245, LLC, network of on-duty pharmacies | ampoules 12.5%-1.0 No. 10 | 986 rub. |
| Tomsk | Voskresenskaya, pharmacy | ampoules 12.5%-1.0 No. 10 | 717 rub. |
| Tomsk | Central, pharmacy | ampoules 12.5%-1.0 No. 10 | 938 rub. |
| Tomsk | Avicenna, pharmacy | ampoules 12.5%-1.0 No. 10 | 938 rub. |
| Tuapse | Social Pharmacy, LLC | ampoules 12.5%-1.0 No. 10 | 707 rub. |
| Tyumen | Lavr, LLC, pharmacy | ampoules 12.5%-1.0 No. 10 | 686 rub. |
| Ulyanovsk | On Minaeva, pharmacy | ampoules 12.5%-1.0 No. 10 | 69 rub. |
| Ulyanovsk | Vita Express, a chain of low-price pharmacies | ampoules 12.5%-1.0 No. 10 | 722 rub. |
| Ufa | Vita Express, pharmacy | ampoules 12.5%-1.0 No. 10 | 725 rub. |
| Ufa | Pharmacy point No. 350, MUP | ampoules 12.5%-1.0 No. 10 | 736 rub. |
| Ufa | Pharmacy on Halle | ampoules 12.5%-1.0 No. 10 | 743 rub. |
| Chelyabinsk | Apteka.ru, LLC, pharmacy | ampoules 12.5%-1.0 No. 10 | 560 rub. |
| Engels | Vita-Express, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 807 rub. |
| Engels | Aliya, pharmacy | ampoules 12.5%-1.0 No. 10 | 899 rub. |
| Yaroslavl | Maksavit, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 635 rub. |
| Yaroslavl | Trika, pharmacy chain | ampoules 12.5%-1.0 No. 10 | 695 rub. |
Stage 2 of the study Material and methods
The second stage of the study was carried out from March 2013 to February 2021 in a multidisciplinary hospital in Moscow. We performed transvaginal ultrasound cervicometry in 550 women with singleton pregnancies, and 43 of them with a cervix length ≤25 mm were included in the study after obtaining the informed consent of the patients. The 1st group consisted of 10 pregnant women with asymptomatic shortening of the cervix (a cervix length of 15-25 mm at 15-24 weeks) and the 2nd group - 33 pregnant women with clinical manifestations of threatening PV/PR: 23 - with a cervix length of 13-25 mm in a period of 15-24 weeks (in 13 of them, at the first measurement, the length of the cervix was in the range of 26-30 mm and during 3-7 days of observation it decreased by 2-8 mm to ≤25 mm) and 10 - with a cervical length of 10- 20 mm in later stages of pregnancy - 25-32 weeks.
The Bishop scale for assessing the cervix was not used due to the possible progression of ICI under the influence of digital examination of the cervical canal during premature pregnancy, as well as due to the lack of advantages of assessing the consistency, position and other characteristics of the cervix in predicting PB compared to simple measurement of its length [39 , 40]. The selection of women was based only on ultrasound cervicometry data, without taking into account concomitant somatic diseases (with the exception of decompensated ones), obstetric and gynecological history data and the course of this pregnancy before the study (excluding fetal malformations). The average age of women was 27±4.85 years (20 years - 41 years) and the number of pregnancies per woman was 2.0±0.9 (1-5).
10 pregnant women with asymptomatic shortening of the cervix (group 1), following international recommendations [41], were prescribed VP 200 mg/day; 30 pregnant women with threatening PV/PR (group 2) received complex therapy for VP with the prostaglandin synthesis inhibitor indomethacin according to the scheme of the 1st stage of the study. Indomethacin was prescribed rectally, in a course dose of no more than 1000 mg, while repeated tocolysis (according to indications) was carried out with a break of at least 3 weeks no later than 32 weeks of pregnancy.
All women with a short cervix complained of pathological leucorrhoea from the genital tract. After confirmation of BV (in 12 of them in combination with vaginal candidiasis) and exclusion of STIs, local therapy with clindamycin 100 mg/day for 3 days and probiotics for 5-7 days was carried out. For vaginal candidiasis, 300 mg of sertaconazole was added. All drugs were administered one hour after VP application.
Next, the course of pregnancy and the dynamics of the length of the cervix after 1, 5 and 9 weeks from the start of treatment and the date of delivery were assessed. If threatening PV/PR was detected during treatment and negative dynamics in the length of the cervix, the dose of VP was increased to 600 mg/day and tocolysis was performed with indomethacin. After normalization of the condition, VP was reduced to 200 mg/day within a week. In pregnant women with repeated asymptomatic shortening of the cervix during maintenance therapy with VP, taking into account the results of the first stage of the study, the dose of VP was increased to 400 mg/day, followed by ultrasound cervicometry a week later and reduced to 200 mg/day. If there were complaints about pathological discharge from the genital tract, vaginal microbiocenosis was corrected again.
Results of the study in groups 1 and 2
In pregnant women with asymptomatic shortening of the cervix (group 1), after 1 week of use of VP at a dose of 200 mg/day, the average length of the cervix increased from 22.8 ± 3.2 mm to 26.4 ± 5.3 mm ( p
=0.0004) (Table 5, (Fig. 2). In 6 women with an initial increase in the length of the cervix by 2-12 mm, it remained stable throughout the entire period of progesterone support. In one of them, who independently canceled VP for 2 weeks , the cervix decreased by 5 mm. After resuming the use of VP at a dose of 400 mg/day for a week, its length was restored and subsequently with daily intake of VP 200 mg did not change, pregnancy proceeded without complications. 4 pregnant women without an initial increase in the length of the cervix complained after a month for cramping pain in the lower abdomen, and ultrasound cervicometry showed a decrease in the length of the cervix by 3-6 mm. After increasing the dose of VP to 600 mg/day and tocolysis with indomethacin, the contractile activity of the uterus was stopped within 3 days, and the cervix increased again by 3-8 mm .
Table 5. Length Sh.M. initially and after 1 week of taking VP in women with asymptomatic shortening of the cervix (group 1) and threatening PV/PR (group 2)
Rice.
2. Dynamics of the length of the cervix after 1 week of taking VP with asymptomatic shortening of the cervix (group 1), threatening PV/PR at 15-24 weeks (2nd group) and at 25-32 weeks (3rd group). In the group of women with threatening PV/PR, after a week of complex therapy, including VP 600 mg/day, indomethacin and correction of vaginal microbiocenosis, the contractile activity of the uterus was completely stopped, and the length of the cervix increased by 3-11 mm (on average by 6.6 ± 2 .3 mm) (see Table 5, Fig. 2). For the next week, VP was continued at a dose of 400 mg/day and then long-term at a dose of 200 mg/day. In 23 (69.6%) of 33 pregnant women, the length of the cervix remained stable and there were no signs of threatening pregnancy loss. In 9 (27.3%) women (in 8 - after 1 month and in 1 - after 2 months from the start of therapy), the cervix shortened again by 4-9 mm and signs of threatening P.R. appeared. After repeated tocolysis with indomethacin with an increase in VP to 600 mg/day for a week and treatment with BV (in 6 patients), uterine activity was stopped, and the length of the cervix increased again by 3-9 mm. Another 4 (12.1%) women independently stopped taking VP at 26 and 29 weeks of pregnancy and the length of their cervix decreased by 6 and 12 mm. With the resumption of the use of VP at a dose of 400 mg/day, it again increased by several mm and then remained stable until 34 weeks with constant progesterone support. All pregnancies in both groups ended in full-term delivery.
Thus, the results obtained fully confirmed the conclusions of the first stage of the study about the high effectiveness of VP in the prevention of late pregnancy losses in women with a short cervix. The main goal - “full term pregnancy” - was achieved in all 43 women included in the study.
Discussion
Comparative analysis of the effectiveness of dydrogesterone, 17-OPK, PP, VP and cervical sutures in pregnant women with a short cervical tumor.
A summary analysis of pregnancy outcomes in women with a short cervical cervix using various progesterone preparations in comparison with cervical sutures showed significant advantages of using VP in the prevention of perinatal complications both in pregnant women with asymptomatic shortening of the cervical cervix and with threatening cervical cervical cancer. In pregnant women with asymptomatic shortening of the cervix (see Table 3), indicators such as delivery time, latent period before delivery, body weight of the newborn, low birth weight of the newborn and perinatal death were comparable in the groups with the use of VP and sutures on the cervix. M. But unlike suturing the cervix, which was associated with surgery and was always accompanied by the development of recurrent vulvovaginitis, there were no side effects when using VP ( p
=0,001).
In pregnant women with short cervical cancer and symptoms of threatening PV/PR (see Table 4), the greatest effectiveness in the prevention of obstetric and perinatal complications was shown by the use of VP with indomethacin. 47 (92.2%) of 51 observations of threatening PV/CR, including 9 repeated ones, were stopped within a week of using VP at a dose of 600 mg/day and tocolysis with indomethacin at a course dose of 1000 mg. The frequency of side effects of indomethacin was minimal and manifested itself as diarrhea in 3 (5.9%) women out of 51, which was significant ( p
=0.0180) lower than the side effects of β-mimetics, intravenous infusions of which were accompanied by headache, tachycardia, heart pain, tremor of the hands and/or constipation in 11 (40.7%) of 27 pregnant women.
In this case, a significant factor influencing the effectiveness of tocolysis of VP with indomethacin was the correction of vaginal microbiocenosis, in the absence of which ICI progressed and amniotic fluid was poured out. At the same time, the latent period before delivery was only 1.5±06 weeks. The use of three-component therapy followed by long-term use of VP at a dose of 200 mg/day up to 36 weeks and dynamic monitoring of the condition of the cervix and the course of pregnancy significantly reduced the risk of developing pregnancy loss in periods less than 37 weeks compared with suturing the cervix (OR—0.001; CI 95% 0.0001–0.24), birth of newborns with low body weight (<2500 g) (OR—0.04, 95% CI 0.01–0.96), improved indicators of delivery time (38.7±0. 3 and 34±5.2 weeks, respectively; p
=0.042), latent period before delivery (12±8.6 and 8.5±6.8 weeks, respectively;
p
=0.042) and newborn body weight (3320±341 and 2800 ±916 g, respectively,
p
=0.046). Carrying out tocolytic therapy together with other progesterone drugs (dydrogesterone, 17-OPK, PP) in women with short cervical cancer in order to prolong pregnancy and reduce the risk of perinatal complications is ineffective.
Assessment of the prognostic significance of the dynamics of the length of the cervix when taking dydrogesterone, 17-OPK, PP and VP in pregnant women with a short cervix
Our results showed that a marker of the effectiveness of the therapy in preventing late pregnancy losses is the positive dynamics of the length of the cervix in the first week of treatment and the stabilization of its length subsequently (Table 6). Thus, in 60 (88.2%) of 68 women who received VP as part of complex therapy, the length of the cervix after 1 week increased by 2-12 mm ( p
<0.001) (Fig. 3, a, b) and in 47 (78.3%) out of 60 - with further progesterone support up to 36 weeks it did not change.
All pregnancies with positive dynamics of cervical cancer at the beginning of treatment and a stable length against the background of prolonged use of VP proceeded without complications and ended in timely birth (47 out of 47). The prognosis of pregnancy directly depended on its clinical course before the appointment of V.P. Positive dynamics of the length of the cervix with the start of taking VP in women with asymptomatic shortening of the cervix was always (13 out of 13) associated with the absence of pregnancy complications during the period of prolonged use of VP 200 mg/day, with a stable length of the cervix and delivery at term. With positive dynamics of cervicometry data in 34 (71.3%) of 47 pregnant women with threatening PT/PR, it also remained stable throughout the entire period of progesterone support. But in 13 (27.7%) of 47 women, the cervical spine was shortened again and in 9 (19.2%) of 47, symptoms of threatening PV/PR again arose ( p
= 0.0113). The absence of positive dynamics in the length of the cervix in the first week of treatment (8 out of 8), regardless of the clinical course of pregnancy, or negative dynamics during the period of progesterone support (17 out of 17) were always subsequently associated with threatening PT/PR.
Table 6. Dependence of the course of pregnancy on the dynamics of the length of the cervix in the first week of VP therapy (n=68)
Rice.
3. Dynamics of the length of the cervix after 1 week of taking progesterone drugs in pregnant women with asymptomatic shortening of the cervix (a) and threatening PT/PR (b). When other forms of progesterone were prescribed (dydrogesterone, 17-OPK and PP), the length of the cervix in the first week of treatment in pregnant women with asymptomatic shortening of the cervix remained stable (Fig. 3, a), but subsequently PR occurred in 83.3%. In all pregnant women with threatening PT/PR (see Fig. 3, b), the length of the cervix continued to shorten and, despite additional tocolysis with β-mimetics, the contractile activity of the uterus was not stopped, which also led to PR (100%).
Analysis of the effectiveness of various treatment regimens for CAP in pregnant women with short cervical cancer
To analyze the effectiveness of various schemes (1, 2, 3) for the use of VP (Table 7) in the prevention of late pregnancy losses, we divided all (n=68) pregnant women into groups depending on the clinical course of pregnancy and the daily dose of VP before treatment (Table . 8).
Table 7. Treatment regimens for VP and correction of vaginal microbiocenosis in pregnant women with short cervical menstruation
Table 8. Groups of pregnant women with short cervical cancer depending on the clinical course of pregnancy and the daily dose of VP before prescribing regimens 1, 2, 3
Comparative assessment of the effectiveness of VP 200 (Scheme 1) and 400 mg/day (Scheme 2) in pregnant women with asymptomatic shortening of the cervix
Ten pregnant women with asymptomatic shortening of the cervix (Table 9) received VP 200 mg/day (a). In 6 women, the length of the cervix increased after a week of treatment and, with daily intake of VP, remained stable for up to 36 weeks. All pregnancies proceeded without complications and ended in delivery at term. Pregnant women without positive dynamics of cervical cancer in the first week (40% of 10) subsequently developed threatening PV/PR, which is combined with the data of the meta-analysis by R. Romero [20] on the effectiveness of VP in the prevention of PR (OR compared with placebo 0.51— 0.79). When prescribed to pregnant women with asymptomatic shortening of the cervical cord at a dose of 400 mg/day (b, c, d), the length of the cervical cord initially always (17 out of 17) increased ( p
<0.05 compared to the values before treatment) and then remained stable; no symptoms of threatening PV/PR were observed during prolonged administration of VP 200 mg/day.
Table 9. The effectiveness of various treatment regimens for VP in the prevention of late pregnancy losses in women with a short cervical cervix.
Thus, in pregnant women with asymptomatic shortening of the cervical cervix, starting therapy with VP is 400 mg/day per day
Indications
In order to understand how 17-OPK acts on the endometrium, it is necessary to have a good understanding of what generally happens to the endometrium during its hyperplasia. Normally, the thickness of the endometrial layer varies depending on the phase of the cycle. With hormonal imbalance, this ratio is disrupted. And then the abnormal proliferation of cells begins.
With abnormal thickness of the endometrium, the fertilized egg cannot be qualitatively strengthened, resulting in miscarriages. The endometrium can grow both over the entire inner surface of the uterus and in small areas.
Among the reasons provoking changes, endocrine and hormonal disorders come first. In second place are inflammatory processes that can cause active growth of the endometrium.
Endometrial hyperplasia can occur in different forms. According to the glandular type, when it is the glandular tissues that grow. According to the glandular-cystic type, in this case the appearance of cysts is added to the proliferation of glandular tissue. With the atypical type, many cells with an atypical structure appear in the endometrial tissues. Against the background of such changes, the appearance of cancer cells and the formation of a tumor is possible.
Therefore, treatment for this pathology is mandatory. Doctors are faced with a choice of which of the two methods will be most effective. As for the patients themselves, they are afraid of the curettage procedure itself.
Drug treatment will be beneficial if carried out at the initial stage of the disease and in young women. Endometriosis with the presence of atypical cells cannot be treated with medication. Also, this method of treatment is not used in the presence of heavy bleeding.
