UTEROTONIC DRUGS IN THE PREVENTION OF POSTPARTUM HEMORRHAGES

In the world practice, hemorrhages in obstetrics take leading positions within the causes of maternal morbidity and mortality. 800 women die every day due to childbirth complications under the data of the World Health Organization. The majority of maternal deaths occur during the perinatal period, usually within 24 hours postpartum. It is possible to prevent most of them. Lack of adequate pre-conceptional training, uncompensated extragenital diseases increase the percentage of pathological births. Consequently, practicing obstetricians-gynecologists have to face such childbirth complications as postpartum hemorrhage with increasing frequency. Uterine atonia is the main cause of postpartum hemorrhages. Uterotonic drugs administration enables to reduce the risk of postpartum atonic hemorrhages. Particular attention should be paid to postpartum hemorrhage prevention, i.e. the use of uterotonic drugs as an integral part of the active management during the third period in natural labor and caesarean section.

500 ml of blood within 24 hours postpartum, and severe PPH is defined as a loss of at least 1000 ml of blood during the same period [1]. PPH is the main cause of maternal mortality in low-income countries and the key factor of almost a quarter of all maternal deaths in the world. Most PPH-related fatalities occur within the first 24 hours postpartum; most of them can be avoided by the preventive use of uterotonics in the third period of labor and the correct childbirth management. The prolonged third period of labor is the key factor of postpartum hemorrhage worldwide and can increase the maternal mortality rate [14]. Due to the delay of umbilical cord detachment in about 2-3.3% of women during spontaneous delivery, the Republican Center for Healthcare Development of the Republic of Kazakhstan has developed and adopted the protocol named "Management of birth" that has the clause "Active management of the third stage of labor" [15]. PPH is the main cause of severe diseases and prolonged disability of maternity patients, as well as many other severe conditions of maternity patients that usually develop due to more severe blood loss, including shock and organ failure [1].
Under the data of the Department of Social and Demographic Statistics of the Ministry of Health and Social Development of the Republic of Kazakhstan for 2018, obstetric hemorrhages rank third in the structure of maternal mortality causes, amounting to 12.5%, and follow by extragenital diseases (35.8%) and hypertensive conditions during pregnancy (preeclampsia, eclampsia -21.4%). As for 2019, obstetric hemorrhages rank second, amounting to 20%, giving place only to extragenital diseases (43.6%), other causes are in third place (18.2%) where pregnant women's septic conditions have an essential role. The increase in maternal mortality due to extragenital diseases can also be associated with the epidemic situation in the world and the effect of coronavirus infection on pregnant women [17]. Under the report of the Obstetric, Gynaecological and Neonatal Service of the Multi-Field City Hospital No. 3 in Nur-Sultan for 2019, obstetric hemorrhages for three years (2017-2019) are at the same level, amounting to 1.0% (83-82 women per year), with a blood loss of more than 1,000 ml -0.6% (46-47 women per year). The number of hysterectomies decreased slightly from 15 cases per year to 13 cases per year associated with an increase in the surgical hemostasis rate to stop hemorrhage (B-Lynch compression suture and O-Leary uterine arterial dressing) from 30 cases per year to 42 cases per year. The structure of the indications for hysterectomy is the atonia of the uterus -in four cases, premature detachment of normally situated placenta (Cuveler's uterus) -in four cases, and the increment of the placenta (histologically approved) -in five cases. Particular attention should be paid to the fact that there is an increase in the health index of fertile age women in Kazakhstan and the number of high-risk pregnant women in recent years. The incidence of nosology, such as placental increment, increases. If the figures for the 9 months of 2018, 2019, and 2020 (currently) are compared, the number of births as a whole remains unchanged (6225; 6240; 6454, respectively), maternal mortality remains consistently at zero points. There were 70 obstetric hemorrhages in the cases for 9 months in 2018 (of which 41 with more than 1 liter), in 2019 there were 72 (of which 43 with more than 1 liter), in 2020 there were 73 (of which 18 with more than 1 liter). In general, obstetric hemorrhages occur in 1.1% of cases over three years, including 0.6% of cases with more than 1 liter. If surgical hemostasis methods are analyzed comparatively, i.e. the application of B-Lynch and O-Leary sutures, it is possible to identify a logical increase in indicators, as well. 62 B-Lynch sutures and 69 O-Leary sutures were put for 9 months in 2018, and 71 and 96 sutures in 2019, respectively. In 2020 surgical hemostasis was used in 108 and 151 cases, respectively. It is also important to note the tendency towards an increase in organ-resecting operations during hemorrhages: 16 cases were reported for 9 months of 2018, 14 cases in 2019, 18 cases -2020 (an increase from 0.2% to 0.3%). These indicators prompt us to think about more effective preventive measures to avoid adverse effects on the reproductive function of women with risk factors.
The cause of postpartum hemorrhages is uterine atonia in the early postpartum period in 80% of cases [2] caused in its turn by the following factors: the uterus overdistention (in pluripara women, women with hydramnios, polycyesis, macrosomia), prolonged labor, rapid labor, labor induction, placenta attachment abnormalities, chronic inflammatory process of the uterine cavity. It should be noted that the postpartum hemorrhage risk increases by 3-5 times during caesarean section in comparison with vaginal delivery [2]. However, atonic hemorrhage can occur in a woman without any risk factors.
The use of uterotonics in the third period of labor is recommended for all births to prevent PPH under the WHO recommendations for postpartum hemorrhage prevention and treatment. Oxytocin (10 IU, i.v. or i.m.) is a recommended uterotonic drug to prevent PPH. If there is no oxytocin, it is recommended to use other injection uterotonics (i.e. oxytocin derivatives (carbetocin), ergometrin/methylergometrin, or a fixed combination of oxytocin and ergometrin) or ergot alkaloids and prostoglandin analogs -misoprostol by mouth (600 μg) [1].
Under the literature review of databases: Scopus, Med Line, The Cochrane Library, EMBASE, RSCI, materials of such organizations as the World Health Organization, Royal College of Obstetricians and Gynaecologists (RCOG), International Federation of Obstetrics and Gynecology (FIGO), American College of Obstetricians 4 and Gynecologists (ACOG), Cochrane Reviews oxytocin is the most common uterotonic drug. The oxytocin receptor system has a key role in many physiological processes. Transcription and expression of oxytocin receptors are tightly regulated in reproductive, cardiovascular, and neural tissues. The potent uterotonic action of oxytocin in the uterus is mediated by receptors via G -protein activation to stimulate phospholipase C. The activated receptor increases the frequency of contractions and increases strength by sensitizing the myocyte contractive apparatus to calcium [3].
As oxytocin receptors are not only in the unstriated muscle of the uterus but also in the heart and large vessels, cardiovascular effects in women who have undergone caesarean section include tachycardia, hypotension, reduced cardiac output, myocardial ischemia. It may be sufficient to cause serious damage to high-risk patients [4]. Other clinical manifestations of metabolic effects of oxytocin are hyperemia, nausea, vomiting, chest pain, headache, pulmonary edema [5]. Recent studies show that the effective dose of oxytocin used to prevent uterine atonia during caesarean section is significantly lower than the 5-10 IU historically used by anesthesiologists. Slow administration of small bolus doses of oxytocin minimizes a mother's hemodynamic disorders. Continuous oxytocin infusions are recommended to maintain uterine tone after bolus administration, although ideal infusion rates have yet to be found [6].
The "rule of triples" method was developed due to the little half-life of oxytocin based on the administration of oxytocin three times at a dose of 3IU. It means that the first dose is the loading dose, the rest two doses are salvage doses with 3 minutes' interval administration. A randomized doubleblind trial of this algorithm in comparison with continuous administration of oxytocin during a planned caesarean section showed that intravenous bolus administration of small doses of OT (0.5-3 IU) results in satisfactory uterine contraction without increased blood loss, and it is not accompanied by pronounced cardiovascular side effects [7]. At the same time, a community of doctors from Rutgers's Medical School in New Jersey performed a systematic review and meta-analysis of randomized controlled clinical trials for pharmacological intervention to treat retained placenta which proved that oxytocin contributes to placental expulsion compared to placebo but one of the largest studies gave negative results. Oxytocin was inferior to carbetocin (risk ratio [RR] 1.61; 95% confidence interval [CI] 1.03-2.52) and prostaglandins (RR 2.63; 95% CI 1.18-5.86) by the main result. It is interesting that oxytocin was associated with a higher risk of requiring manual afterbirth removal compared to carbetocin (RR 1.44; 95% CI 1.03-2.02) and prostaglandins (RR 1.48; 95% CI 1.13-1.93) [16].
Recently, a long-acting oxytocin agonist named carbetocin is of increasing interest for this reason. Carbetocin is not inferior to oxytocin in the prevention of postpartum hemorrhages after a natural delivery and significantly exceeds oxytocin after operative delivery [16]. Carbetocin selectively binds to oxytocin receptors in the unstriated muscle of the uterus, stimulates rhythmic contractions of the uterus, increases the frequency of contractions, and increases the tone of uterine muscles. Carbetocin increases the speed and strength of spontaneous uterine contractions in the postpartum uterus. Uterine contractions increase after the carbetocin administration, and a sharp contraction occurs in 2 minutes. A single dose of 100 μg is sufficient to maintain adequate uterine contractions preventing uterine atonia and abundant hemorrhages that can be compared with continuous administration of oxytocin for several hours since the halflife of carbetocin is approximately 4-10 times greater than that of oxytocin.
Carbetocin is indicated for use to prevent uterine atonia in a cesarean section and women giving birth with an increased risk of hemorrhage in the postpartum period after spontaneous delivery. Carbetocin is administered once intravenously or intramuscularly immediately after childbirth.
Data from three randomized controlled trials of caesarean section and meta-analysis show that carbetocin significantly reduces the need for additional uterotonics or uterine massage to prevent excessive hemorrhage compared to placebo or oxytocin. The risk of headache, tremor, hypotension, hot flashes, nausea, abdominal pain, itching, and heat sensation was the same in women who received carbetocin or oxytocin [8].
A large randomized trial was conducted in Canada that showed that a single intravenous administration of 100 μg carbetocin (pabal) was more effective to prevent uterine atonia compared to 5 IU of oxytocin administered intravenously by bolus followed by intravenous infusion thereof at a dose of 20 IU for 8 hours. Moreover, the need for additional administration of oxytocin to eliminate uterine atonia was significantly less in the pabal group (I B) administration [9].
The second randomized trial also conducted in Canada compared the efficacy of carbetocin and oxytocin. As a result, it was found that a single intravenous administration of 100 μg of pabal immediately after childbirth was as effective as a 16-hour administration of 32.5 IU of oxytocin as for intraoperative blood loss reduction. There were significantly fewer women (53%) in the carbetocin (pabal) group who had a blood loss volume of ≥200 ml than in the oxytocin group (79%) (р=0,041) [13].
Some authors have noted the function of carbetocin to lower blood pressure having a positive effect on the complex therapy of patients with postpartum pre-eclampsia [10][11][12].
A meta-analysis made by a group of scientists from New Jersey showed that carbetocin and prostaglandins presented better results than oxytocin in the direct comparative trials. Carbetocin has an additional advantage of thermal stability for transportation and safe storage under a lack of resource conditions [16].
A prospective study was made based on the Multi-Field City Hospital No. 3 in Nur-Sultan to compare the effectiveness of two uterotonic drugs (oxytocin, carbetocin). The number of women under examination was n = 254, period -2019. The enrollment conditions were at least one risk factor for postpartum hemorrhage, planned, or emergency caesarean section management.
Atonic hemorrhage risk groups were identified among all maternity patients under the statistics of "Multi-Field City Hospital" No. 3. The following states were categorized as absolute risk factors: • Obstetric complications of pregnancy (placental previa, polycyesis, high parity, evident hydramnios, two or more scars on the uterus, multiple organ failure in pregnant women).
• Hemostasis system change (Willebrandt disease, thrombocytopenia (less than 80 thousand or less), thrombocytopathy, thrombophilia with a high risk of thrombosis) • Extragenital pathology of pregnant women (severe anemia, oncological diseases of the blood and other organs and systems).
• Severe preeclampsia, premature detachment of the normally located placenta with blood loss of 300 ml or more.
We classified the following as relative risk factors: • Situations resulting in uterus overextension, including twins, big fetus.
• Thrombocytopenia (from 80 to 100 thousand) Group No. 1 (n = 127) received the prophylactic carbetocin in the form of a single 100 μg intravenous bolus, Group No. 2 (n = 127) received prophylactic oxytocin in the form of 10 IU intravenous infusion for 2 hours. Less than 500 ml was observed in the carbetocin group in 103 cases, and in 69 cases in the oxytocin group under the results of the blood loss study. Blood loss of more than 500 ml in the carbetocin group was observed in 24 cases, and in 58 cases in the oxytocin group. The need for additional uterotonic preparations was 13% (16 cases) in Group No. 1, 72% (91 cases) in Group No. 2.

CONCLUSIONS
Obstetric hemorrhage is a cause that results in high rates of morbidity, disability, and mortality among women to the present day. Obstetrician-gynecologists and anesthesiologists-resuscitators should use an arsenal of all possible and accessible means, knowledge, and skills against obstetric hemorrhage. And first of all, we must pay attention to the prevention of obstetric hemorrhage that means correct management of the third period of labor, both in natural and in operative delivery.
Due to the localization of oxytocin receptors in the cardiovascular system involving a high risk of side effects development, one should carefully administer oxytocin by bolus in risk group women. It is required to perform the studies to identify an ideal, possibly individually selected dosage and administration rate for oxytocin to avoid the development of numerous side effects because the use of conventional dosages 5-10 IU is both excessive and even dangerous for a certain group of women. Dosage reduction and slow bolus administration can minimize the hemodynamic effects of oxytocin.