RU2627441C1 - Method for respiratory disorders syndrome prevention for newborns - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: for prevention of respiratory disorders syndrome in newborns, the patients receive Dexamethazon intramuscularly, 8 mg №3 in 8:00 hours on 25(0)-27(6) week of pregnancy, the course is repeated in 7 days with the total dose of 48 mg.

EFFECT: invention provides prolongation of pregnancy, complicated by fetal bladder prolapse or premature amniotic fluid discharge.

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Description

The invention relates to medicine, namely to obstetrics.

It is known that 1,500,000 premature births occur annually in the World and 1,100,000 children die from complications associated with prematurity. According to the WHO, the frequency of preterm births in 184 countries varies from 5% to 18% and is associated with the socio-economic situation of the region and the ethnic group of the population. About 80-85% of preterm birth occurs at 32-37 weeks of gestation, however, the highest frequency of perinatal losses is observed in fetuses with extremely low body weight (ENMT) up to 28 weeks of gestation [Blencowe H, Cousens S, Oestergaard M, et al. National, regional and worldwide estimates of preterm birth. // The Lancet. - 2012. - Vol. 9. - N. 379 (9832). - P. 2162-2172].

Improved perinatal and neonatal care has led to an increase in the survival rate of babies with extremely low birth weight, especially in the group with gestational age over 24 weeks [Claas MJ, de Vries LS, Koopman C, Uniken Venema MM, Postnatal growth of preterm born children ≤ 750g at birth . // Early Hum Dev. - 2011 .-- N. 87 (7). - P. 495-507]. In recent years, many authors have noted a significant increase in surviving very low birth weight babies, especially in the category of less than 1000 g [Doyle LW, Roberts G, Anderson PJ. Changing long-term outcomes for infants 500-999 g birth weight in Victoria, 1979-2005 .; Victorian Infant Collaborative Study Group. // Arch Dis Child Fetal Neonatal Ed. - 2011 .-- N. 96 (6). - P. 443-447].

In the structure of morbidity and mortality of deeply premature newborns, the main place is occupied by the syndrome of respiratory disorders (SDR) (up to 54%). SDR almost exclusively affects preterm infants with gestational age less than 35 weeks (with body weight at birth less than 2000). Typical concomitant diseases of SDR are intraventricular hemorrhage, cerebral leukomalacia, acute and chronic pulmonary complications, including bronchopulmonary dysplasia. The frequency of these complications in the population depends on the proportion of premature babies with extremely low birth weight [John P. Newnham, Jan E. Dickinson, Roger J. Hart, at al. Strategies to Prevent Preterm Birth. // Front Immunol. - 2014. - N. 5. - P. 584].

At present, glucocorticoid therapy (GCT) is an effective specific prophylaxis of SDR. Of corticosteroids, betamethasone is most preferred. A review of 10 randomized controlled trials (4,733 women and 5,700 newborns) from 20 countries shows the use of repeated courses of GCT with the threat of preterm birth, starting from 24 weeks of pregnancy for the prevention of respiratory distress syndrome [Citation: Crowther CA, McKinlay CJD, Middleton P, Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes. // Cochrane Database of Systematic Reviews. - 2015. - Issue 7. Art. - N .: CD003935.DOI: 10.1002 / 14651858].

Glucocorticoids are steroid hormones synthesized by the adrenal cortex. In some diseases, anti-inflammatory, immunosuppressive, anti-allergic, anti-shock and other properties of these drugs are used. The main and most active glucocorticoid formed in the human body is hydrocortisone (cortisol), other less active ones are cortisone, corticosterone, 11-deoxycortisol, 11-dehydrocorticosterone. The production of adrenal hormones is controlled by the central nervous system and is closely related to the function of the pituitary gland. Adrenocorticotropic pituitary hormone (ACTH, corticotropin) is a physiological stimulator of the adrenal cortex. Corticotropin enhances the formation and secretion of glucocorticoids. The latter, in turn, affect the pituitary gland, inhibiting the production of corticotropin and thus reducing further stimulation of the adrenal glands (by the principle of negative feedback). A number of synthetic glucocorticoids have been synthesized, among which are non-fluorinated (prednisone, prednisolone, methylprednisolone) and fluorinated (dexamethasone, betamethasone, triamcinolone, flumethasone, etc.) glucocorticoids. These compounds, as a rule, are more active than natural glucocorticoids, act in smaller doses. The action of synthetic steroids is similar to the action of natural corticosteroids, but they have a different ratio of glucocorticoid and mineralocorticoid activity. The more favorable ratio between glucocorticoid / anti-inflammatory and mineralocorticoid activity is fluorinated derivatives. So, the anti-inflammatory activity of dexamethasone (compared with that of hydrocortisone) is 30 times higher, betamethasone is 25-40 times, triamcinolone is 5 times, and the effect on water-salt metabolism is minimal. Glucocorticoids cause many effects, as affect most body cells. They have anti-inflammatory, desensitizing, anti-allergic and immunosuppressive effects, anti-shock and anti-toxic properties.

There are two equivalent treatment regimens of corticosteroids: this is the introduction of two doses of 12 mg betamethasone intramuscularly for 24 hours or four 6 mg doses of dexamethasone after 12 hours. The course dose is 24 mg. A second course with prolongation of pregnancy is carried out after 7 days. The total course dose is 48 mg. Repeated GCT courses reduce the incidence of RDS and severe postnatal complications in the first weeks of life [Crowther CA., McKinlay CJ., Middleton P., Harding JE. Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes. Cochrane Database Syst Rev. 2011. - Vol. 15, No. 6. - CD003935].

According to the methodological letter of the Ministry of Health of the Russian Federation and WHO recommendations from 2011, the prevention of respiratory distress syndrome (RDS or SDR) of the fetus should be carried out at 24-34 weeks of gestation.

The closest analogue is the method described in Art. "Antenatal prevention of respiratory distress syndrome of the newborn" / S.V. Pavlovich // Obstetrics and gynecology. - 2011. - N3. - S. 81-85 - prototype. The method proved the feasibility of appointing a single course therapy with betamethasone or dexamethasone in pregnant women with a risk of premature birth during the coming 7 days during pregnancy 24-34 weeks, as well as within 24-32 weeks in cases of premature rupture of membranes (PRPO) in the absence of signs chorioamnionitis. Questions about conducting repeated courses of antenatal corticosteroid therapy, as well as about conducting the so-called rescue therapy - the introduction of corticosteroid drugs directly during preterm delivery or before elective cesarean section surgery - require further study, and at present, the use of these approaches cannot be recommended for use in everyday practice. It is impractical to prescribe antenatal corticosteroid therapy (ACT) during pregnancy for more than 34 weeks.

Antenatal corticosteroid therapy to accelerate fetal lung maturation has been used since 1972. ACT is highly effective in reducing the risk of developing RDS, intraventricular hemorrhage (IVH), and neonatal death in premature infants with a gestational age of 24-34 full weeks (34 weeks 0 days) of cases where there is evidence of immaturity of the fetal lungs. According to the clinical protocol of the Ministry of Health of Russia dated December 17, 2013, the course dose of ACT is 24 mg. Recommended regimens: 2 doses of intravenous betamethasone 12 mg every 24 hours (the most commonly used regimen in RCTs included in a systematic review); or 4 doses of IM dexamethasone 6 mg every 12 hours; or 3 doses of 8 mg dexamethasone IM after 8 hours. Regarding repeated courses, it says that the question remains controversial and that repeated courses of glucocorticoids compared with a single course do not lead to a decrease in the incidence of newborns and are not recommended for use. Recent systematic reviews, although there is information about the possibility of conducting repeated RDS courses of prevention after 7 days for women who still have the risk of preterm delivery, emphasize the need to inform them of the benefits and risks of such therapy and limited information about its long-term effects on the health of the child.

According to the order of the Ministry of Health of Russia dated 01.11.2012 No. 572H, glucocorticoids (GCT) (betamethasone and dexamethasone) are included in the list of drugs used in preterm delivery for the prevention of fetal RDS.

However, in all the presented works and orders above there is no evidence base on the effectiveness or inefficiency of using repeated courses of GCT.

The invention is aimed at solving the problem of preventing the decrease in the frequency of respiratory distress syndrome in a newborn in early preterm birth.

The method consists in the administration of the drug Dexamethasone (Dexamethazon) intramuscularly at 8 mg No. 3, after 8 hours. After 7 days, repeat the course. The course dose is 48 mg.

Indications for use:

- with prolongation of early preterm birth at 25 (0) - 27 (6) weeks, complicated by prolapse of the fetal bladder and premature rupture of the fetal bladder;

- a living fetus.

Contraindications:

- Hypersensitivity to the drug or the components of the drug;

- tuberculosis, acute (or exacerbation of a chronic) viral and bacterial infection, diabetes mellitus, acute renal failure, hypertension, Cushing's syndrome, bacterial endocarditis, osteoporosis, porphyria.

EFFECT: prolongation of pregnancy complicated by prolapse of the fetal bladder or PRPO.

The possibility of implementing the invention and achieving the specified result is confirmed by the following data. The authors analyzed the effect of the drug Dexamethasone (Dexamethazon, Dexon (C)) as a prophylaxis of the respiratory distress syndrome in fetuses with RPR.

The study group included 143 pregnant women with gestational age of 25 (0) -27 (6) weeks, who were hospitalized for threatening or preterm labor, complicated by prolapse of the fetal bladder, as well as in the first hours after the premature discharge of amniotic fluid ( PRPO). Upon admission, an anamnesis was collected, a general and special obstetric examination, a microscopic and bacterial analysis of the vaginal flora. After confirmation of amniotic fluid flow, the patients were hospitalized in isolated wards in compliance with sanitary and epidemiological standards. Further, the authors conducted a study of live births of newborns (n = 65) in the group of 25 (0) -27 (6) weeks of pregnancy, where the effect of single or double courses of glucocorticoids was considered as a prophylaxis of the development of SDR during prolongation of pregnancy and the further development of respiratory syndrome disorders in newborns in this gestational group.

Prevention was carried out with dexamethasone (KRKA, Slovenia) at a dose of 24 mg according to the 8 mg scheme after 8 hours. The course was considered completed with an exposure of at least 2 days. A single course of prevention of SDR was performed in 29 pregnant women. A repeated course of glucocorticoid therapy was performed in 36 pregnant women with an interval of 7-10 days. The authors' data showed reliable efficacy of the repeated course of prophylaxis of diabetes and a decrease in the frequency of respiratory disorders by 2.3 times - from 38.0 to 16.7% (FIG. 1.).

The results are shown in the graphs, where:

FIG. 1. The effect of glucocorticoid prophylaxis courses on the severity of SDR in the group of 25 (0) -27 (6) weeks (n = 65);

FIG. 2. The effect of glucocorticoid prophylaxis courses on the frequency of infectious complications of newborns at 25 (0) -27 (6) weeks (n = 65).

Numerous literature data indicate an increased risk of infectious complications and sepsis of newborns during a second course of GCT. In this regard, the authors analyzed the frequency of development of infectious complications in the mother and fetus during one or two courses of glucocorticoids (FIG. 2.).

The data obtained indicate the absence of a reliable effect on the implementation of the infection during repeated courses of GCT. Thus, the frequency of intrauterine pneumonia during the 1st and 2nd courses of gastrointestinal tract was 44.8 and 55.2%, neonatal sepsis - 46.7 and 53.3%, and chorioamnionitis - 42.8 and 57.2%, respectively (p <0.05) (FIG. 2.).

Analyzing their own results of the effectiveness of glucocorticoid prophylaxis of SDR, the authors consider it appropriate to conduct prophylactic courses of SDR after 25 (0) weeks of pregnancy, reducing the level of neonatal mortality, as well as the frequency and severity of intraventricular hemorrhage. The authors also recommend a repeated course of glucocorticoids in order to reduce the severity of SDR, including with prolonged prolongation of pregnancy complicated by prolapse of the fetal bladder and PRPO.

Thus, the presented data showed the effectiveness and feasibility of conducting a second course of prophylaxis of SDR with glucocorticoids in order to reduce the severity of SDR with prolonged prolongation of pregnancy complicated by prolapse of the bladder and PRPO at certain gestational dates - 25 (0) -27 (6) weeks with RPR.

Example 1. A woman in labor A., 21 years old. A history of ectopia of w / uterus. This pregnancy is the first spontaneous, proceeded with the threat of termination of pregnancy from an early date, carriage of HSV types 1 and 2. Complicated by the threat of early preterm birth and prolapse of the fetal bladder. Diagnosis at admission to the hospital: Pregnancy 25 weeks. The threat of premature birth. Prolapse of the fetal bladder. Immediately upon admission, intramuscular administration of 24 mg dexamethasone began according to the 8 mg schedule after 8 hours. Antibacterial therapy was also performed. After 7 days, a second course was carried out according to the same scheme. The course dose was 48 mg.

Outcome: spontaneous preterm delivery ended at 26 weeks of gestation, with the birth of a premature male fetus weighing 780.0 g. In an ICU, a newborn is diagnosed with SDR 1-2 tbsp. After 10 days, transferred to the second stage of nursing.

Example 2. A woman in labor A., 35 years old. This pregnancy is repeated, complicated by the threat of early preterm birth. During pregnancy, antibiotic therapy was carried out aimed at treating mycoplasma infection. Diagnosis at admission to the hospital: Pregnancy 24-25 weeks. The threat of premature birth. Prolapse of the fetal bladder. On admission, antibiotic therapy has been started. Immediately upon admission, intramuscular administration of betamethasone at a dose of 24 mg according to the 12 mg schedule began after 6 hours. After 7 days, a second course was carried out according to the same scheme. The course dose was 48 mg.

Outcome: spontaneous preterm delivery ended in 27-28 weeks of gestation, with the birth of a female preterm fetus weighing 890.0 g. In an ICU, a newborn was diagnosed with SDR 1-2 tbsp. After 13 days, transferred to the second stage of nursing.

Example 3. A mother of E., 24 years old. A history of uterine fibroids. This pregnancy was the first, proceeded with mild toxicosis, from the early stages there was a threat of abortion, took gestagens from the first trimester of pregnancy. Diagnosis at admission to the hospital: Pregnancy 25-26 weeks. The threat of premature birth. Premature discharge of amniotic fluid. The patient was hospitalized in an isolated ward in compliance with sanitary and epidemiological standards. Immediately upon admission, antibiotic therapy was carried out, intramuscular administration of dexamethasone at a dose of 24 mg according to the 8 mg scheme after 8 hours began. After 7 days, a second course was carried out according to the same scheme. The course dose was 48 mg.

Outcome: spontaneous preterm delivery ended at 27 weeks of gestation with the birth of a preterm male fetus weighing 980.0 g. In an ICU, a newborn is diagnosed with SDR 1-2 tbsp. After 13 days, transferred to the second stage of nursing.

Claims (1)

A method for the prevention of respiratory distress syndrome in newborns, including the administration of a glucocorticoid preparation to patients, characterized in that a course of the drug Dexamethazon (Dexamethazon) is administered intramuscularly at 8 mg No. 3 after 8 hours after a gestation of 25 (0) -27 (6) weeks of gestation course after 7 days with a total course dose of 48 mg.

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