Preterm Birth: Clinical Guidelines

List of Abbreviations

Terms and Definitions

See Section 1.1.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Preterm birth (PTB) is defined as birth occurring at a gestational age from 22 to 36+6 weeks [1, 2], with the gestational age established based on the date of the 1st day of the last menstrual period (in regular menstrual cycles) and fetal ultrasound performed at 11–13+6 weeks [3, 4].

Comment: recently, data have emerged regarding a new starting point for PTB, specifically from 20+0 instead of 22 weeks (ACOG, WHO); however, in the Russian Federation, the gestational age criteria for PTB remain unchanged.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

PTB belongs to the category of great obstetrical syndromes, which are characterized by a prolonged subclinical course and the involvement of paternal factors, environmental factors, and the fetus in the pathological process [5]. A significant contribution to overall PTB statistics is made by induced PTBs caused by obstetric and extragenital pathology, as well as those associated with fetal condition [6].

The association between PTB and lower genital tract infection has been proven [1]. One in ten patients with PTB shows signs of intra-amniotic inflammation, which in most cases is subclinical. These patients are at high risk for preterm premature rupture of membranes (PPROM) and purulent-inflammatory postpartum complications [7–9]. The infectious and inflammatory process leads to increased myometrial contractile activity and extracellular matrix degradation with remodeling of the cervix and amniotic membrane [10, 11], which clinically manifests as cervical insufficiency and PPROM. Long-term persistent infection leads to the development of manifest chorioamnionitis and fetal systemic inflammatory response syndrome (FIRS). The leading diagnostic criterion for FIRS is the presence of IL-6 in umbilical cord blood plasma at a concentration of more than 11 pg/mL [5, 12]. The contribution of heredity to the development of PTB, including paternal heredity, is also considered [13, 14].

[1] NICE Guidance, Preterm labour and birth, 2016 (updated June 10, 2022)

1.3 Epidemiology of the Disease or Condition

The prevalence of PTB (28–36⁶ weeks of gestation) in the Russian Federation has remained stable over the past 10 years and in 2020 amounted to 59.9 thousand cases out of the total number of births (1,220.8 thousand) [1].

A global, regional, and national analysis of the incidence and neonatal mortality of PTB from 1990 to 2019, published in 2022, showed an overall decrease of 5.26% (from 16.06 million in 1990 to 15.22 million in 2019), as well as a 47.71% reduction in neonatal mortality (from 1.27 million in 1990 to 0.66 million in 2019) [15].

PTB accounts for 70% of neonatal mortality, 36% of infant mortality, and 25–50% of long-term neurological sequelae in children [16, 17]. Among infants born at 22⁰–23 ⁶ weeks, mortality within several weeks is 97–98%, with only 1% surviving without neurodevelopmental impairments. Among infants born at 24⁰–24⁶ weeks, 55% of newborns survive, but only 32% have no neurological deficits at 18–22 months of age [18].

[1] Healthcare in Russia. 2021: Statistical Handbook / Rosstat. - M., Z-46 2021. – 171 p., p. 57

1.4 Features of Coding the Disease or Condition

O60 - Preterm labor and delivery

O60.0 - Preterm labor without delivery

O60.1 - Preterm spontaneous labor with premature delivery

O60.2 - Preterm spontaneous labor with term delivery

O60.3 - Preterm delivery without spontaneous labor

O47.0 - False labor before 37 completed weeks of gestation

O42 - Premature rupture of membranes

1.5 Classification of the disease or condition

Clinical classification of PTB[4] [19]:

Threatened PTB – potential risks of PTB are present, but their realization within the next 7 days is highly unlikely.

Incipient (Inevitable) PTB – high risk of progression within the next 7 days (diagnosis must be confirmed by objective diagnostic tests)

Active PTB – active labor combined with progressive cervical dilation (from 4 cm).

Classification of PTB according to etiology [6]

[1] WHO, Preterm birth, 10.05.2023 (https://www.who.int/news-room/fact-sheets/detail/preterm-birth)

[2] ACOG Practice bulletin, № 234, Prediction and Prevention of Spontaneous Preterm Birth, 08.2021 

[3] Predicting and Preventing Preterm Birth: Recommendations From ACOG. Am Fam Physician. 2022;106(3):337-339

[4] NICE Guidance, Preterm labour and birth, 2016 (updated June 10, 2022)

1.6 Clinical presentation of the disease or condition

The following signs may be observed for several hours before the onset of classic labor symptoms:

• menstrual-like cramping pain;

• painless and irregular uterine contractions;

• low back pain;

• feeling of pressure in the vagina or pelvis;

• vaginal mucus discharge, which may be clear, pink, or slightly blood-tinged ("mucus plug").

The clinical symptoms that determine the true onset of labor (i.e., initiated preterm labor) are identical regardless of gestational age and are manifested by regular contractions and progressive cervical change and dilatation. Cervical changes include widening of the internal os, shortening, softening, and centralization of the cervix. Cervical changes in initiated preterm labor occur within a few hours, which distinguishes them from the process of cervical ripening that takes place over several days or even weeks [5, 20–23].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for diagnosing preterm labor [1]

Threatened preterm labor — presence of symptoms (complaints!) reported by patients that may indicate preterm labor (e.g., abdominal pain) without objective confirmatory signs (cervical length primarily assessed by transvaginal ultrasound [TVUS cervical length], as well as bimanual vaginal examination) and laboratory tests to determine the probability of preterm labor occurring within the next 7–14 days (determination of phosphorylated insulin-like growth factor-binding protein 1 [phIGFBP-1] in cervical mucus, interleukin-6 [IL-6], and placental alpha-microglobulin-1 [PAMG-1] in cervical mucus) [24–28].

Initiated/inevitable preterm labor — presence of symptoms (complaints!) reported by patients indicating preterm labor (e.g., abdominal pain), confirmed by objective signs (cervical length primarily assessed by transvaginal ultrasound [TVUS cervical length], as well as bimanual vaginal examination, laboratory tests), but in the absence of regular labor activity.

Active preterm labor — characterized by the presence of 4 contractions within 20 minutes (and/or 8 contractions within 60 minutes) and cervical dilatation ≥4 cm.

Criteria for diagnosing preterm premature rupture of membranes (PPROM) [2]

The diagnosis of spontaneous preterm premature rupture of membranes is established based on the pregnant woman's complaints (abundant liquid discharge from the genital tract, constant fluid leakage from the vagina), confirmed by a subsequent sterile speculum examination demonstrating amniotic fluid leakage from the cervical canal. If the speculum examination does not show reliable amniotic fluid leakage, consideration should be given to testing for phosphorylated insulin-like growth factor-binding protein 1 (phIGFBP-1) in cervical mucus or placental alpha-microglobulin-1 (PAMG-1) in cervical mucus (in the discharge of the posterior vaginal fornix). The role of ultrasound assessment of amniotic fluid volume (amniotic fluid index and/or deepest vertical pocket) remains unclear.

[1] NICE Guidance, Preterm labour and birth, 2016 (updated June 10, 2022)

[2] Care of Women Presenting with Suspected Preterm Prelabour Rupture of Membranes from 24+0 Weeks of Gestation, Green-top Guideline № 73, 06.2019

2.1 Complaints and Anamnesis

Complaints — see section 1.6.

• Before conception or in early pregnancy, taking a history and identifying risk factors for preterm labor is recommended [5, 9, 24], [20], [25], [26], [27, 28], [29], [30], [31], [32], [33], [34, 35], [36]. [1]

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

Comments: Risk factors include: history of induced preterm labor in the patient [25], history of abortions in the patient [26], preterm birth in the patient's mother [27, 28], advanced reproductive age of the patient [29], cervical pathology in the patient [30], uterine malformations in the patient [30], sudden infant death syndrome in previously born children of the patient [31], current pregnancy achieved using assisted reproductive technologies (ART) [32], multiple gestation in the current pregnancy [33], bleeding in early pregnancy [20], urogenital infections [34, 35], [36]. A cervical length ≤25 mm and/or cervical dilatation ≥10 mm before 24 weeks of gestation are associated with an increased risk of preterm labor. Numerous studies have established a link between preterm labor and urogenital infection. The risk of preterm labor depending on the pathogen is presented in Table 1 [5, 9, 24].

Table 1

Association between preterm labor and urogenital infection

• Pregnant women with two clinical factors—history of preterm birth before 34⁰ weeks (or < 32⁰ weeks in multiple gestation) or spontaneous miscarriage after 16⁰ weeks—and a shortened cervical length of less than 25 mm (confirmed by transvaginal ultrasound) between 16⁰ and 24⁶ weeks of the current pregnancy are recommended to be classified as high risk for preterm labor [2] [37, 38].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

[1] Preterm Labor and Birth Management: Recommendations from the European Association of Perinatal Medicine, 2017. 

[2] ISUOG Practice Guidelines: role of ultrasound in the prediction of spontaneous preterm birth, 2022

2.2 Physical Examination

• In threatened preterm labor, speculum examination of the cervix is recommended [39].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment: Cervical examination is performed using sterile single-use polymer gynecological specula by Cusco (medical device type 227960) (to exclude any effect when performing diagnostic tests) in order to assess the state of the cervical canal, presence/absence and amount of bloody discharge, exclude/confirm bulging of the fetal membranes, exclude/confirm umbilical cord prolapse or small fetal parts in PPROM, and exclude inflammatory changes of the cervix [39].

• To determine the state of the birth canal and the degree of cervical "ripening", vaginal examination is recommended to be performed only after placenta previa (on ultrasound) and prolapse/rupture of fetal membranes have been excluded (inspect the cervix via speculum and, if PPROM is suspected, perform an amniotic fluid leakage test) [39–41].

Strength of Recommendation C (SRC)Level of Evidence 5 (LoE 5)Strength of Recommendation Grade C (Level of Evidence — 5).

Comments: in the absence of active labor, initiated preterm labor, or PPROM, vaginal examination should be avoided as it provides no additional crucial information while increasing the risk of ascending infection.

• All patients are recommended to have blood pressure, pulse, and respiratory rate measured to assess vital functions [42].

GCR CLOE 4Grade of Recommendation C (Level of Evidence - 4).

• All patients are recommended to undergo fetal auscultation, as well as determination of the frequency, duration, and intensity of uterine contractions to assess fetal condition and signs of labor onset [43].

GCR CLOE 4Grade of Recommendation C (Level of Evidence - 4).

2.3 Laboratory Diagnostics

• In PPROM, it is recommended to test blood leukocyte levels and serum C-reactive protein levels for the timely diagnosis of septic complications [44], [45].

Strength of Recommendation B (SRB)Level of Evidence 2 (LoE 2)Strength of Recommendation Grade B (Level of Evidence — 2).

Comments: The leukocyte count increases 24 hours after the administration of corticosteroids (CS) and gradually returns to baseline 3 days after fetal respiratory distress syndrome (RDS) prophylaxis. C-reactive protein is the most accurate marker, with a sensitivity of 68.7% and specificity of 77.1% [45]. A combination of clinical signs (maternal and fetal condition) and laboratory parameters should be used to diagnose chorioamnionitis in women with PPROM [1].

• In threatened and, especially, inevitable preterm labor, as well as in PPROM, it is recommended:

— detection of group B Streptococcus (S. agalactiae) antigen (DNA) in cervical canal discharge by PCR, and/or

— detection of group B Streptococcus (S. agalactiae) DNA in vaginal and rectal swabs by PCR,

— bacteriological culture of cervical canal discharge for group B Streptococcus (S. agalactiae),

— bacteriological culture of vaginal and rectal discharge for group B Streptococcus (S. agalactiae) for intrapartum prevention of septic complications in the newborn in the event of preterm labor ^14, [2] [46].

Strength of Recommendation B (SRB)Level of Evidence 2 (LoE 2)Strength of Recommendation Grade B (Level of Evidence — 2).

Comment: The association between GBS colonization during pregnancy and preterm labor has not been proven, but there is an increased risk of neonatal sepsis, making this test clinically appropriate [47].

• To clarify the diagnosis of preterm labor at 24⁰ - 33⁶ weeks of gestation, it is recommended to perform a combination of the following laboratory tests to determine the probability of preterm labor occurring within the next 7 - 14 days:

— determination of interleukin-6 (IL-6) in vaginal secretions;

— determination of the phosphorylated form of insulin-like growth factor-binding protein 1 (phIGFBP-1) in cervical mucus;

— determination of placental alpha-microglobulin-1 (PAMG-1) in

— cervical mucus [24, 25, 51–53].

GOM ALOE 2Recommendation Grade A (Level of Evidence - 2).

Comments: IGFBP-1 is produced by placental decidual cells and is detected in cervical mucus as a result of choriodecidual interface damage [26]. A negative result indicates a low risk of preterm labor within 7 days after the test (PPV=94%) [54]. The presence of fragmented forms of IGFBP-1 indicates significant local proteolytic activity and fetal stress caused by uterine contractions. IL-6 is the primary mediator of the body's response to infection and tissue damage. Numerous accumulated data have established that the development of preterm labor against the background of intrauterine infection is accompanied by pronounced changes in its concentration in amniotic fluid. A negative result of the triple test, which determines insulin-like growth factor-binding protein 1 (IGFBP-1), fragmented forms of insulin-like growth factor (PAMG-1), and IL-6, indicates a low risk of preterm labor within 7 days after the test (PPV=98.5%) [25].

The sensitivity of the PAMG-1 test in patients with threatened preterm labor and an intact amniotic sac is 84%, specificity is 95%, NPV is 93-97%. Sensitivity and NPV for preterm labor at 7 days in patients with a cervical length of 15-30 mm are 100%. For predicting preterm labor at less than 34 weeks, NPV is 93% [3] [27].

• In preterm premature rupture of membranes (PPROM), an examination of the cervix using sterile disposable polymer gynecological specula by Cusco is recommended to identify amniotic fluid leakage [4][5] [38].

GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).

Comment: Express laboratory tests include the "cytological test" (fern test, false-negative rate over 20%), nitrazine test (examination of hydrogen ion concentration (pH) of amniotic fluid in cervical mucus (amniotic fluid leakage test, false-positive rate 5-30%), and tests for IGFBP-1 and PAMG-1 (determination of the phosphorylated form of insulin-like growth factor-binding protein 1 (phIGFBP-1) in cervical mucus, determination of placental alpha-microglobulin-1 (PAMG-1) in cervical mucus) [48–53] (Table 2). Amniotic fluid leakage from the cervical canal and/or pooling of fluid in the vagina upon examination with sterile disposable polymer gynecological specula by Cusco strongly indicates rupture of the membranes, and further diagnostic tests are not required. In cases where amniotic fluid cannot be clearly visualized, testing for IGFBP-1 and PAMG-1 (determination of the phosphorylated form of insulin-like growth factor-binding protein 1 (phIGFBP-1) in cervical mucus, determination of placental alpha-microglobulin-1 (PAMG-1) in cervical mucus) should be considered¹⁶.

Table 2

Predictive value of test systems for determining PPROM

SN – sensitivity, SP – specificity, PPV and NPV – positive and negative predictive value, respectively.

[1] Care of Women Presenting with Suspected Preterm Prelabour Rupture of Membranes from 24+0 Weeks of Gestation, Green-top Guideline № 73, 06.2019

[2] Prevention of Group B Streptococcal Early-Onset Disease in Newborns (Number 797 (Replaces Committee Opinion No. 782), 2020

[3] Preterm Labor and Birth Management: Recommendations from the European Association of Perinatal Medicine, 2017.

[4] Care of Women Presenting with Suspected Preterm Prelabour Rupture of Membranes from 24+0 Weeks of Gestation, Green-top Guideline № 73, 06.2019

[5] ACOG, Practice Bulletin No. 172: Premature Rupture of Membranes, 2016.

2.4 Instrumental Diagnostics

• Patients at risk for preterm labor are recommended to undergo transvaginal cervical ultrasound (cervicometry) for timely diagnosis of cervical insufficiency [1]^, [2] [21, 54].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comments: A cervical length ≤25 mm prior to 24⁶ weeks of gestation is a predictor of preterm labor. At 20 weeks of gestation, a cervical length ≤25 mm is associated with a 6-fold increase in the risk of preterm labor. Prior to 34 weeks in singleton pregnancies, a cervical length measurement ≤25 mm has a sensitivity of 76%, specificity of 68%, PPV of 20%, and NPV of 96% for the diagnosis of preterm labor [55], [56].

Comments: normally, cervical length is stable between 14 and 28 weeks of gestation and subsequently tends to gradually shorten: thus, the mean length decreases from ~43 mm at 16 weeks to ~31 mm by 36 weeks of gestation [60].

[1] Preterm Labor and Birth Management: Recommendations from the European Association of Perinatal Medicine, 2017.

[2] ISUOG Practice Guidelines: role of ultrasound in the prediction of spontaneous preterm birth, 2022

2.5 Other Procedures

• To exclude/confirm an infectious and inflammatory process and to address the feasibility of surgical correction of cervical insufficiency (CI) with a cervical length ≤25 mm at 22⁰-23⁶ weeks of gestation based on a collegial decision (joint examination, medical board), diagnostic transabdominal amniocentesis is recommended [61].

LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).

Comments: The incidence of acute chorioamnionitis in patients delivered at 22⁰-23⁶ weeks of gestation is 94.4% [62]. In the 2nd trimester of pregnancy with extremely early preterm labor combined with cervical insufficiency, ruling out an infectious-inflammatory factor to improve pregnancy outcomes when planning surgical correction of cervical insufficiency is a necessary stage of patient management [1]. Subclinical chorioamnionitis is an important risk factor for premature shortening and maturation of the cervix; therefore, amniocentesis is an objective method to rule out inflammation/infection prior to performing surgical correction of cervical insufficiency. Elevated concentrations of IL-6, leukocytes, and low glucose concentrations in the amniotic fluid, even in the absence of a positive microbiological culture, significantly increase adverse pregnancy outcomes in patients who underwent non-elective (urgent) cerclage [61]. Assessment of fetal lung maturity is also possible via amniotic fluid analysis [63]. When intra-amniotic infection is confirmed based on amniotic fluid analysis, surgical correction of cervical insufficiency, given the high risk of obstetric and perinatal complications, is generally not performed [5, 9, 61, 62].

[1] ACOG Practice Bulletin No.142: Cerclage for the management of cervical insufficiency, 2014.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Pharmacotherapy

• In cases of onset (imminent) preterm labor at 24⁰ – 33⁶ weeks of gestation [64], tocolytic therapy is recommended [65–69].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comment: The administration of tocolytic drugs can reduce the strength and frequency of uterine contractions, delay the onset of labor for 48 hours and/or even 7 days, but does not prolong pregnancy to term [70]. The drugs are administered for 48 hours for the purpose of fetal RDS prevention, magnesium sulfate therapy for fetal neuroprotection, and transfer of the pregnant woman to a Level 3 hospital.[1] Contraindications to tocolytic therapy include[2]: intrauterine fetal demise, congenital malformations incompatible with life, severe preeclampsia and eclampsia, maternal hemorrhage with hemodynamic instability, chorioamnionitis, maternal contraindications to this therapy, preterm premature rupture of membranes (PPROM) at a gestational age of more than 32⁰ weeks, placental abruption, uterine scar dehiscence, and cervical dilation greater than 4 cm. Tocolytic therapy at less than 24⁰ weeks of gestation should be considered individually, with an explanation to the family regarding the unfavorable prognosis for the newborn if delivered at this gestational age[3]. 34⁰ weeks of gestation is the threshold at which perinatal morbidity and mortality are low enough to justify the potential maternal and fetal complications and the costs associated with tocolytic therapy[4].

• In the absence of objective signs of preterm labor (no cervical shortening according to cervical ultrasound and with negative test results for preterm labor (if performed)), tocolytic therapy is not recommended [74].

GPR CLEL 2Grade of Recommendation C (Level of Evidence - 2).

Comments: tocolytic therapy is performed only in cases of imminent preterm labor. In 75–95% of cases in this category of pregnant women, preterm labor does not occur within 7 days, which requires an extremely selective approach when making a decision to perform acute tocolysis [72].

• As the first line of tocolytic therapy, #nifedipine** (slow calcium channel blocker, ATC selective calcium channel blockers with predominant vascular effect) [73–75] and atosiban** (oxytocin receptor antagonist - ATC G02CX Other gynecological drugs) are recommended [68].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comments: #Nifedipine** [77] is not registered as a tocolytic agent and is used off-label; therefore, its use requires a medical commission conclusion (head of the department and 2 obstetrician-gynecologists) and the patient's written informed consent. Regimen: 20 mg orally, followed by 10 mg every 6 hours for 3–7 days if uterine contractions persist or until the pregnant patient is transferred (whichever comes first) [5]. Side effects (maternal only): arterial hypotension (in such cases, dose reduction is indicated), tachycardia, headaches, dizziness, nausea. Recommended monitoring: periodic monitoring of fetal heart rate, pulse measurement, blood pressure (BP) every 30 minutes for the first hour, then every hour for the first 24 hours, then every 4 hours. WHO recommendations published in 2022 identify #Nifedipine** as the drug of choice based on the optimal benefit-harm ratio, cost, and acceptability²⁷.

Atosiban** is a highly selective oxytocin receptor antagonist with few side effects; however, its advantages over #nifedipine** have not been proven [76], [74]. Considering this, as well as the high cost of the drug, it should be prescribed when there are contraindications to the use of #nifedipine** and other tocolytics, especially at 32⁰ – 33⁶ weeks 24 [73]. Regimen: administered intravenously in 3 successive steps according to the instructions. The total duration of treatment should not exceed 48 hours, and the maximum dose should not exceed 330 mg. A repeat course can be started at any time after the first administration of the drug and can be repeated for up to 3 cycles. Side effects (maternal): nausea, vomiting, hyperglycemia, headache, dizziness, tachycardia, arterial hypotension (in such cases, dose reduction is indicated), itching, skin rash. Recommended monitoring: similar to monitoring with #nifedipine**.

• As a second line of tocolytic therapy, non-steroidal anti-inflammatory drugs (ATX Non-steroidal anti-inflammatory and antirheumatic products) (#indometacin) are recommended up to 28⁶ weeks [6] [78].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comments: #Indometacin [77] is used starting with 50–100 mg rectally or orally, then 25 mg every 6 hours (no more than 48 hours). Maternal side effects: nausea, reflux esophagitis, gastritis. Fetal side effects after 31 weeks of gestation: premature closure of the ductus arteriosus, oliguria, and oligohydramnios. Contraindications: blood clotting disorders, increased bleeding tendency, liver dysfunction, peptic ulcer disease, bronchial asthma, aspirin hypersensitivity, fetal growth restriction (FGR), fetal renal congenital malformations [7]. The frequency of side effects is significantly lower when used for no more than 48 hours at a gestational age of less than 28 weeks. The presence of oligohydramnios and/or detection of constriction of the ductus arteriosus is an indication for discontinuing therapy.

Comments: Recent studies show that beta-adrenomimetics may affect perinatal programming (associated with the development of asthma in children). A study by Ogawa, 2017 showed that their in utero exposure is associated with a dose- and time-dependent increased risk of asthma in children [79].

It should be noted that this recommendation also applies to hexoprenaline**, despite the fact that it is a tocolytic with proven efficacy [65].

• In PPROM that has begun or is planned (induced) preterm labor, intravenous administration of magnesium sulfate** at 24⁰ - 33⁶ weeks of gestation is recommended for fetal neuroprotection [8][82], [83].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comments: Magnesium therapy reduces the incidence of cerebral palsy and motor disorders. The maximum effect is observed before 30⁶ weeks [83]. The use of magnesium sulfate** is contraindicated in women with myasthenia gravis, as it can provoke a severe myasthenic crisis. Its administration should also be avoided in women with cardiac conduction disorders due to its anti-inotropic effect. Since magnesium is excreted by the kidneys, women with impaired renal function may have an increased serum magnesium level, which can provoke toxic effects; therefore, in this category of patients, the dose should be selected individually [84]. Regimen: a bolus of 4 g of magnesium sulfate** over 20–30 minutes, followed by continuous intravenous infusion of 1 g per hour until delivery or for 24 hours (whichever comes first)³³. Clinical signs of magnesium toxicity must be monitored at least every 4 hours (pulse, blood pressure, respiratory rate, and deep tendon (e.g., knee) reflexes) [9] [77]. Magnesium sulfate** infusion should be started when preterm labor is planned or expected, preferably within the 4 hours preceding delivery. If labor does not occur, the infusion should be discontinued after 24 hours. Magnesium sulfate** should be administered regardless of the cause of preterm labor (spontaneous or induced), as well as in multiple pregnancies [10]^. Although therapy is generally administered once, data have emerged indicating that a single bolus injection of 4 g of magnesium sulfate** to stimulate BDNF production in cases of extremely 'suspicious' preterm labor, followed by a repeat 4 g dose when preterm labor becomes inevitable, may be superior in terms of safety and appears to have a stronger rationale for neuroprotection [85].

• In PPROM, antibacterial therapy is recommended to prolong pregnancy and reduce neonatal morbidity from the moment of PPROM diagnosis for 10 days, or until delivery (if it occurs earlier) [11]^{, [12]} [86].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comments: Scientifically proven and confirmed drugs are #ampicillin** 2 g intravenously every 6 hours for 48 hours, and #amoxicillin** 250 mg every 8 hours for 5 days, or #erythromycin** 250 mg every 6 hours for a maximum of up to 10 days. The use of systemic antibacterial drugs is associated with a significant reduction in the incidence of chorioamnionitis, neonatal infection, and perinatal mortality [87]. The decision on a repeated course of antibacterial therapy is made based on the dynamics of the infectious and inflammatory process and the results of microbiological (culture) studies. Broad-spectrum penicillins and erythromycin** remain the recommended antibiotic regimens to reduce the clinical course of chorioamnionitis [88]. At the same time, comparative studies on the efficacy of erythromycin and #azithromycin showed that the use of #azithromycin in women with preterm prelabor rupture of membranes was associated with a similar latent period, but a lower incidence of clinical chorioamnionitis compared to erythromycin [89]. Other studies showed a higher incidence of neonatal respiratory distress syndrome with 5 days of #azithromycin, which is why the authors believe that a one-day course of #azithromycin is possible if there are contraindications to erythromycin [90]. Combination therapy with parenteral penicillins and a single oral dose of 1,000 mg of #azithromycin may be prescribed. This regimen covers Streptococcus agalactiae, gram-negative bacteria (Neisseria gonorrhoeae, Escherichia coli), and atypical bacteria such as Chlamydiae and Ureaplasma, which may be present in the vaginal flora [91].

Before using #azithromycin, a medical commission conclusion (head of the department and 2 obstetrician-gynecologists) and the patient's written informed consent are required, as the dosages and duration of therapy are off-label.

Regimens:

- #Azithromycin 1,000 mg orally once

- #Azithromycin 500 mg orally followed by 250 mg orally for four days

- #Azithromycin 500 mg intravenously for two days followed by 500 mg orally for five days [92].

• In PPROM, the use of amoxicillin+clavulanic acid is not recommended due to the high incidence of necrotizing enterocolitis in newborns [93].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• In PPROM, amnioinfusion is not recommended in routine clinical practice [94].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comment: Amnioinfusion may improve neonatal outcomes by preventing umbilical cord compression, postural deformations, reducing pulmonary hypoplasia, and intrauterine infection; however, due to insufficient research, it is currently not recommended in routine clinical practice [94].

3.2. Surgical treatment

• In case of cervical shortening with intact fetal membranes, cervical cerclage is recommended [22, 95].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comments: Cervical cerclage (suturing of the cervix) is performed at 16⁰ – 26⁶ weeks of gestation[13]. Cervical cerclage can be performed as a preventive measure in patients with a burdened history (late miscarriage and/or preterm birth) or applied as an emergency procedure when the patient exhibits premature ripening and shortening of the cervix, frequently accompanied by prolapse of the fetal membranes [96]. The benefits and risks of the procedure must be carefully weighed, taking into account the gestational age (risks increase with advancing gestation), the degree of cervical dilation, the qualifications of the obstetriciangynaecologist, and the capabilities of the inpatient facility. After 24⁰ weeks of gestation, cervical cerclage is performed exclusively in Level III inpatient facilities. Regardless of the gestational age, the decision to perform cervical cerclage must be made collectively, weighing the benefits and risks, and taking into account the limited evidence base regarding the efficacy of this intervention[14].

• For adequate anesthetic management during cervical cerclage, the use of both neuroaxial anesthesia methods (epidural, spinal, combined spinal-epidural) and general anesthesia is recommended [98–102].

ACLE 5Level of evidence C (level of data certainty - 5).

Comments: There is compelling evidence that none of the specified types of anesthesia increases the concentration of endogenous oxytocin or affects surgical outcomes [103]. If the patient is in the Trendelenburg position during spinal anesthesia, hyperbaric local anesthetic solutions should be avoided. For transvaginal cerclage, anesthesia is performed while maintaining spontaneous breathing; for transabdominal laparoscopic access, anesthesia with mechanical ventilation is used [104].

3.3. Other treatment

• In PPROM at 24⁰ - 36⁶ weeks of gestation, expectant management aimed at prolonging pregnancy is recommended, under the supervision of the mother's and fetus's condition, except for pregnant women with confirmed GBS carriage, where expectant management is possible up to 34⁰ weeks [15] [44].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comments: Expectant management includes hospitalization with periodic assessment of clinical and laboratory parameters to exclude infection, placental abruption, umbilical cord compression, onset of labor, and fetal assessment [16]. Prolongation of pregnancy in GBS-carrier women beyond 34⁰ weeks is associated with a higher risk of infectious perinatal complications compared to prematurity per se⁴⁰.

• In PPROM, monitoring of all patients in an inpatient setting 24/7 is recommended [17] [106].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comments: Modern international guidelines⁴⁰ cautiously consider outpatient management of pregnant women with PPROM after properly informing patients about the symptoms of chorioamnionitis and regular examinations (frequency determined individually depending on the clinical situation) (including blood tests [leukocyte count and C-reactive protein], fetal heart rate recording and monitoring); if the patient has any concerns, she should immediately report to the hospital ⁴⁰.

3.4. Delivery

• In preterm labor through the natural birth canal, in the absence of contraindications, neuroaxial analgesia (epidural, spinal, combined spinal-epidural) is recommended as a method of pain relief [107–112], [113–115].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comments: Neuroaxial analgesia is the most effective method of pain relief in preterm labor through the natural birth canal [116]. Any neuroaxial analgesia technique can be used: epidural analgesia using boluses, continuous infusion of a local anesthetic into the epidural space, patient-controlled analgesia, programmed (automated) epidural boluses, computer-integrated patient-controlled analgesia, and dural puncture epidural analgesia.

• Taking into account the negative impact on the condition of the fetus and newborn in preterm labor and existing contraindications, it is recommended to avoid the use of opioids as adjuvants for neuroaxial analgesia [117].

GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).

• In preterm labor, cesarean section (CS) is not recommended as the method of choice for delivery [118].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comments: There is a similar rate of birth trauma, birth asphyxia, and perinatal mortality between CS and vaginal delivery, but a higher maternal morbidity rate with CS compared to delivery through the natural birth canal [117]. If the estimated fetal weight does not correspond to the gestational age, CS is preferable at up to 31⁶ weeks. When the estimated fetal weight corresponds to gestational age, delivery through the natural birth canal at 32⁰ - 33⁶ weeks has more favorable neonatal outcomes compared to CS [119]. The specifics of fetal extraction are described in the clinical guidelines «Cesarean Section».[18]

• In cases of premature rupture of membranes and breech presentation of the fetus up to 32⁶ weeks of gestation, Cesarean section is recommended as the preferred method of delivery [19] [120].

LeveL of Recommendation BGrade of Evidence 2LeveL of Recommendation B (Grade of Evidence - 2).

Comments: The mode of delivery should be individualized depending on the stage of labor, type of breech presentation, fetal condition, and the availability of a physician skilled in breech delivery techniques. In a favorable obstetric situation, preterm delivery with breech presentation is possible[20]. At a gestational age of less than 27⁶ weeks, delivery via CS is associated with a lower rate of neonatal mortality and severe intraventricular hemorrhage (IVH) [121]. If technical capabilities are available, extraction of the fetus within intact fetal membranes is recommended. During preterm labor, the patient and her relatives should be informed about the benefits and potential consequences of a particular delivery method, especially before 26 weeks.

Comments: The use of a vacuum extractor is not recommended due to the higher incidence of subgaleal hematomas, IVH, subcutaneous hemorrhages, and jaundice in premature infants. In situations where CS is impossible, the application of obstetric (gynecological) forceps is preferred, although these data are contradictory [124]. At 34⁰ - 36⁶ weeks of gestation, there is insufficient evidence regarding the safety/harm of applying obstetric (gynecological) forceps and vacuum extractors.

• In surgical delivery via CS during preterm labor, it is recommended to use both neuroaxial anesthesia techniques (epidural, spinal, combined spinal-epidural) and general anesthesia for adequate anesthetic management [126–133].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comment. With the undeniable predominance of neuroaxial anesthesia in CS, general anesthesia retains its position when there are contraindications to neuroaxial anesthesia [116].

• In the absence of concomitant risk factors, continuous fetal monitoring during labor is not recommended [96]. [22]

GPR CLOCE 5 Grade of Recommendation C (Level of Evidence - 5).

Comment: The use of a scalp electrode for direct fetal ECG and fetal blood sampling is possible at 34⁰–36⁶ weeks of gestation when the benefits outweigh the risks and the fetal heart rate cannot be determined using external cardiotocography (CTG) and intermittent auscultation.

Comments: Delayed cord clamping is performed when the umbilical cord pulsations exceed 100 beats per minute (pulsation is assessed by palpation). Clamping for a minimum of 60 seconds, but not exceeding 3 minutes, is considered effective provided the mother and newborn are in a stable condition. Before cord clamping, the infant should be placed at or below the level of the placenta. In exceptional cases, if resuscitation of a preterm newborn is required or if the mother is bleeding, it is advisable to use cord milking ("umbilical cord milking") and subsequent clamping. A clinical study demonstrated a fourfold increase in the incidence of severe intraventricular hemorrhage (IVH) with cord milking compared to delayed cord clamping in extremely preterm newborns [136].

Comment: It is also advisable to increase the ambient temperature in the delivery room to 26–28°C [138].

[1] ACOG, Practice Bulletin No. 171: Management of Preterm Labor, 2016.

[2] Preterm Labor and Birth Management: Recommendations from the European Association of Perinatal Medicine, 2017.

[3] Obstetric Care Consensus No. 3: Periviable Birth, ACOG, 2015.

[4] ACOG, Practice Bulletin No. 171: Management of Preterm Labor, 2016.

[5] WHO recommendation on Tocolytic therapy for improving preterm birth outcomes, 2022.

[6] WHO recommendation on Tocolytic therapy for improving preterm birth outcomes, 2022.

[7] Preterm Labor and Birth Management: Recommendations from the European Association of Perinatal Medicine, 2017

[8] Care of Women Presenting with Suspected Preterm Prelabour Rupture of Membranes from 24+0 Weeks of Gestation: Green-top Guideline No. 73, 2019.

[9] NICE Guidance, Preterm labour and birth, 2016 (with updates as of 10.06.2022)

[10] FIGO good practice recommendations on magnesium sulfate administration for preterm fetal neuroprotection, 2021

[11] ACOG, Practice Bulletin No. 172: Premature Rupture of Membranes, 2016.

[12] Care of Women Presenting with Suspected Preterm Prelabour Rupture of Membranes from 24+0 Weeks of Gestation: Green-top Guideline No. 73, 2019.

[13] NICE Guidance, Preterm labour and birth, 2016 (with updates as of 10.06.2022)

[14] ISUOG Practice Guidelines: role of ultrasound in the prediction of spontaneous preterm birth, 2022

[15] Care of Women Presenting with Suspected Preterm Prelabour Rupture of Membranes from 24+0 Weeks of Gestation: Green-top Guideline No. 73, 2019.

[16] ACOG, Practice Bulletin No. 172: Premature Rupture of Membranes, 2016.

[17] Care of Women Presenting with Suspected Preterm Prelabour Rupture of Membranes from 24+0 Weeks of Gestation: Green-top Guideline No. 73, 2019.

[18] Clinical Guidelines "Cesarean Section" http://prof.ncagp.ru/index.php?_t8=85

[19] NICE Guidance, Preterm labour and birth, 2016 (with updates as of 10.06.2022)

[20] Management of Breech Presentation (Green-top Guideline No. 20b), 2017.

[21] Operative Vaginal Delivery (Green-top Guideline No. 26), 2011.

[22] NICE Guidance, Preterm labour and birth, 2016 (with updates as of 10.06.2022)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: Preterm labor is a distressing event for parents, who frequently report symptoms of post-traumatic stress for several years; sometimes, even 5–6 years after preterm labor, mothers hold a negative perception of their perinatal period. The primary stress experienced by parents is associated with separation from their infant (stay in the intensive care unit) and the loss of the parental role due to the absence of physical and emotional closeness, which are critical factors in bonding between parents and the newborn. During the inpatient treatment of a preterm infant, particularly in the intensive care unit, mothers may experience conflicting emotional reactions such as grief, sadness, guilt, fear, anger, loss of self-esteem, and a sense of failure. In fact, this situation can be so overwhelming for mothers that they may react by emotionally distancing themselves from their children. This hinders their positive outlook regarding their child's prospects. Specifically, mothers of preterm infants often hold fewer positive thoughts and expectations regarding their children than mothers of term newborns [139, 140].

5. Prevention and Dispensary Observation

5.1. Antenatal prevention of fetal respiratory distress syndrome

• In the event of impending (inevitable) preterm labor and preterm premature rupture of membranes (PPROM) at 24⁰–33⁶ weeks of gestation, antenatal prevention of fetal respiratory distress syndrome (RDS) in singletons (or multiples) is recommended [141, 142], [143].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comment: The maximum effect of glucocorticosteroids (GCS) is observed on days 2–7 after the initiation of prophylaxis; however, if a full course cannot be completed, RDS prophylaxis should still be initiated (the "incomplete dose" effect has been proven) [144]. GCS should not be administered if there are no serious concerns regarding impending preterm labor and reasonable certainty that delivery will not occur within 7 days [1]. Evidence suggests that in the presence of chorioamnionitis, GCS are safe and improve perinatal outcomes [145, 146].

• A single repeat course of antenatal RDS prophylaxis may be recommended at 24⁰–33⁶ weeks of gestation if clinical symptoms of threatened preterm labor persist, provided the previous course was administered more than 14 days earlier, especially at <28 weeks of gestation [147]. A "rescue" (from the English rescue) course may be given as early as 7 days later if clinically indicated[2] [148, 149].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comment: A repeated course of antenatal fetal RDS prophylaxis is not routine, and the decision to use it should be made based on the time elapsed since the last course of prophylaxis, gestational age, and the likelihood of delivery within the next 48 hours. The question of a repeat/rescue course of antenatal fetal RDS prophylaxis in PPROM remains controversial [150].

Comment: Multiple repeated courses are associated with a higher risk of short-term and long-term perinatal complications [151, 152]; 4 or more courses are associated with an increased risk of cerebral palsy [153].

• Antenatal fetal RDS prophylaxis at 22⁰–23⁶ weeks of gestation is not recommended [142].

GCR ALEL 3Grade of Recommendation A (Level of Evidence - 3).

Comment: In certain situations, antenatal fetal RDS prophylaxis at this gestational age may be considered on an individual basis after the obstetrician-gynecologist and neonatologist have informed the patient and her family about the poor prognosis for an extremely preterm newborn delivered at this gestation.

• Fetal RDS prophylaxis at 34⁰–35⁶ weeks of gestation may be recommended if no prior course of antenatal prophylaxis has been administered, as well as in the presence of clinical indications (diabetes mellitus) ^[4] [154].

LeveL of Recommendation AGrade of Evidence 2LeveL of Recommendation A (Grade of Evidence - 2).

• For the prevention of fetal RDS, it is recommended to use #betamethasone** intramuscularly at a dose of 12 mg twice 24 hours apart, or #dexamethasone** intramuscularly at a dose of 6 mg 4 times 12 hours apart, or at a dose of 12 mg twice 24 hours apart [5] [141, 155].

GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).

Comment: Smaller interval dosages than those described above, often referred to as an "accelerated course," even when delivery appears imminent, have not demonstrated potential benefits. #Dexamethasone** and #betamethasone** are off-label drugs in the context of fetal RDS prevention, and written informed consent must be obtained from the patient prior to their use.

• If fetal RDS prophylaxis is administered in the early neonatal period, it is recommended to closely monitor the newborn's blood glucose levels (periodic blood glucose testing) to control and timely detect neonatal hypoglycemia [154].

LeveL of Recommendation AGrade of Evidence 2LeveL of Recommendation A (Grade of Evidence - 2).

Comments: blood glucose testing in a clinical diagnostic laboratory is the standard for detecting neonatal hypoglycemia. According to research, neonatal hypoglycemia is more common when betamethasone** is used for RDS prophylaxis [154].

5.2. Antibiotic prophylaxis

Comment: GBS is a leading cause of neonatal infection. A recent systematic review reported an increased risk of preterm birth in pregnant women with GBS colonization, which was higher in case-control studies compared to cohort or cross-sectional studies [156]. Intrapartum antibiotic prophylaxis should be initiated at the onset of labor or, if not possible, at any time during labor. An effective systemic antibiotic exposure time prior to delivery is considered to be 4 hours; however, microorganism colonization decreases after just 2 hours of antibiotic exposure. If preterm labor is halted and a new threat arises, antibiotic prophylaxis must be repeated. If the GBS culture was negative when sampled no more than 5 weeks prior, antibiotic prophylaxis is not required ⁵³.

Comment: Intrauterine bacterial infection is an important cause of preterm birth (PTB), especially at a gestational age of less than 32 weeks [5, 8, 9, 11, 35]. However, the use of systemic antibacterial drugs does not contribute to prolonging pregnancy or preventing PTB, nor does it reduce the incidence and severity of neonatal respiratory distress syndrome (RDS) and neonatal sepsis. There is evidence of adverse long-term consequences of antibacterial drugs for the child [157].

NB! This recommendation does not apply to patients with preterm prelabor rupture of membranes (PPROM) and Group B Streptococcus (GBS) carriers.

5.3. Prophylaxis with vaginal progesterone**

Comments: Prevention of PTB with vaginal progesterone preparations** in patients with a cervical length of 25 mm or less reduces the risk of PTB, fetal RDS, the birth of infants with a birth weight <1500 g and <2500 g, neonatal morbidity and mortality, and admission to the neonatal intensive care unit. At the same time, it does not increase the risk of maternal adverse events, congenital anomalies, and/or adverse effects on the fetal nervous system development and child health [58].

5.4. Other prophylaxis

Comment: Placement of an obstetric pessary reduces the frequency of tocolytic therapy and cesarean section, does not increase the likelihood of PPROM, and does not worsen perinatal outcomes for the fetus [162]. After 24 weeks of pregnancy, the use of an obstetric pessary is the method of choice. It should be noted that in some protocols of leading obstetric societies, pessaries are not mentioned as a method of PTB prevention. However, clinical experience allows the use of pessaries in a specific clinical niche. It should also be noted that currently there are no studies comparing different types of obstetric pessaries for the purpose of PTB prevention; various types of obstetric pessaries were used in the conducted studies. Therefore, various obstetric pessaries registered in the Russian Federation may be used in accordance with the operating manual of a specific medical device – perforated silicone cervical pessary, uterine pessary, single-use unloading obstetric pessary, cup pessary (perforated), type SSP, obstetric pessary type A (non-perforated), etc. [162, 163].

• In case of asymptomatic cervical shortening, bed rest is not recommended as it does not reduce the risk of PTB [164].

LeR ALoE 1Level of Evidence Recommendation A (Level of Evidence - 1).

• To reduce the risk of PTB at the preconception stage, routine use of multivitamins, ascorbic acid**, and alpha-tocopherol acetate (vitamin E) is not recommended [169].

GPR CLEL 2Grade of Recommendation C (Level of Evidence - 2).

[1] ACOG Committee Opinion No. 677: antenatal corticosteroid therapy for fetal maturation, 2017.

[2] ACOG Committee Opinion No. 677: antenatal corticosteroid therapy for fetal maturation, 2017.

[3] ACOG Committee Opinion No. 677: antenatal corticosteroid therapy for fetal maturation, 2017.

[4] NICE Guidance, Preterm labour and birth, 2016.

[5] ACOG, Practice Bulletin No. 171: Management of Preterm Labor, 2016.

[6] Prevention of Group B Streptococcal Early-Onset Disease in Newborns (Number 797 (Replaces Committee Opinion No. 782), 2020

[7] ACOG, Practice Bulletin No. 171: Management of Preterm Labor, 2016.

[8] NICE Guidance, Preterm labour and birth, 2016.

[9] Preterm Labor and Birth Management: Recommendations from the European Association of Perinatal Medicine, 2017.

[10] ISUOG Practice Guidelines: role of ultrasound in the prediction of spontaneous preterm birth, 2022

[11] ACOG Practice bulletin, № 234, Prediction and Prevention of Spontaneous Preterm Birth, 08.2021 

[12] NICE Guidance, Preterm labour and birth, 2016.

[13] Preterm Labor and Birth Management: Recommendations from the European Association of Perinatal Medicine, 2017.

6. Organization of Medical Care

In PTB, including PPROM, at a gestational age of less than 34⁰ weeks, in the absence of contraindications for transportation, the patient is hospitalized in a Group 3a medical organization.

In PTB, including PPROM, at a gestational age of 34⁰–36⁰ weeks, the patient is hospitalized in a Group 3a obstetric inpatient facility, or, if not feasible, in a Group 2 obstetric inpatient facility (having a neonatal intensive care unit / beds).

7. Additional Information

Not applicable.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

Authors

1. Khodzhayeva Zulfiya Sagdullayevna – MD, Professor, Deputy Director for Scientific Work, Institute of Obstetrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

2. Shmakov Roman Georgiyevich – MD, Professor, Director of the Institute of Obstetrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). Chief freelance specialist in obstetrics of the Russian Ministry of Health. No conflict of interest.

3. Adamyan Leila Vladimirovna – Academician of the Russian Academy of Sciences, MD, Professor, Deputy Director, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of the Russian Ministry of Health, Chief freelance specialist in obstetrics and gynecology of the Russian Ministry of Health (Moscow). No conflict of interest.

4. Natalia V. Artymuk - MD, PhD, Professor, Head of the Department of Obstetrics and Gynecology named after Professor G.A. Ushakova, Kemerovo State Medical University of the Russian Ministry of Health, Chief freelance specialist in obstetrics and gynecology of the Russian Ministry of Health in the Siberian Federal District (Kemerovo). No conflict of interest.

5. Bashmakova Nadezhda Vasilievna – MD, PhD, Professor, Chief Researcher, Ural Research Institute of Maternal and Infant Care of the Russian Ministry of Health, Chief Freelance Specialist of the Russian Ministry of Health in Obstetrics and Gynecology in the Ural Federal District (Yekaterinburg). No conflict of interest.

6. Bezhenar Vitaly Fedorovich - MD, Professor, Head of the Clinic of Obstetrics and Gynecology, Head of the Department of Obstetrics, Gynecology and Neonatology, Head of the Department of Obstetrics, Gynecology and Reproductology, Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health, Chief freelance specialist in obstetrics and gynecology of the Russian Ministry of Health in the Northwestern Federal District (Saint Petersburg). No conflict of interest.

7. Belokrinitskaya Tatyana Yevgenyevna – MD, Professor, Head of the Department of Obstetrics and Gynecology of the Faculty of Advanced Training and Professional Retraining, Chita State Medical Academy of the Russian Ministry of Health, Honored Doctor of the Russian Federation, Chief freelance specialist in obstetrics and gynecology of the Russian Ministry of Health in the Far Eastern Federal District (Chita). No conflict of interest.

8. Gladkova Kristina Aleksandrovna – PhD in Medical Sciences, Head of the 1st Obstetric Department of Pregnancy Pathology, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

9. Gorina Kseniya Alekseyevna – Junior Researcher, 1st Obstetric Department of Pregnancy Pathology, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

10. Dolgushina Natalia Vitalievna – MD, Professor, Deputy Director – Head of the Department for Organization of Scientific Activities, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

11. Kostin Igor Nikolaevich - MD, Prof., Professor of the Department of Obstetrics and Gynecology with a Course in Perinatology, Medical Institute of the Peoples' Friendship University of Russia (Moscow). No conflict of interest.

12. Victoria A. Krutova – D.Sc. (Medicine), Professor, Chief Physician of the Clinic, Vice-Rector for Clinical Work at the Kuban State Medical University of the Russian Ministry of Health, Chief freelance specialist in obstetrics and gynecology of the Russian Ministry of Health in the Southern Federal District (Krasnodar). No conflict of interest.

13. Kulikov Alexander Veniaminovich – MD, Professor, Head of the Department of Anesthesiology, Reanimatology, Toxicology and Transfusiology, Ural State Medical University of the Russian Ministry of Health (Yekaterinburg). No conflict of interest.

14. Malyshkina Anna Ivanovna – MD, Professor, Director of the V.N. Gorodkov Ivanovo Research Institute of Motherhood and Childhood of the Russian Ministry of Health, Chief Non-Resident Specialist of the Russian Ministry of Health in Obstetrics and Gynecology in the Central Federal District (Ivanovo). No conflict of interest.

15. Martirosyan Sergey Valerievich – PhD, Deputy Chief Physician for Obstetric and Gynecological Care, Head of the Perinatal Center of City Clinical Hospital No. 67 named after L.A. Vorokhobov of the Moscow Healthcare Department, Assistant at the Department of Obstetrics and Gynecology, Faculty of Fundamental Medicine, Lomonosov Moscow State University (Moscow). No conflict of interest.

16. Nikolaeva Anastasia Vladimirovna – PhD, Chief Physician, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

17. Perevozkina Olga Vladimirovna - PhD, Head of the Department of Clinical and Expert Work, Perinatal Center of City Clinical Hospital No. 67 named after L.A. Vorokhobov of the Moscow Healthcare Department, Assistant at the Department of Obstetrics and Gynecology, Faculty of Fundamental Medicine, Lomonosov Moscow State University (Moscow). No conflict of interest.

18. Radzinsky Viktor Evseevich - MD, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department of Obstetrics and Gynecology with a Course in Perinatology, Peoples' Friendship University of Russia, Honored Worker of Science of the Russian Federation (Moscow). No conflict of interest.

19. Savelyeva Galina Mikhailovna - Academician of the Russian Academy of Sciences, MD, Professor, Hero of Labour of the Russian Federation, Honored Worker of Science of the Russian Federation, Honorary Professor of the Department of Obstetrics and Gynecology, Pediatric Faculty, Pirogov Russian National Research Medical University (Moscow). No conflict of interest.

20. Serov Vladimir Nikolayevich – Academician of the RAS, D.Sc. (Medicine), Professor, Honored Scientist of the Russian Federation, President of the Russian Society of Obstetricians and Gynecologists, Chief Researcher, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). There is no conflict of interest.

21. Tatiana V. Priputnevich – Corresponding Member of the RAS, MD, PhD, Director of the Institute of Microbiology, Antimicrobial Therapy and Epidemiology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Professor at the Department of Microbiology and Virology, Pediatric Faculty, Pirogov Russian National Research Medical University, Chief freelance specialist in medical microbiology of the Russian Ministry of Health (Moscow). There is no conflict of interest.

22. Tetruashvili Nana Kartlosovna – MD, Head of the 1st Obstetric Department of Pregnancy Pathology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

23. Shabanova Natalya Evgenyevna – Candidate of Medical Sciences, Associate Professor, Head of the Department of Clinical Pharmacology of Antimicrobial and Immunobiological Drugs, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia (Moscow). No conflict of interest.

24. Shalina Raisa Ivanovna - MD, Professor, Honored Doctor of Russia, Professor of the Department of Obstetrics and Gynecology, Pediatric Faculty, Pirogov Russian National Research Medical University (Moscow). No conflict of interest.

25. Ildar F. Fatkullin – D.Sc. (Medicine), Professor, Head of the Prof. V.S. Gruздеv Department of Obstetrics and Gynecology, Kazan State Medical University, Chief freelance specialist of the Russian Ministry of Health in obstetrics and gynecology in the Volga Federal District (Kazan). No conflict of interest.

26. Filippov Oleg Semenovich – MD, Professor, Professor of the Department of Obstetrics and Gynecology, Faculty of Advanced Training for Physicians, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health, Deputy Director of the Department of Medical Care for Children and Obstetrics Services of the Russian Ministry of Health (Moscow). No conflict of interest.

27. Shifman Efim Munevich – MD, Professor of the Department of Anesthesiology and Reanimatology, Faculty of Advanced Training for Physicians, Moscow Regional Research Clinical Institute named after M.F. Vladimirsky, Expert in Anesthesiology and Reanimatology of the Federal Service for Surveillance in Healthcare (Moscow). No conflict of interest.

28. Tskhay Vitaly Borisovich - MD, Professor, Head of the Department of Perinatology, Obstetrics and Gynecology, Krasnoyarsk State Medical University named after Professor V.F. Voino-Yasenetsky (Krasnoyarsk). No conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. obstetrician-gynecologists

2. students; clinical residents, postgraduate students in obstetrics and gynecology

3. educators, researchers

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Appendix A3. Reference Materials

• Federal Law No. 323-FZ "On the Fundamentals of Protecting Citizens' Health in the Russian Federation" dated November 21, 2011.

• Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017 "On Approval of Criteria for Assessing the Quality of Medical Care".

• Order of the Ministry of Health and Social Development No. 1687n dated December 27, 2011 "On Medical Criteria of Birth, Form of the Birth Document and Procedure for its Issuance" (registered with the Ministry of Justice of the Russian Federation on March 15, 2012, No. 23490).

• Preterm birth, WHO, 2018, https://www.who.int/ru/news-room/fact-sheets/detail/preterm-birthObstetrics: National Guidelines / ed. by G.M. Savelyeva, G.T. Sukhikh, V.N. Serov, V.E. Radzinsky. - 2nd ed. - M.: GEOTAR-Media, 2018.

• Order of the Russian Ministry of Health No. 804n dated October 13, 2017 (as amended on April 16, 2019) "On Approval of the Nomenclature of Medical Services"

• Preterm Labor and Birth Management: Recommendations from the European Association of Perinatal Medicine, 2017.Preterm birth, WHO, 2015, https://www.who.int/news-room/fact-sheets/detail/preterm-birth.

• Committee Opinion No 700: Methods for Estimating the Due Date, Committee Opinion No 700: Methods for Estimating the Due Date, 2017.

• NICE Guidance, Preterm labour and birth, 2016 (with updates as of June 10, 2022)

• ACOG Committee Opinion No. 677: antenatal corticosteroid therapy for fetal maturation, 2017.

• Practice Bulletin No. 171: Management of Preterm Labor, ACOG, 2016.

• Obstetric Care Consensus No. 3: Periviable Birth, ACOG, 2015.

• Care of Women Presenting with Suspected Preterm Prelabour Rupture of Membranes from 24+0 Weeks of Gestation: Green-top Guideline No. 73, 2019.

• ACOG Practice Bulletin No.142: Cerclage for the management of cervical insufficiency, 2014.

• ACOG, Practice Bulletin No. 169: Multifetal Gestations: Twin, Triplet, and Higher-Order Multifetal Pregnancies, 2016.

• ACOG, Practice Bulletin No. 171: Management of Preterm Labor, 2016.

• ACOG, Practice Bulletin No. 172: Premature Rupture of Membranes, 2016.

• Management of Breech Presentation (Green-top Guideline No. 20b), 2017.

• Operative Vaginal Delivery (Green-top Guideline No. 26), 2011.

• Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection. Committee Opinion No 455, 2010.

• FIGO good practice recommendations on magnesium sulfate administration for preterm fetal neuroprotection, 2021

• ISUOG Practice Guidelines: role of ultrasound in the prediction of spontaneous preterm birth, 2022

• ACOG Practice bulletin, № 234, Prediction and Prevention of Spontaneous Preterm Birth, 08.2021

• Prevention of Group B Streptococcal Early-Onset Disease in Newborns (Number 797 (Replaces Committee Opinion No. 782), 2020

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

What is preterm birth?

Preterm birth is defined as regular uterine contractions leading to cervical changes that begin before 37 weeks of gestation. Cervical changes include effacement (shortening of the cervix) and dilation (opening of the cervix, which facilitates the entry of the fetus into the birth canal).

Why is preterm birth a concern?

Preterm birth is a major medical and social problem because babies born "too early" are not sufficiently developed for extrauterine life. They may be born with serious health problems. Some health problems, such as cerebral palsy, can last a lifetime. Other problems, such as decreased learning ability, may appear later in childhood or even in adulthood.

Which premature babies are at the highest risk for health problems?

The risk of health problems is highest for infants born before 34 weeks of gestation. However, babies born between 34 and 37 weeks of gestation also face risks.

What are the risk factors for preterm birth?

Factors that increase the risk of preterm birth include: a history of prior preterm birth, shortened cervix, short interpregnancy interval, a history of certain types of uterine or cervical surgery, certain pregnancy complications such as multiple pregnancy and a history of bleeding, lifestyle factors such as low pre-pregnancy body weight, smoking during pregnancy, and substance abuse during pregnancy.

Is there anything that can be done to prevent preterm birth if I am in a high-risk group?

If you have had a preterm birth and are planning another pregnancy, preconception evaluation is recommended. Once you become pregnant, it is essential to be followed by an obstetrician-gynecologist from the earliest stages. You may be referred to a healthcare specialist experienced in managing high-risk pregnancies. Additionally, you may be given specific medications or other treatments to help prevent preterm birth if you have risk factors.

What are the signs and symptoms of preterm birth and what should I do if I have any of them?

Call your obstetrician or other healthcare provider immediately if you notice any of these signs or symptoms: changes in the nature of vaginal discharge (watery, mucous, or bloody), periodic or cramp-like uterine pain, lower abdominal and lower back pain, mild abdominal cramps, with or without diarrhea.

How is preterm birth diagnosed?

Preterm birth can only be diagnosed upon detecting cervical changes. Your obstetrician must perform a physical examination to determine whether cervical changes are present. You may need to be examined several times over the course of a few hours to assess dynamic changes. Transvaginal ultrasound may be performed to measure cervical length.

If I have symptoms of preterm labor, does it mean delivery will definitely happen?

It is difficult for healthcare specialists to predict which women with symptoms of preterm labor will definitively experience preterm birth. Only approximately 1 in 10 women with symptoms of preterm labor will deliver within the next 7 days. About 3 in 10 women experience cessation of preterm labor spontaneously.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.