List of Abbreviations
APS – antiphospholipid syndrome
CI – cervical insufficiency
STI – sexually transmitted infections
NIPT – non-invasive prenatal testing
LPD – luteal phase defect
LMWH – low molecular weight heparin
RPL – recurrent pregnancy loss
PT – preterm labor
TEC – thromboembolic complications
TM – threatened miscarriage
US – ultrasound examination
CA – chromosomal aneuploidy
Terms and Definitions
Miscarriage (spontaneous abortion) is the spontaneous termination of pregnancy (expulsion or extraction of the embryo/fetus) prior to 22 weeks of gestation.
Recurrent pregnancy loss (RPL) — the presence in a woman of 2 or more clinical pregnancy losses at gestational ages up to 22 weeks.
Threatened miscarriage (TM) — a state of ongoing pregnancy up to 22 weeks characterized by vaginal bleeding or signs of chorionic/placental detachment according to ultrasound examination (US).
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Recurrent pregnancy loss (RPL) — the presence in a woman of two or more clinical pregnancy losses at gestational ages up to 22 weeks [1], [2], [3], [4], [5], [6]
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
Among the causes of RPL are: genetic (3-6%), anatomical (10-16%), infectious-inflammatory (10-15%), endocrine (12-15%), autoimmune (up to 15%), and thrombophilic (10%). In the absence of identified factors, idiopathic RPL is distinguished (15-50%), which also includes alloimmune RPL (5-10%) [7], [8]. RPL is polyetiological, and a single couple may have multiple causes, therefore identifying one of them should not be grounds for refusing a full evaluation.
Chromosomal aneuploidy (CA) in the embryo/fetus is the most common cause of miscarriage in the 1st trimester of pregnancy [9], [10]. The earlier in pregnancy a miscarriage occurs, the higher the probability that the embryo/fetus had CA [11]. The risk of embryonic/fetal trisomy resulting from CA increases with maternal age. The most common cause of miscarriage is trisomy 16, followed by trisomy 22. Triploidy is found in approximately 15% of fetuses with anomalies according to cytogenetic studies. Monosomy X accounts for approximately 20% of miscarriages occurring in the 1st trimester of pregnancy. No correlation between maternal age and monosomy X, polyploidy, or structural chromosomal abnormalities has been established [11].
Causes and risk factors for recurrent pregnancy loss (RPL) include [3], [7], [12], [13], [14], [15], [15] [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29]:
maternal age >35 years, paternal age >40 years;
obesity or underweight (>30 kg/m2 or <18.5 kg/m2);
excessive caffeine intake (>5 cups of coffee per day or >100 g of caffeine/day);
alcohol and substance use;
smoking (>10 cigarettes per day);
adverse occupational conditions (exposure to mercury, lead, benzene vapor, cyclohexane, nitro paint, resin, dust, pesticides, noise, vibration), as well as prolonged exposure to chemical and/or physical factors unrelated to occupation;
chronic diseases: antiphospholipid syndrome (APS), thrombophilia with a high risk of thromboembolic events, polycystic ovary syndrome, thyroid diseases, decompensated diabetes mellitus, celiac disease, rheumatic diseases, undifferentiated connective tissue dysplasia, iron deficiency anemia;
acute and chronic infectious diseases: listeriosis, syphilis, chlamydia, toxoplasmosis, acute respiratory viral infections, human immunodeficiency virus infection, tuberculosis;
uterine disorders: uterine developmental anomalies, uterine fibroids, cervical surgery, intrauterine synechiae;
history of artificial abortions and miscarriages;
tubal factor infertility;
pregnancy resulting from assisted reproductive technologies;
family history of stillbirth, perinatal deaths of unclear origin, RPL, preterm birth (PTB);
bacterial vaginosis and sexually transmitted infections (STIs);
urinary tract inflammatory diseases;
chronic endometritis;
menstrual cycle disorders caused by hyperprolactinemia, hypothyroidism, luteal phase defect (LPD), hyperandrogenism
1.3 Epidemiology of the Disease or Condition
The prevalence of RPL in the population is 1–5%. About 80% of RPL miscarriages occur before 12 weeks of gestation [30].
The risk of recurrent miscarriage after the 1st miscarriage is 13–17%, which corresponds to the population miscarriage rate, whereas after 2 previous miscarriages, the risk of miscarriage increases more than 2-fold to 36–38% [7]. The prognosis for carrying a pregnancy depends on the woman's age and history of childbirth: parous women have a lower risk of miscarriage (Tables 1 and 2).
Table 1
Risk of miscarriage, maternal age, and history of miscarriages [22]
Table 2
Risk of pregnancy loss depending on the history of childbirth [22]
1.4 Features of Coding the Disease or Condition
O26.2 - Medical care for woman with habitual miscarriage
N96 - Recurrent pregnancy loss
1.5 Classification of the disease or condition
Primary RPL – Miscarriages occur starting from the 1st pregnancy; no history of childbirth.
Secondary RPL – Miscarriages occur after at least one delivery.
Tertiary RPL – Miscarriages precede a full-term pregnancy and then recur after delivery.
1.6 Clinical presentation of the disease or condition
The main complaint of partners with RPL is the inability to conceive/bear children.
Outside of pregnancy, patients with RPL may be asymptomatic. Complaints may be present that are characteristic of the pathology leading to RPL: menstrual cycle disorders – scanty menses, irregular menstrual pattern (in hormonal disorders, anatomical causes of RPL), lower abdominal pain, dysuria, dyspareunia, changes in vaginal discharge, vulvar pruritus (complaints typical of STIs and pelvic inflammatory diseases), impaired function of adjacent organs (with large uterine fibroids), etc. There may be complaints of failure to conceive after RPL as a manifestation of secondary infertility. Patients with RPL are at risk for secondary infertility after the 3rd pregnancy loss.
The most common clinical manifestations of miscarriage are lower abdominal or lower back pain of a spastic nature and vaginal bleeding against the background of delayed menstruation. The patient may also experience a sensation of pelvic pressure and vaginal discharge, which may be clear with pink or bloody streaks (typically after 12 weeks of gestation).
2. Diagnostics, medical indications and contraindications for diagnostic methods
Applies to all patients with RPL unless otherwise specified.
Management of patients during pregnancy is carried out in accordance with the clinical guidelines "Normal Pregnancy" [32].
Upon the development of clinical symptoms of miscarriage, patient management is carried out in accordance with the clinical guidelines "Miscarriage (Spontaneous Abortion)" [33].
Diagnostic criteria
The diagnosis is based on anamnestic data on the loss of 2 or more clinically diagnosed pregnancies
2.1 Complaints and Anamnesis
It is recommended to assess RPL risk factors for their potential elimination [24], [34], [35], [36].
GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).
2.2 Physical Examination
Preconception screening and examination during pregnancy are carried out in accordance with the clinical guidelines "Normal Pregnancy" [32].
2.3 Laboratory Diagnostics
At the preconception stage, it is recommended to refer a patient with RPL and her partner for cytogenetic testing (karyotyping) to rule out balanced chromosomal rearrangements [37], [38].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comment: Cytogenetic testing (karyotyping) is prescribed after risk factor assessment. The frequency of balanced chromosomal rearrangements (translocations, inversions) in the population is 0.3–0.6%, reaching 6–7% in couples with RPL. If one or both partners have balanced chromosomal rearrangements, the prognosis for offspring will depend on the type of chromosomal rearrangement and the carrier's sex. The risk of fetal chromosomal pathology can range from 1 to 100% [39], [40], [41].
In case of pregnancy loss, if tissue collection is possible, it is recommended to perform karyotyping of the abortive material (cytogenetic or molecular karyotyping) to detect chromosomal abnormalities in the embryo/fetus [42].
LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).
Comment: The study is recommended to be performed using molecular karyotyping. This improves the success rate of karyotyping results when the quality of the abortive material is unsatisfactory and allows storage of the biomaterial in a frozen state for delayed genetic studies [42].
At the preconception stage or during the 1st visit in pregnancy, it is recommended to refer a patient with RPL for the determination of blood anticardiolipin antibodies, blood anti-beta-2-glycoprotein I antibodies, and lupus anticoagulant in the blood (Russell's viper venom or taipan time test) for the diagnosis of APS [43], [44].
GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).
Comment: The test must be performed twice with an interval of 12 weeks. The laboratory criterion for diagnosing APS is a repeatedly positive value for one of the APS markers.
At the preconception stage, it is recommended to refer a patient with RPL for thyroid-stimulating hormone (TSH) testing and blood anti-thyroperoxidase (anti-TPO) antibodies to rule out or detect and treat thyroid diseases as a potential cause of RPL [45], [46], [47], [48].
LeveL of Recommendation BGrade of Evidence 2LeveL of Recommendation B (Grade of Evidence - 2).
Comment: Manifest hyperthyroidism [48] and hypothyroidism [45], [47], [49] are associated with an increased incidence of RPL. If thyroid dysfunction is detected, it is recommended to refer the patient for a consultation with an endocrinologist. For the algorithm of examination and treatment of patients with hypothyroidism, see the clinical guidelines "Hypothyroidism" [50].
At the preconception stage, it is recommended to refer a patient with RPL and signs of hyperprolactinemia (oligo/amenorrhea, galactorrhea) for blood prolactin testing on days 2–5 of the menstrual cycle (if menstruating, or regardless of cycle day in case of amenorrhea) to rule out or detect and treat hyperprolactinemia [51].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: Routine blood prolactin testing is not indicated for patients with RPL.
At the preconception stage, it is recommended to refer a patient with RPL for blood glucose testing to diagnose diabetes mellitus as a potential cause of RPL [52], [53], [54].
GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).
Comment: Decompensated diabetes mellitus is one of the causes of RPL.
It is not recommended to routinely refer a patient with RPL for blood androgen testing to clarify the cause of RPL [55], [56].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comment: Screening for androgens (testing total testosterone, sex hormone-binding globulin, free androgen index, and 17-hydroxyprogesterone in the blood) is performed in the presence of signs of hyperandrogenism. Hyperandrogenism is a condition associated with excessive androgen secretion and/or their enhanced effect on the body, which in women most commonly manifests as virilization (appearance of male traits) and androgen-dependent dermopathy (acne, hirsutism, alopecia) [57]. The most frequent cause of hyperandrogenemia is polycystic ovary syndrome (PCOS). For the algorithm of examination and treatment of patients with PCOS, see the clinical guidelines "Polycystic Ovary Syndrome" [57].
It is not recommended to routinely refer a patient with RPL for blood progesterone testing in the 2nd phase of the menstrual cycle to clarify the cause of RPL [58], [59].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: Progesterone levels in the 2nd phase of the menstrual cycle are variable, as the secretion of this hormone is cyclical and can change up to 7-fold with a 7-hour interval [60]. For the progesterone level that can confirm ovulation, see the clinical guidelines "Polycystic Ovary Syndrome" [57]. Due to the recommended prescription of progestogens to patients with RPL, there is no need to determine progesterone outside of pregnancy to detect LPD.
At the preconception stage, it is recommended to refer a patient with RPL for a complete blood count (CBC) and blood ferritin testing to diagnose anemia and iron deficiency [61, 62], [63, 64], [65].
LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).
Comments: Early screening and detection of anemia contribute to timely treatment and a reduction in the risk of early pregnancy loss and adverse perinatal outcomes. An inverse correlation has been shown between serum ferritin levels in women and the number of early pregnancy losses [66]. If abnormalities are detected in the complete blood count, it is recommended to refer the patient for a consultation with a general practitioner (internist).
At the pregravid stage, it is recommended to refer a patient with pregnancy loss to a microscopic examination of vaginal smears and determination of the hydrogen ion concentration (pH) of the vaginal mucosa discharge in order to exclude or detect and treat infectious and inflammatory diseases of the genital tract and bacterial vaginosis as a potential cause of pregnancy loss [67], [68], [69].
LeveL of Recommendation BGrade of Evidence 2LeveL of Recommendation B (Grade of Evidence - 2).
Comment: For the algorithm of examination and treatment of patients with bacterial vaginosis, see the clinical guidelines «Bacterial Vaginosis» [68]. For the algorithm of examination and treatment of patients with vulvovaginitis, see the clinical guidelines «Inflammatory Diseases of the Cervix, Vagina and Vulva» (draft) [70].
At the pregravid stage or at the 1st visit during pregnancy, it is recommended to refer the patient for a molecular biological test of the discharge from the mucous membranes of the female genital organs for STI pathogens (Neisseria gonorrhoeae, Trichomonas vaginalis, Chlamydia trachomatis, Mycoplasma genitalium) to clarify the cause of pregnancy loss [71].
GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).
Comment: The presence of STI pathogens increases the risk of miscarriage if pregnancy occurs. For the algorithm of examination and treatment of patients with STIs, see the clinical guidelines «Gonococcal Infection» [72], «Urogenital Trichomoniasis» [73], «Chlamydial Infection» [74], «Urogenital Diseases Caused by Mycoplasma genitalium» [75].
It is not recommended to refer a patient with pregnancy loss for routine immunological and immunogenetic testing to clarify the cause of pregnancy loss [76], [77].
GCR BLOE 2Grade of Recommendations B (Level of Evidence – 2).
Comment: Testing for alloimmune factors, such as lymphocyte subset analysis (Th1/Th2 or T4/T8 cell ratios, assessment of NK cell count in peripheral blood and decidual tissue, NK cell cytotoxicity assay), evaluation of lymphocyte proliferative activity, molecular genetic testing for non-classical HLA clusters or KIR family receptors, as well as determination of HLA antigens, anti-sperm antibodies, native DNA antibodies, anti-Sm nuclear antibodies, antileukocyte antibodies, cytokine levels and their polymorphisms (serum interleukin-8, serum interleukin-10, molecular genetic testing of genetic polymorphisms associated with interleukin-28B functions in blood, interleukin-B28 gene polymorphism) in women with pregnancy loss without signs of autoimmune disease currently lacks an evidence base. Screening for alloimmune and rare autoimmune causes of pregnancy loss may be performed in specialized centers experienced in working with couples suffering from idiopathic pregnancy loss.
It is not recommended to routinely refer a patient for a uterine (endometrial) tissue biopsy to clarify the cause of pregnancy loss [78].
GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).
Comment: This test has not shown efficacy for the routine assessment of ovulation and endometrial secretory transformation.
At the pregravid stage, it is recommended to refer the patient's partner for a spermogram to clarify the cause of pregnancy loss [79], [80], [81].
GPP BLE 2Grade of Recommendations B (Level of Evidence 2).
Comments:The couple's workup for pregnancy loss should be initiated for both men and women simultaneously. Examination of male patients is carried out by a urologist, guided by clinical guidelines developed by the Russian Society of Urology [82]., [83], [84], [85].
At the pregravid stage or during the 1st visit in pregnancy, it is recommended to refer a patient with pregnancy loss for molecular genetic testing for the G1691A mutation in the coagulation factor V gene (Factor V Leiden mutation), determination of the G20210A prothrombin polymorphism in the coagulation factor II gene, blood protein C level assay, and blood protein S activity assay for the diagnosis of hereditary thrombophilia [43], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96].
LeR ALoE 1Level of Evidence Recommendation A (Level of Evidence - 1).
At the pregravid stage, it is recommended to refer a patient with idiopathic pregnancy loss, recurrent implantation failure after embryo transfer in assisted reproductive technology programs, and/or ultrasound signs of chronic endometritis for a pathomorphological examination of uterine (endometrial) biopsy (surgical) material using immunohistochemical methods to determine the expression of the plasma cell surface antigen CD138 in an endometrial biopsy to clarify the cause of pregnancy loss [97].
GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).
2.4 Instrumental Diagnostics
At the pregravid stage, it is recommended to refer a patient with pregnancy loss for a comprehensive pelvic ultrasound (transvaginal and transabdominal) in the early follicular phase of the cycle and in the secretory phase of the cycle (if a menstrual cycle is present, or regardless of the day of the menstrual cycle in case of amenorrhea) to detect pathology of the internal genital organs and determine endometrial thickness [24].
GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).
Comment: The preferred diagnostic method for assessing the condition of the uterus is 3D ultrasound when available; hysteroscopy may be prescribed according to indications [98], [99].
At the pregravid stage, it is recommended to refer a patient with unexplained pregnancy loss for hysterosalpingography (HSG) or contrast hysterosalpingo-contrast sonography to rule out or detect uterine and fallopian tube pathology as a potential cause of pregnancy loss [59], [24].
GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).
Comments: HSG and contrast hysterosalpingo-contrast sonography have equivalent accuracy in assessing the condition of the fallopian tubes [100]. However, the diagnosis of genital tuberculosis is only possible with HSG [101]. If genital tuberculosis is suspected based on HSG findings, the patient must be referred for a consultation with a phthisiatrician. Pelvic magnetic resonance imaging is used according to indications for diagnosing congenital malformations of the internal genital organs, neoplasms, advanced forms of endometriosis, and assessing uterine scar competence.
During pregnancy, it is recommended to refer a patient with pregnancy loss for cervical ultrasound (transvaginal cervicometry) from 15–16 to 24 weeks of pregnancy at a frequency of once every 1–2 weeks for the timely diagnosis of cervical insufficiency [102, 103].
LeR ALoE 1Level of Evidence Recommendation A (Level of Evidence - 1).
Comment: A cervical length ≤25 mm before 34 weeks of gestation is a prognostic factor for preterm birth. At 20 weeks of gestation, a cervical length ≤25 mm is associated with a 6-fold increase in the risk of preterm birth. Before 34 weeks in singleton pregnancies, a cervical length threshold of ≤25 mm has a sensitivity of 76%, specificity of 68%, PPV of 20%, and NPV of 96% for the diagnosis of preterm birth [104], [105].
2.5 Other Procedures
At the pregravid stage in the presence of karyotype abnormalities, it is recommended to refer the patient and her partner for a consultation with a geneticist to determine further management tactics [24].
GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).
During pregnancy with a high risk of chromosomal abnormalities according to screening results, it is recommended to refer the patient for a consultation with a geneticist to determine indications for invasive prenatal diagnosis with analysis of the obtained material using cytogenetic or molecular karyotyping methods [106], [107], [108].
LeR ALoE 1Level of Evidence Recommendation A (Level of Evidence - 1).
Comment: In case of biochemical marker abnormalities with normal fetal ultrasound findings in patients with pregnancy loss, the possibility of non-invasive prenatal testing (NIPT) (cell-free fetal DNA analysis from maternal blood) after 10 weeks of gestation should be considered [109]. Deviations of biochemical markers from normative values during 1st-trimester screening in pregnant women with pregnancy loss may be due to the peculiarities of placentation under conditions of prior miscarriage and medication use. Performing NIPT in patients with pregnancy loss allows for optimizing pregnancy management tactics, avoiding unjustified invasive procedures in the context of prior miscarriage, and conversely, performing timely invasive intervention in case of positive NIPT results.
At the pregravid stage in the presence of endocrine disorders, it is recommended to refer the patient for a consultation with an endocrinologist to correct the identified abnormalities [59].
GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).
At the pregravid stage, it is recommended to refer the patient's partner for a consultation with a urologist to establish the cause of pregnancy loss [85].
GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).
At the pregravid stage and during pregnancy in the presence of signs of reactive depression, it is recommended to refer the patient for a consultation with a psychotherapist to determine the need for therapy [97].
ACLE 5Level of evidence C (level of data certainty - 5).
Comment: Primary prevention methods include: family planning under the age of 35, prevention of artificial abortions, instrumental removal of products of conception, treatment of STIs, endometritis, and other pelvic inflammatory diseases. Secondary prevention of pregnancy loss involves timely examination of patients with pregnancy loss, identification and elimination of causes leading to recurrent gestational losses to prevent future reproductive disorders.
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
Applies to all patients with RPL unless otherwise specified.
Upon establishing the cause of pregnancy loss, treatment is carried out in accordance with the clinical guidelines for the respective diseases and conditions.
Management of patients during pregnancy is carried out in accordance with the clinical guidelines "Normal Pregnancy" [32].
Upon the development of clinical symptoms of miscarriage, patient management is carried out in accordance with the clinical guidelines "Miscarriage (Spontaneous Abortion)" [33].
When the clinical picture of cervical incompetence develops, management of patients is carried out in accordance with the clinical guidelines «Cervical Incompetence» [110].
3.1. Non-pharmacological treatments
Not applicable.
3.2. Pharmacotherapy
It is recommended to prescribe dydrogesterone** or progesterone preparations** up to 20 weeks of gestation [59], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129].
GOM BLOE 1Grade of Recommendation B (Level of Evidence - 1).
Comment: According to randomized clinical trials, progestogens significantly increase the live birth rate in pregnancy loss [112], [115], [116], [117], [119], [120], [121], [122], [123], [124], [129]. Studies on both progestogens are ongoing, which in the future will allow personalization of pregnancy loss therapy; however, currently it is necessary to follow the above recommendation for their use [97], [112], [126], [127], [128], [130]. The safety profile of dydrogesterone** and progesterone** at recommended doses in early pregnancy is well studied and favorable (there is no evidence of an increased incidence of adverse events in the pregnant woman and fetus compared with no therapy/placebo, or in direct comparison of these drugs) [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [128], [131], [132], [133], [134], [135]. These drugs are usually prescribed from the 2nd phase of the expected fertile cycle or at the 1st visit during pregnancy.
In confirmed antiphospholipid syndrome, it is recommended to prescribe heparin group drugs (ATX: heparins) at a prophylactic dose, starting from the establishment of intrauterine pregnancy until its completion and for 6 weeks of the postpartum period [136].
GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).
In antiphospholipid syndrome, it is recommended to prescribe oral #acetylsalicylic acid** from 12 to 36 weeks of gestation at 100 mg/day [137], [138].
LeR ALoE 1Level of Evidence Recommendation A (Level of Evidence - 1).
It is not recommended to routinely prescribe heparin group drugs (ATX: heparins) for the purpose of miscarriage prevention in a patient with pregnancy loss of unclear origin without risk factors for thromboembolic events [139].
LeR ALoE 1Level of Evidence Recommendation A (Level of Evidence - 1).
In latent iron deficiency, it is recommended to prescribe oral iron preparations [66], [140].
GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).
Comment: The administration of iron preparations helps reduce the risk of a number of pregnancy complications (early preterm birth (before 34 weeks), anemia, postpartum infections, low birth weight) and is not associated with significant risks of side effects [140].
At the pregravid stage, a patient with chronic endometritis confirmed by histological examination is recommended complex antibacterial therapy [97], [141].
Level of Evidence CGrade of Evidence 5Level of Clinical Effectiveness C (level of evidence reliability - 5).
Comment: Antibacterial therapy includes the prescription of doxycycline**, and in case of persistent endometritis (persistence of plasma cells on histological examination) - the prescription of ciprofloxacin** with / without metronidazole** [142].
3.3 Surgical Treatment Methods
At the pregravid stage, it is recommended to refer a patient with suspected intrauterine pathology according to ultrasound data for hysteroscopy in order to exclude or detect and surgically treat intrauterine pathology as a potential cause of pregnancy loss [143], [144] .
LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).
Comment: Hysteroscopy is the leading treatment method in the presence of such intrauterine pathology as endometrial polyp, intrauterine synechiae, endometrial hyperplasia, uterine malformations (uterine septum), submucous uterine myoma. In a number of cases, a combination of hysteroscopy and laparoscopy is necessary to treat intrauterine pathology. In the presence of gynecological diseases, examination and treatment at the pregravid stage must comply with the clinical guidelines for these diseases.
At the pregravid stage, it is recommended to refer a patient with gynecological diseases requiring surgical treatment for diagnostic laparoscopy in order to exclude or detect and surgically treat these diseases as a potential cause of pregnancy loss [145], [146], [147], [148], [149].
LeveL of Recommendation AGrade of Evidence 2LeveL of Recommendation A (Grade of Evidence - 2).
Comment: In the presence of gynecological diseases, examination and treatment at the pregravid stage must comply with the clinical guidelines for these diseases
At the preconception stage, it is recommended to refer patients with preterm birth and cervical insufficiency caused by cervical tissue deficiency (conization, trachelectomy), when cervical suture (cerclage) cannot be placed during pregnancy, for abdominal cervical cerclage (preferably via a laparoscopic approach) [150].
GPP BLE 2Grade of Recommendations B (Level of Evidence 2).
Comment: Abdominal cerclage may also be considered as an alternative treatment method for cervical insufficiency in patients with failed vaginal cerclage in a previous pregnancy.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
Not applicable.
5. Prevention and Dispensary Observation
Management of patients during pregnancy is carried out in accordance with the clinical guidelines "Normal Pregnancy" [32].
At the preconception stage and during pregnancy, a patient who is overweight, obese, or underweight is recommended to receive counseling on weight normalization to prevent preterm birth and other pregnancy complications [151], [152].
GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).
Comments: The optimal BMI for a woman is 19–25 kg/m2. Both excess and insufficient body weight are associated with a reduced clinical pregnancy rate, an increased risk of miscarriage and preterm birth, as well as obstetric and perinatal complications. In case of obesity, the patient should be referred for a consultation with an endocrinologist. For the examination and treatment algorithm for obese patients, see the clinical guidelines on «Obesity» [153].
At the preconception stage and during pregnancy, the patient should be recommended to quit smoking in order to prevent preterm birth and other pregnancy complications [154, 155], [156].
LeveL of Recommendation BGrade of Evidence 2LeveL of Recommendation B (Grade of Evidence - 2).
Comments: Smoking is associated with various obstetric and perinatal complications: stillbirth, placenta previa, preterm birth, low birth weight, and congenital malformations of the fetus [154, 155], [156], [157].
At the preconception stage and during pregnancy, the patient should be recommended to abstain from alcohol in order to prevent preterm birth and other pregnancy complications [158], [159].
GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).
Comment: A large body of observational data has accumulated regarding the negative impact of alcohol on the course of pregnancy regardless of the dose consumed [158], [160–162], for example, fetal alcohol syndrome and psychomotor development delay [159].
At the preconception stage and during pregnancy, the patient is recommended proper nutrition: avoiding strict vegetarianism, refined foods, fast food, and foods high in easily digestible carbohydrates, as well as reducing caffeine intake to prevent preterm birth and other pregnancy complications [163–166].
GPP ALE 2Grade of Recommendations A (Level of Evidence 2).
Comments: Vegetarianism during pregnancy increases the risk of fetal growth restriction [167]. High caffeine intake (more than 300 mg/day) increases the risk of miscarriage and low birth weight infants [163–166]. Healthy eating during pregnancy is characterized by adequate caloric intake, protein, vitamins, and minerals obtained from a variety of foods, including green and orange vegetables, meat, fish, legumes, nuts, fruits, and whole-grain products [168].
During pregnancy, the patient is recommended to avoid working night shifts to prevent preterm birth [169], [170], [171].
GPP ALE 2Grade of Recommendations A (Level of Evidence 2).
Comments: Night shift work is associated with an increased risk of miscarriage (1.5 times higher according to meta-analysis data).
6. Organization of Medical Care
Indications for inpatient hospitalization in pregnant women with preterm birth include the following complications:
Threatened miscarriage.
Need for surgical correction of cervical incompetence.
Threatened preterm birth.
Premature rupture of membranes.
Indications for discharging a patient with preterm birth from the hospital include: relief of symptoms of threatened abortion, threatened premature birth, and cervical insufficiency with pregnancy progression.
7. Additional Information
Not applicable.
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria for diagnosis and treatment of preterm birth | Yes/No |
|---|---|---|
1. | A referral for a cytogenetic study (karyotyping) was issued (at the preconception stage). | Yes/No |
2. | A referral for blood anticardiolipin antibody testing was issued (at the preconception stage or at the first prenatal visit). | Yes/No |
3. | A referral for blood anti-beta-2-glycoprotein antibody testing was issued (at the preconception stage or at the first prenatal visit). | Yes/No |
4. | A referral for a Russell's viper venom or taipan venom test was issued (determination of lupus anticoagulant in the blood) (at the preconception stage or at the first visit during pregnancy). | Yes/No |
5. | A referral for blood thyroid-stimulating hormone (TSH) testing was issued (at the preconception stage). | Yes/No |
6. | A referral for blood anti-thyroperoxidase antibody testing was issued (at the preconception stage). | |
7. | A referral for blood glucose testing was issued (at the preconception stage). | Yes/No |
8. | A referral for a complete blood count was issued (at the preconception stage). | Yes/No |
9. | A referral for blood ferritin testing was issued (at the preconception stage). | Yes/No |
10. | A referral for molecular biological testing of female genital mucosal discharge for sexually transmitted infection pathogens (Neisseria gonorrhoeae, Trichomonas vaginalis, Chlamydia trachomatis, Mycoplasma genitalium) was issued (at the preconception stage or at the first visit during pregnancy). | Yes/No |
11. | A referral for transabdominal or transvaginal ultrasound of the uterus and appendages was issued (at the preconception stage). | Yes/No |
12. | A referral for cervical ultrasound (cervicometry) was issued (from 15-16 to 24 weeks of gestation, every 1-2 weeks). | Yes/No |
13. | Didrogesterone** or progesterone** was prescribed (up to 20 weeks of gestation, in the absence of medical contraindications). | Yes/No |
14. | Heparin group drugs were prescribed from the establishment of intrauterine pregnancy throughout the entire pregnancy and for 6 weeks of the postpartum period (in case of antiphospholipid syndrome, in the absence of medical contraindications). | Yes/No |
References
Show references
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Appendix A1. Working Group Composition
Tetruashvili Nana Kartlosovna – MD, PhD, Head of the 2nd Department of Obstetric Pathology of Pregnancy, Deputy Director of the Institute of Obstetrics (Fetal Medicine Department), 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.
Dolgushina Nataliia Vitalievna – MD, PhD, Professor, Deputy Director for Research, 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 women's reproductive health of the Russian Ministry of Health (Moscow). There is no conflict of interest.
Baranov Igor Ivanovich – MD, PhD, Professor, Head of the Department of Scientific and Educational Programs, Department of Scientific Activity Organization, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health. There is no conflict of interest.
Khodzhaeva Zulfia Sagdullaevna – MD, PhD, Professor, Chief Researcher, Deputy 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). There is no conflict of interest.
Shmakov Roman Georgievich – MD, PhD, Professor, Professor of the RAS, Director of the Moscow Regional Research Institute of Obstetrics and Gynecology named after Academician V.I. Krasnopolsky (Moscow). There is no conflict of interest.
Adamyan Leila Vladimirovna – Academician of the RAS, MD, PhD, Professor, Deputy Director for Research, 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 gynecology of the Russian Ministry of Health (Moscow). There is no conflict of interest.
Artymuk Natalia Vladimirovna – 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, gynecology, and women's reproductive health in the Siberian Federal District (Kemerovo). There is no conflict of interest.
Bashmakova Nadezhda Vasilievna – MD, PhD, Professor, Chief Researcher, Ural Research Institute of Maternal and Infant Welfare of the Russian Ministry of Health, Chief freelance specialist in obstetrics, gynecology, and women's reproductive health in the Ural Federal District. There is no conflict of interest.
Bezhenar Vitaly Fedorovich – MD, PhD, Professor, 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 in the Northwestern Federal District (Saint Petersburg). There is no conflict of interest.
Belokrinitskaya Tatiana Evgenievna – MD, PhD, Professor, Head of the Department of Obstetrics and Gynecology of the Faculty of Additional Professional Education, Chita State Medical Academy of the Russian Ministry of Health, Honored Doctor of the Russian Federation, Chief freelance specialist in obstetrics, gynecology, and women's reproductive health in the Far Eastern Federal District (Chita). There is no conflict of interest.
Kalugina Alla Stanislavovna – MD, PhD, Professor, Professor of the Department of Obstetrics, Gynecology and Neonatology, Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health (Saint Petersburg), Chief freelance specialist in women's reproductive health in the Northwestern Federal District. There is no conflict of interest.
Malyshkina Anna Ivanovna – MD, PhD, Professor, Director of the Ivanovo Research Institute of Motherhood and Childhood named after V.N. Gorodkov of the Russian Ministry of Health, Head of the Department of Obstetrics and Gynecology, Medical Genetics of the Faculty of Medicine, Ivanovo State Medical Academy of the Russian Ministry of Health, Chief freelance specialist in obstetrics, gynecology, and women's reproductive health in the Central Federal District (Ivanovo). There is no conflict of interest.
Mikhailov Anton Valerievich – MD, DSc, Professor, Chief Physician of Maternity Hospital No. 17 (St. Petersburg), Professor at the Department of Obstetrics and Gynecology, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, and the Department of Obstetrics, Gynecology, and Perinatology, First Pavlov State Medical University of St. Petersburg of the Russian Ministry of Health, Chief freelance specialist in obstetrics and gynecology of the Russian Ministry of Health in the North-Western Federal District (St. Petersburg). No conflict of interest.
Moiseeva Irina Valerievna – MD, DSc, Head of the Department of Assisted Reproductive Technologies, Samara Regional Medical Center "Dynasty", Chief freelance specialist in reproductive health of the Ministry of Health of the Samara Region, Chief freelance specialist in women's reproductive health in the Volga Federal District (Samara). No conflict of interest.
Neredko Sergey Alexandrovich – MD, DSc, Head of the Department of Assisted Reproductive Technologies, Stavropol Regional Clinical Perinatal Center, Chief freelance specialist in reproductive health of the Ministry of Health of the Stavropol Krai, Chief freelance specialist in women's reproductive health in the North Caucasian Federal District (St. Petersburg / Stavropol). No conflict of interest.
Olenev Anton Sergeevich – MD, DSc, Associate Professor, Deputy Chief Physician for Obstetric and Gynecological Care, City Clinical Hospital No. 31 named after Academician G.M. Savelyeva of the Moscow Healthcare Department, Chief freelance specialist in obstetrics of the Moscow Healthcare Department (Moscow). No conflict of interest.
Popandopulo Victoria Alexandrovna – MD, DSc, Professor, Head of the Department of Obstetrics and Gynecology, Maykop State Technological University, Professor at the Department of Obstetrics and Gynecology, Faculty of General Medicine, Astrakhan State Medical University of the Russian Ministry of Health, Chief Physician of Kuban Medical Center LLC, Chief freelance specialist of the Russian Ministry of Health in obstetrics, gynecology, and women's reproductive health in the Southern Federal District (Krasnodar). No conflict of interest.
Radzinsky Viktor Evseevich – Corresponding Member of the Russian Academy of Sciences, MD, DSc, Professor, Head of the Department of Obstetrics and Gynecology with a Course in Perinatology, Peoples' Friendship University of Russia (Moscow). No conflict of interest.
Savelyeva Galina Mikhailovna – Academician of the Russian Academy of Sciences, MD, DSc, Professor, Honored Scientist of the Russian Federation, Hero of Labor of the Russian Federation (Moscow). No conflict of interest.
Serov Vladimir Nikolaevich – Academician of the Russian Academy of Sciences, MD, DSc, Professor, Chief Researcher, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, President of the Russian Society of Obstetricians and Gynecologists (ROAG) (Moscow). No conflict of interest.
Fatkullin Ildar Faridovich – MD, DSc, Professor, Head of the Department of Obstetrics and Gynecology named after Prof. V.S. Gruzdev, Kazan State Medical University of the Russian Ministry of Health, Chief freelance specialist of the Russian Ministry of Health in obstetrics and gynecology in the Volga Federal District (Kazan). No conflict of interest.
Filippov Oleg Semenovich – MD, DSc, Professor, Professor at the Department of Obstetrics and Gynecology, Faculty of Advanced Training for Physicians, Moscow State University of Medicine and Dentistry named after A.I. Evdokimov of the Russian Ministry of Health, Chief freelance specialist in obstetrics and gynecology of the FMBA of Russia (Moscow). No conflict of interest.
Sheshko Elena Leonidovna – PhD in Medicine, Director of the Department of Medical Care for Children, Maternity Services, and Public Health, Ministry of Health of the Russian Federation (Moscow). No conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
1. obstetrician-gynecologists
2. obstetrics and gynecology residents
Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)
LoE | Definitions |
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Appendix A3. Reference Materials
Not required.
Appendix B. Physician Action Algorithms
Appendix C. Patient Information
Recurrent miscarriage (RM) is a condition characterized by the loss of 2 or more pregnancies at gestational ages under 22 weeks. RM occurs in 3–5% of couples. The probability of miscarriage increases with maternal age and the number of previously lost pregnancies. Thus, after 1 miscarriage, the chances of a successful pregnancy are about 85%, whereas after 3 failures, they drop to 38–50% depending on age and prior term deliveries.
A healthy lifestyle, smoking and alcohol cessation, a balanced diet, and normal body weight increase the likelihood of a successful pregnancy. Excessive caffeine intake (more than 5 cups per day) may also negatively affect fertility and pregnancy maintenance.
Screening to identify the causes of RM is performed at women's health clinics (zhenskaya konsultatsiya) or outpatient clinics by an obstetriciangynaecologist, or, if necessary, upon referral by an obstetrician-gynaecologist, by other specialists: an endocrinologist, dermatovenerologist, general practitioner, or geneticist.
Pre-conception evaluation includes:
screening for sexually transmitted infections;
determination of autoimmune markers;
ultrasound examination of the uterus and adnexa;
hormone level assessment.
Evaluation of the male partner is mandatory and includes a spermiogram and other tests as recommended by a urologist.
Based on the examination results, the physician may prescribe treatment and provide lifestyle and dietary recommendations.
If uterine pathology is detected (polyps, submucosal fibroids, synechiae, uterine septum), operative hysteroscopy with laparoscopic assistance is recommended. Surgical treatment helps eliminate intrauterine barriers to embryo implantation and promotes a successful pregnancy outcome.
During pregnancy, the most frequent complication is threatened miscarriage, manifested by pain and vaginal spotting. If this complication occurs, medical attention must be sought immediately. If the gestational age exceeds 10 weeks and vaginal bleeding is heavy, emergency medical services must be called immediately.
At 12 weeks, the first-trimester screening is performed. This method is critically important in women with RM as it provides information on fetal development, cervical length, and potential risks of pregnancy complications. Based on the screening results, a geneticist consultation may be recommended to address the need for prenatal diagnostics.
It is essential to regularly visit the physician during pregnancy and follow all instructions regarding examinations and medication intake. If necessary, in cases of cervical shortening, cervical cerclage or placement of an obstetric pessary may be recommended. These interventions are safe and aimed at prolonging the pregnancy.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Not required.