List of Abbreviations
GnRH agonists – gonadotropin-releasing hormone agonists (ATC – Gonadotropin-releasing hormone analogues);
AUB – abnormal uterine bleeding;
COCs – combined oral contraceptives (ATC – progestogens and estrogens, fixed combinations);
LNG-IUS – levonorgestrel-releasing intrauterine system (levonorgestrel in the form of an intrauterine therapeutic system);
ICD-10 – International Classification of Diseases 10th Revision;
IMB – intermenstrual bleeding;
MRI – magnetic resonance imaging;
MHT – menopausal hormone therapy;
NSAIDs – non-steroidal anti-inflammatory and antirheumatic drugs;
HMB – heavy menstrual bleeding;
EA – endometrial adenocarcinoma;
ultrasound – ultrasound examination;
hCG – human chorionic gonadotropin.
Terms and Definitions
Abnormal uterine bleeding (AUB) is bleeding that is excessive in duration, blood loss volume, frequency, and/or regularity [1].
Heavy menstrual bleeding (HMB) is excessive menstrual blood loss that has a negative impact on a woman's physical, social, emotional, and/or material well-being [1].
Intermenstrual bleeding (IMB) is irregular bleeding occurring between menstrual periods [1].
Acute AUB is an episode of bleeding requiring immediate intervention to prevent excessive blood loss [1].
Chronic AUB is bleeding that is excessive in duration, volume, and/or frequency, persisting for more than 3 cycles [1].
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Abnormal uterine bleeding (AUB) is bleeding that is excessive in duration (more than 8 days), volume of blood loss (more than 80 mL), frequency (less than 24 days or more than 38 days), and/or regularity (cycle variability >9 days) [2], [3].
According to the NICE definition, heavy menstrual bleeding (HMB) is excessive menstrual blood loss that negatively impacts a woman's physical, social, emotional, and/or material well-being [4], [5].
Obsolete terms such as "menorrhagia", "metrorrhagia", "hypermenorrhea", "hypomenorrhea", "menometrorrhagia", and "dysfunctional uterine bleeding" have been replaced by AUB, HMB, and IMB [2].
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
HMB can be caused by either organic or non-organic pathology. In 2011, the "FIGO Classification System (PALM-COEIN) for Causes of AUB in Non-Pregnant Women of Reproductive Age" was developed and subsequently revised in 2018 [2]. In 2022, FIGO developed the Classification of Ovulatory Disorders [3].
Within the PALM-COEIN system, there are 4 categories of organic causes of AUB (polyp, adenomyosis, leiomyoma, malignancy or hyperplasia), 4 categories of AUB without visually apparent structural abnormalities (coagulopathy, ovulatory dysfunction, endometrial disorders, iatrogenic category), and 1 unclassified category.
In the 2022 classification of ovulatory disorders, AUB-O is considered a consequence of ovulatory dysfunction manifested by any alteration in the normal frequency, regularity, duration, or volume of menstrual bleeding during reproductive age, not associated with pregnancy, organic or iatrogenic uterine pathology, or coagulation disorders [3].
IMB occurring against the background of a regular cycle is more characteristic of endometrial polyps, chronic endometritis, and ovulatory dysfunction. Irregular, unpredictable prolonged and/or heavy spotting, typically occurring after menstrual delays, is more characteristic of endometrial hyperplasia and endometrial adenocarcinoma (EA).
1.3 Epidemiology of the Disease or Condition
The prevalence of AUB is approximately 30% among patients of reproductive age and can reach 70% during the perimenopausal period [2].
1.4 Features of Coding the Disease or Condition
N92 – Excessive, frequent and irregular menstruation:
N92.0 – Excessive and frequent menstruation with regular cycle (menorrhagia, polymenorrhea);
N92.1 – Excessive and frequent menstruation with irregular cycle (irregular intermenstrual bleeding, irregular shortened intervals between menstruations, menometrorrhagia, metrorrhagia);
N92.2 – Excessive menstruation at puberty (excessive bleeding at the onset of the menstrual period, pubertal menorrhagia, pubertal bleeding);
N92.3 – Ovulatory breakthrough bleeding (regular menstrual bleeding);
N92.4 – Excessive bleeding in the premenopausal period (menorrhagia or metrorrhagia: climacteric, menopausal, preclimacteric, premenopausal);
N93 – Other abnormal uterine and vaginal bleeding;
N93.8 – Other specified abnormal uterine and vaginal bleeding (dysfunctional or functional uterine or vaginal bleeding NOS);
N93.9 – Abnormal uterine and vaginal bleeding, unspecified;
N95.0 – Postmenopausal bleeding.
1.5 Classification of the disease or condition
FIGO Classification (PALM-COEIN) (2011, 2018) of causes of AUB in non-pregnant women of reproductive age:
polyp (AUB-P);
adenomyosis (AUB-A);
leiomyoma (AUB-L);
malignancy (AUB-M) and hyperplasia;
coagulopathy (AUB-C);
ovulatory dysfunction (AUB-O);
endometrial (AUB-E);
iatrogenic (AUB-I);
not yet classified (AUB-N) [2], [6].
Terminology and parameters of the normal menstrual cycle and characteristics of AUB (2018 FIGO revision) are presented in Tables 1 and 2 of Appendix A3.1.
1.6 Clinical presentation of the disease or condition
See section "History and Symptoms".
2. Diagnostics, medical indications and contraindications for diagnostic methods
The diagnosis of abnormal uterine bleeding is established based on patient complaints, medical history, physical examination, and instrumental methods.
2.1 Complaints and Anamnesis
Complaints of HMB, IMB, prolonged and/or heavy genital bleeding.
2.2 Physical Examination
It is recommended that all patients with AUB undergo a gynecological and reproductive history taking, a physical examination according to standard propaedeutics principles, as well as a speculum examination of the cervix and bimanual pelvic examination to identify the cause of bleeding [5], [7], [8].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: Determining the amount, frequency, and regularity of bleeding, the presence of postcoital spotting or IMB, AUB associated with hormone therapy, and dysmenorrhea allows for presumptive identification of the cause of AUB, including pathologies related to the cervix and vagina.
It is recommended to obtain information from the patient with AUB regarding medication use to rule out iatrogenic causes of bleeding [7], [9], [10], [11], [12], [13].
Level CLevel 3Level of recommendation evidence C (reliability level of evidence – 3).
Comments: Drugs that can provoke AUB:
— sex hormone preparations (ATC group: Sex hormones and modulators of the genital system): estrogens, progestogens, including drugs that affect their synthesis or act as analogues;
— nonsteroidal anti-inflammatory and antirheumatic drugs (NSAIDs) may cause ovulatory disorders;
— drugs affecting dopamine metabolism, including phenothiazines (ATC: antipsychotics) and tricyclic antidepressants (ATC: non-selective monoamine reuptake inhibitors);
— antithrombotic agents — direct oral anticoagulants (such as apixaban**) and low molecular weight heparins (ATC: Heparin group) have a greater impact on menstrual blood volume, while indirect anticoagulants (warfarin**) — ATC: Vitamin K antagonists and others.
2.3 Laboratory Diagnostics
It is recommended to test blood levels of human chorionic gonadotropin, complete blood count, coagulogram (exploratory hemostasis screening), and blood ferritin levels in patients with AUB to clarify the cause of bleeding and diagnose anemia [8], [14], [15], [16].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: In cases of AUB, it is necessary to rule out pregnancy in sexually active women, assess the impact of blood loss on hemoglobin levels, and evaluate iron stores (serum ferritin levels in the absence of inflammation reflect body iron stores). Ferritin values are not altered by iron supplementation taken shortly before the test (unlike serum iron), making ferritin the primary test for detecting iron deficiency.
When signs of hypothyroidism are present, it is recommended that patients with AUB undergo blood testing for thyroid-stimulating hormone (TSH) receptor antibodies to evaluate thyroid function [15].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: There is no convincing evidence supporting the rationale for measuring gonadotropin, estradiol, or progesterone levels in the setting of AUB.
It is recommended to perform microscopic examination of vaginal smears in patients with AUB to rule out pelvic inflammatory disease (if facilities permit) [3], [8], [17], [18], [19].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to perform cervical cytology in patients with AUB to detect cervical intraepithelial neoplasia (if facilities permit) [20].
GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)
It is recommended that patients with suspected congenital hemostasis disorders undergo an initial consultation (examination, assessment) with a hematologist and testing for hereditary coagulopathies [1], [14], [15], [21].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: Screening for hemostatic disorders in patients with heavy menstrual bleeding should be based on the presence of one or more of the following features:
1) Heavy menstrual bleeding since menarche;
2) Any of the following bleeding histories: postpartum hemorrhage, surgical bleeding, or bleeding associated with dental procedures.
3) Two or more of the following symptoms: bruising 1–2 times per month, epistaxis 1–2 times per month, frequent gum bleeding, a family history of bleeding.
Congenital coagulopathies occur in up to 50% of adolescents and 10–20% of women presenting with heavy menstrual bleeding (HMB) since menarche. In 70% of cases, von Willebrand disease is identified, less commonly factor XI, VII, or VIII deficiency, or carrier status for hemophilia A or B [1], [14].
2.4 Instrumental Diagnostics
It is recommended that all patients with abnormal uterine bleeding (AUB) undergo a comprehensive pelvic ultrasound (transvaginal and transabdominal) to verify the diagnosis [22], [23].
GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)
Comments: Comprehensive pelvic ultrasound (transvaginal and transabdominal) is performed to assess the condition of the endometrium, myometrium, cervix, fallopian tubes, and ovaries. It allows for the diagnosis of endometrial polyps, adenomyosis, uterine fibroids, uterine developmental anomalies, diffuse endometrial thickening associated with hyperplasia and malignancies, as well as hormone-producing tumors and ovarian masses.
It is recommended to perform pelvic MRI for the differential diagnosis of combined endo- and myometrial pathology (fibroids, nodular adenomyosis, mass lesions, etc.) as an additional diagnostic method in AUB [15], [24].
GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)
Comments: Pelvic MRI is not an informative diagnostic method for endometrial pathology in patients with AUB.
It is recommended that patients with AUB undergo a pathomorphological examination of uterine biopsy material (endometrium) to verify the diagnosis [25], [26].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
Comments: Uterine tissue (endometrial) biopsy must be performed in women with AUB over 40 years of age, as well as in younger women with risk factors for endometrial cancer or in cases of ineffective medical therapy. When focal pathology is suspected (endometrial polyp, uterine fibroids), the biopsy should be performed under hysteroscopic control [25], [26].
It is recommended to perform hysteroscopy and fractional diagnostic curettage of the uterine cavity and cervical canal in patients with AUB and suspected intrauterine pathology based on ultrasound data to verify the diagnosis [23].
GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)
2.5 Other Procedures
It is recommended to consult related specialists (initial examination/consultation by an endocrinologist, initial examination/consultation by a general practitioner/internist, initial examination/consultation by a hematologist, initial examination/consultation by a pediatric endocrinologist, initial examination/consultation by an adolescent physician, initial examination/consultation by a pediatrician, etc.) in cases of AUB and concomitant diseases: endocrinopathies (hypo- or hyperthyroidism, metabolic syndrome, congenital adrenal hyperplasia), hemostatic disorders, etc., in order to choose the management strategy and direct treatment for the comorbid condition [14], [16], [27].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1 Conservative Treatment
It is recommended to use tranexamic acid** as the first-line non-hormonal therapy in adult patients with AUB to reduce blood loss volume [28].
Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)
Comments: The use of tranexamic acid** at a dose of 3 g/day (up to 4 g/day in severe cases) for 4 days blocks local fibrinolytic processes in the endometrium and reduces blood loss by 40–60%.
It is recommended to use NSAIDs as non-hormonal therapy in adult patients with AUB to reduce blood loss volume [29].
GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)
Comments: NSAIDs reduce prostaglandin levels by inhibiting cyclooxygenase, which promotes vasoconstriction. The reduction in blood loss with NSAIDs is 30–40%. Treatment is started on the 1st day of menstruation or a few days prior, and continued until bleeding stops according to the instructions for use, in the absence of contraindications.
It is recommended to use iron supplementation therapy in patients with AUB and iron deficiency anemia or latent iron deficiency, in accordance with the clinical guidelines for anemia [7], [8], [13], [14], [30].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
It is recommended to prescribe levonorgestrel-releasing intrauterine system 52 mg ((LNG-IUS) – ATX code: Plastic intrauterine devices with progestogens) to reduce menstrual blood loss in adult patients with HMB who are not planning pregnancy [8], [13], [29], [31].
For children: Strength of recommendation C (Level of evidence – 5)
For adults: Strength of recommendation A (Level of evidence – 1)
Comments: Levonorgestrel-releasing intrauterine system ((LNG-IUS) – ATX code: Plastic progestogen-releasing IUDs) is the most effective medicinal product for reducing menstrual blood loss, with an efficacy reaching up to 90%, and can be used for long-term treatment [8], [13], [29].
It is recommended to prescribe combined hormonal contraceptives (ATX code: Progestogens and estrogens, fixed combinations) to reduce menstrual blood loss in adult patients with HMB who require contraception [32].
GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)
Comments: Monophasic combined hormonal contraceptives (ATX code: progestogens and estrogens, fixed combinations) reduce the volume of menstrual blood loss by 40–50%, whereas combined oral contraceptives (COCs) – ATX code: progestogens and estrogens, fixed combinations, containing estradiol valerate and dienogest with a dynamic dosing regimen – reduce it by up to 88% [33].
It is recommended to prescribe oral progestogens in a prolonged cyclic regimen to reduce menstrual blood loss in patients with HMB [34].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: The efficacy of a 21-day progestogen administration regimen (ATX code: progestogens) is comparable to that of COCs. The use of progestogens in the luteal phase of the cycle has low efficacy in reducing menstrual blood loss and should not be used as a treatment method for HMB.
It is recommended in adult patients to perform hormonal hemostasis as a method for stopping acute AUB in the absence of organic pelvic pathology [32].
GCR BLEL 2Grade of Recommendations B (Level of Evidence – 2)
Comments: For hormonal hemostasis in cases of acute AUB, as well as for subsequent recurrence-preventing therapy, monophasic COCs are used - ATX code: progestogens and estrogens, fixed combinations. COCs are used at a dose of no more than 100 mcg/day until AUB stops, 1 tablet at equal intervals, followed by a dose reduction to 1 tab/day; the duration of therapy is 21 days from the start of treatment. After AUB cessation, it is recommended to continue COC intake according to the contraceptive regimen for the next few months.
It is recommended to use gonadotropin-releasing hormone agonists (GnRH agonists – ATX code: Gonadotropin-releasing hormone analogues) in patients with AUB when other medications are ineffective and/or in the presence of combined pathology (uterine fibroids, endometriosis, etc.) [34].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: GnRH agonists effectively reduce menstrual blood loss, reversibly block steroidogenesis, and induce endometrial atrophy. They are most commonly used in combined pathology (uterine fibroids, endometriosis, endometrial hyperplasia, etc.). During treatment, dysmenorrhea and pelvic pain associated with endometriosis decrease. Patients receiving GnRH agonist treatment for more than 6 months should be prescribed add-back therapy with continuous menopausal hormone therapy (MHT) agents, if not initiated earlier.
In the presence of AUB and organic pathology (uterine fibroids, endometriosis, endometrial polyp, endometrial hyperplasia, etc.), refer to the relevant clinical guidelines.
3.2 Surgical Treatment
It is recommended to perform surgical treatment in adult patients with AUB when medical therapy is ineffective or contraindicated [14], [35].
GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)
Comments: The choice of surgical approach and scope depends on the etiological factor of AUB, age, reproductive plans, and comorbid extragenital pathology. Surgical treatment is performed in accordance with the protocol of relevant clinical guidelines. The possibility of endometrial ablation should be considered in patients with AUB who have completed their reproductive function, in the absence of organic endo- and myometrial pathology. If other methods are ineffective or inapplicable, uterine artery embolization (endovascular embolization of vessels in uterine neoplasms/uterine arteries) may be used in the absence of contraindications. The definitive treatment for AUB is total hysterectomy.
3.3 AUB in adolescents
AUB in adolescents is most commonly caused by ovulatory dysfunction or inherited bleeding disorders; therefore, the diagnostic algorithm must include the diagnosis of coagulopathies and an initial consultation/examination by a hematologist. Other causes of AUB are similar to those in reproductive age and are diagnosed according to the PALM-COEIN classification.
Treatment:
Conservative treatment
Medical therapy is the method of choice in adolescents with AUB in the absence of organic pelvic pathology [13], [16], [39].
It is recommended to use tranexamic acid** as the first line of non-hormonal therapy to reduce blood loss volume [13], [16].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: The use of tranexamic acid** at a dose of 25 mg/kg (maximum single dose 1 g) 2–3 times daily for 4 days (intravenously in acute AUB) reduces blood loss volume by 25–50% [13], [40].
It is recommended to use NSAIDs as non-hormonal therapy in patients with AUB and dysmenorrhea for relief of menstruation-associated pain and indirect reduction of blood loss volume [13], [16],
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: By inhibiting cyclooxygenase and altering the prostacyclin-to-thromboxane ratio, NSAIDs reduce blood loss by 20–60% and are the first-line drugs of choice in the treatment of ovulatory AUB without endometrial or hemostatic system pathology [41], [37], [42], [43], [44]. The drugs are administered 1 day before the start or on day 1 of menstruation for 3–5 days, or until AUB stops, in the absence of contraindications.
It is recommended to prescribe combined oral contraceptives ((COCs) – according to the ATX classification: progestogens and estrogens, fixed combinations) to reduce blood loss volume in patients with AUB and no contraindications to estrogen use [45], [38], [16], [46], [47], [43], [44], [48], [49], [50].
GRC BLEL 2Grade of Recommendation B (Level of Evidence – 2)
Comments: Low-dose (30 mcg ethinylestradiol) monophasic COCs – according to the ATX classification: progestogens and estrogens, fixed combinations – are used every 8 hours to stop AUB, followed by a gradual decrease in the daily dose [43], [51], [52]. The use of COCs in patients with AUB who need contraception allows for a 43–69% reduction in menstrual blood loss volume [44], [49], [50], [53].
In a number of cases, for the treatment of AUB as an alternative to COCs (according to the ATX classification: progestogens and estrogens, fixed combinations) inanovulatory bleeding, progestogens (according to the ATX classification: progestogens) can be used to achieve complete secretory transformation of the endometrium [54], [37], [41], [46], [51], [55], [56].
Surgical treatment
It is recommended to perform fractional diagnostic curettage of the uterine cavity and cervical canal (under hysteroscopic control – if possible) in adolescents with AUB in the absence of an effect from hemostatic therapy, or aspiration evacuation for vital indications [37], [46], [42], [43], [51].
GRC CLeE 5Grade of Recommendation C (Level of Evidence – 5)
3.4 AUB in the postmenopausal period
Postmenopausal bleeding is the occurrence of spotting or bleeding from the genital tract arising 12 months after the last menstruation [57], [58].
The primary goal of diagnostic workup in postmenopausal AUB, regardless of the amount of bleeding, is to rule out organic endometrial pathology (polyps, hyperplasia, EC, etc.) and hormone-producing ovarian tumors [59], [60]. Endometrial atrophy can also be a cause of postmenopausal AUB.
Iatrogenic factors causing postmenopausal AUB are associated with the use of MHT, the selective estrogen receptor modulator tamoxifen**, anticoagulants – according to the ATX classification: antithrombotic agents, etc. [58], [61].
Risk factors for the development of EC include: obesity, nulliparity, early menarche, late menopause (older than 55 years), PCOS, as well as a burdened family history: Lynch syndrome, EC in first-degree relatives, carriers of BRCA 1/2 gene mutations, etc.
It is recommended to perform a pathomorphological examination of the biopsy (surgical) material of the uterus (endometrium) obtained by uterine tissue biopsy or fractional diagnostic curettage of the uterine cavity and cervical canal (depending on ultrasound results and the presence of EC risk factors) to rule out endometrial pathology under hysteroscopic guidance (if possible) [62].
GCR ALEL 1Grade of Recommendations A (Level of Evidence – 1)
Comment: diagnostic hysteroscopy allows for visual assessment of the uterine cavity and targeted biopsy of uterine tissue (endometrium) and/or removal of focal endometrial pathology. Hysteroscopy does not replace uterine curettage, but complements it [63].
3.5 AUB during tamoxifen** therapy.
In postmenopausal women, adjuvant therapy with tamoxifen** can stimulate endometrial proliferation, leading to an increased risk of polyps, hyperplasia, and endometrial cancer, and more rarely, uterine sarcoma. The incidence of intrauterine pathology during tamoxifen** therapy increases with the duration of treatment [64], [65], [66].
It is recommended to perform a comprehensive pelvic ultrasound (transvaginal and transabdominal) in all patients receiving tamoxifen** therapy with postmenopausal AUB to rule out endometrial pathology [67].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
Comment: Ultrasound signs of tamoxifen**-induced endometrial alteration include: increased endometrial thickness due to stromal proliferation, appearance of subendometrial cysts, irregularity of the endometrium-myometrium border, and honeycomb endometrium. During the ultrasound, it is necessary to assess the thickness and structure of the endometrium and endocervix, as well as the structure of the myometrium and ovaries to determine the extent of surgical intervention. Comprehensive pelvic ultrasound (transvaginal and transabdominal) is a screening diagnostic method in this group of patients, but has limited informativeness for diagnosing endometrial pathology [68], [69].
It is recommended to perform a pathomorphological examination of the biopsy (surgical) material of the uterus (endometrium) in all patients with AUB during tamoxifen therapy** to rule out endometrial pathology [65], [66], [69], [70], [71].
GCR CLEL 4Grade of Recommendation C (Level of Evidence - 4)
3.6 Postmenopausal bleeding associated with MHT
The most frequent causes of bleeding during MHT are poor adherence to therapy, drug interactions, benign neoplasms (endometrial polyps), and extragenital pathology [70]. Bleeding during MHT requires investigation.
In postmenopausal women, spotting (often scant) may occur in the first 6 months of initiating monophasic combined MHT [71].
It is recommended to perform a comprehensive pelvic ultrasound (transvaginal and transabdominal) in all postmenopausal patients with AUB receiving MHT [71], [72].
GRC BLeE 1Grade of Recommendation B (Level of Evidence – 1)
Comment: an endometrial thickness of ≤4 mm in postmenopausal patients with AUB receiving continuous combined MHT without risk factors for EC is a threshold indicating a low probability of endometrial pathology. In the absence of EC risk factors and with an M-echo of ≤4 mm, an expectant management approach is acceptable [72].
It is recommended for all postmenopausal patients with AUB receiving a monophasic (continuous) combined MHT regimen with an endometrial thickness of >4 mm to undergo a pathomorphological examination of the biopsy (surgical) material of the uterus (endometrium) obtained by uterine tissue biopsy or fractional diagnostic curettage of the uterine cavity and cervical canal (depending on ultrasound results and the presence of EC risk factors) to exclude endometrial pathology under hysteroscopic guidance (if possible) [73].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
Comment: during ultrasound, it is necessary to assess the thickness and structure of the endometrium and endocervix, the structure of the myometrium and ovaries to rule out pelvic pathology. With an endometrial thickness of ≤4 mm in peri- and postmenopausal women according to comprehensive pelvic ultrasound, MHT is not contraindicated, as the probability of EC is less than 1% [65]. In postmenopausal women with a single episode of AUB, an endometrial thickness of ≤4 mm, homogeneous structure, and absence of EC risk factors (age, burdened family history of EC, comorbidity (obesity, type 2 diabetes mellitus, arterial hypertension, etc.)), additional evaluation or intervention is not required. In cases of recurrent AUB episodes, as well as with an endometrial thickness (M-echo) >4 mm, heterogeneous structure, and additional risk factors for EC in postmenopausal women, hysteroscopy with uterine tissue (endometrial) biopsy is required [73], [74], [79].
4. Medical Rehabilitation and Sanatorium-Resort Treatment
It is recommended to consult a physical therapy doctor to determine a rehabilitation program after clarifying the cause of AUB [27].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
5. Prevention and Dispensary Observation
For the prevention of AUB, it is recommended to undergo an annual routine check-up with an obstetrician-gynecologist for the timely detection of organic pathology (uterine fibroids, endometriosis, endometrial hyperplastic processes) [27].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: When clarifying the causes of AUB, careful monitoring of the medications taken by the patient is necessary. For ovulatory dysfunctions, therapy aimed at treating the underlying condition is recommended. An important factor is the prevention of pelvic inflammatory disease, which in most cases develops as a result of sexually transmitted infections. If these conditions are identified, the patient is assigned to health group IIIa for clinical follow-up [36].
Specific prevention of AUB in adolescents has not been developed.
To prevent the development of AUB, it is advisable to identify groups of adolescent girls at risk for long-term persistence of anovulatory menstrual cycles. These include:
early onset of menstruation (under 10 years of age);
family history of coagulopathies;
history of hemorrhagic syndrome of unclear etiology.
6. Organization of Medical Care
An indication for emergency hospitalization in a gynecological inpatient facility is the presence of acute AUB requiring urgent medical care.
Indication for elective hospitalization: presence of organic pathology causing chronic AUB and requiring surgical treatment.
Indications for discharging a patient from a gynecological inpatient facility: cessation of AUB and stabilization of the patient's condition.
Criteria for Evaluating the Quality of Medical Care
This section contains the criteria for assessing the quality of medical care for AUB recommended by the Working Group (Table 2).
Table 2. Criteria for assessing the quality of medical care for AUB
№ | Quality criteria | Yes/No |
|---|---|---|
1 | Blood human chorionic gonadotropin (hCG) level testing, complete blood count (CBC), coagulopathy screening (coagulation profile), and blood ferritin level testing were performed in patients with AUB | Yes/No |
2 | Microscopic examination of vaginal smears was performed in patients with AUB | Yes/No |
3 | Complex pelvic ultrasound (transvaginal and transabdominal) was performed | Yes/No |
4 | Uterine tissue (endometrial) biopsy or diagnostic dilation and curettage of the uterine cavity and cervical canal (under hysteroscopic guidance if possible) was performed when endometrial pathology was suspected | Yes/No |
5 | Surgical treatment was performed when indicated | Yes/No |
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Mullins, T.L. Evaluation and management of adolescents with abnormal uterine bleeding / T.L. Mullins, R.J. Miller, E.S. Mullins // Pediatr Ann. – 2015. – vol.44. – N 9. – P. 218-222.
Menstruation in girls and adolescents: using the menstrual cycle as a vital sign / ACOG Committee Opinion No. 651 American College of Obstetricians and Gynecologists // Obstet Gynecol. – 2015. – vol.126. – P. 143-146.
Committee on Practice Bulletins—Gynecology. Practice bulletin no. 136: management of abnormal uterine bleeding associated with ovulatory dysfunction. Obstet Gynecol. 2013.
Naoulou, B. Efficacy of tranexamic acid in the treatment of idiopathic and non-functional heavy menstrual bleeding: a systematic review // B. Naoulou, M.C. Tsai // Acta Obstet Gynecol Scand. – 2012. – vol.91. – N 5. – P. 529-537.
Deligeoroglou, E. Abnormal uterine bleeding and dysfunctional uterine bleeding in pediatric and adolescent gynecology / E. Deligeoroglou, V. Karountzos, G. Creatsas // Gynecol Endocrinol. – 2013. – vol.29. – N 1. – P. 74-78.
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Karakus, S. Efficacy of micronised vaginal progesterone versus oral dydrogestrone in the treatment of irregular dysfunctional uterine bleeding: a pilot randomised controlled trial / S. Karakus, G. Kiran, H. Ciralik // Aust N Z J Obstet Gynaecol. – 2009.
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Appendix A1. Working Group Composition
Leyla V. Adamyan - Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Deputy Director of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Honored Worker of Science of Russia, Head of the Department of Reproductive Medicine and Surgery at the A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health, Chief Gynecologist of the Russian Ministry of Health, President of the Society for Reproductive Medicine and Surgery, Russian Association of Gynecological Endoscopists, Russian Association for Endometriosis, member of the Russian Society of Obstetricians and Gynecologists.
Elena N. Andreeva - Doctor of Medical Sciences, Professor, Deputy Director - Director of the Institute of Reproductive Medicine, Head of the Department of Endocrine Gynecology, Professor at the Department of Endocrinology of the National Medical Research Center for Endocrinology of the Russian Ministry of Health, Professor at the Department of Obstetrics, Gynecology and Reproductive Medicine of the Russian University of Medicine, President of the International Association of Obstetricians, Gynecologists and Endocrinologists, member of the Russian Association of Gynecological Endoscopists, Russian Association for Endometriosis, Russian Society of Obstetricians and Gynecologists, ROSGEM.
Natalya V. Artymuk - Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology named after Professor G.A. Ushakova at 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), member of the Presidium of the Board of the Russian Society of Obstetricians and Gynecologists, President of the Kemerovo Regional Public Organization "Association of Obstetricians and Gynecologists".
Yulia S. Absatarova - Senior Researcher at the Department of Endocrine Gynecology of the National Medical Research Center for Endocrinology of the Russian Ministry of Health, Candidate of Medical Sciences, member of the International Association of Obstetricians, Gynecologists and Endocrinologists.
Vitaly F. Bezhenar - Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics, Gynecology and Neonatology at the First Pavlov State Medical University of St. Petersburg of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics and Gynecology for the Healthcare Committee of St. Petersburg, member of the Society for Reproductive Medicine and Surgery, Russian Association of Gynecological Endoscopists, Russian Society of Obstetricians and Gynecologists.
Tatyana E. Belokrinitskaya – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology of the Faculty of Advanced Training and Professional Retraining of Physicians at 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), member of the Russian Society of Obstetricians and Gynecologists, President of the Trans-Baikal Society of Obstetricians and Gynecologists.
Madina R. Dumanovskaya - Candidate of Medical Sciences, Senior Researcher at the Department of Gynecological Endocrinology of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, member of the Executive Committee of ROSGEM
Ilya A. Ivanov - Candidate of Medical Sciences, Researcher at the Department of Gynecological Endocrinology of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov, member of the Executive Committee of ROSGEM
Irina A. Salnikova - Candidate of Medical Sciences, Researcher at the 2nd Gynecological Department of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.
Larisa V. Suturina – Doctor of Medical Sciences, Professor, Head of the Department of Reproductive Health Protection at the Scientific Centre for Family Health and Human Reproduction Problems (Irkutsk), member of the Association of Gynecological Endocrinologists of Russia, member of the Russian Society of Obstetricians and Gynecologists.
Antonina A. Smetnik - Head of the Department of Gynecological Endocrinology, Candidate of Medical Sciences, member of the Russian Society of Obstetricians and Gynecologists, President of the Russian Society of Gynecological Endocrinology and Menopause Specialists (ROSGEM).
Narine M. Tonoyan – Candidate of Medical Sciences, Obstetrician-Gynecologist at the Department of Operative Gynecology of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health.
Elena V. Uvarova - Doctor of Medical Sciences, Professor, Head of the 2nd Gynecological Department (Children and Adolescents) of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health
Oleg S. Filippov – Doctor of Medical Sciences, Professor, Honored Doctor of the Russian Federation, Chief Freelance Obstetrician-Gynecologist of the Federal Medical-Biological Agency (FMBA) of Russia, Deputy Director of the Federal Research and Clinical Center of Children and Adolescents of the FMBA of Russia, Professor at the Department of Obstetrics, Gynecology and Reproductive Medicine of the Russian University of Medicine.
Galina E. Chernukha – Doctor of Medical Sciences, Professor, Chief Researcher at the Department of Gynecological Endocrinology of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, President of the Association of Gynecological Endocrinologists, member of the Russian Society of Obstetricians and Gynecologists.
Sheremeteva Ekaterina Viktorovna – Leading Researcher at the Department of Endocrine Gynecology, National Medical Research Center for Endocrinology of the Russian Ministry of Health, Candidate of Medical Sciences, Member of the International Association of Obstetricians-Gynecologists and Endocrinologists.
Yureneva Svetlana Vladimirovna, Doctor of Medical Sciences, Professor, Deputy Director for Research at the Institute of Oncogynecology and Mammology, Professor at the Department of Obstetrics and Gynecology of Postgraduate Education, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Member of the Russian Association of Obstetricians-Gynecologists, Vice President of the Interregional Association of Gynecologist-Endocrinologists.
Yarmolinskaya Maria Igorevna – Professor of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Head of the Department of Gynecology and Reproductive Endocrinology, D.O. Ott Research Institute of Obstetrics and Gynecology, Professor at the Department of Obstetrics and Gynecology, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, Member of the Russian Society of Obstetricians-Gynecologists, Board Member of the Russian Society of Gynecological Endocrinology and Menopause Specialists.
All working group members declare no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
Obstetrician-gynecologists, general practitioners, family physicians;
Students, residents, postgraduate students;
Faculty members, researchers.
In these clinical guidelines, all information is ranked according to the level of confidence of the recommendations and reliability of evidence based on the quantity and quality of studies on the issue (Table 3, Table 4, Table 5).
Table 3. Scale for assessing the levels of evidence reliability (LER) 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 | There is only a rationale for the mechanism of action or expert opinion |
Table 4. Scale for assessing the levels of evidence reliability (LER) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitation 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 | There is only a rationale for the mechanism of action of the intervention (preclinical studies) or expert opinion |
Table 5. Scale for assessing the levels of confidence of recommendations (LCR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitation 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) |
Procedure for updating clinical guidelines.
The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
These clinical guidelines have been developed taking into account the following regulatory legal and other documents:
1) Order of the Russian Ministry of Health No. 1130n dated October 20, 2020, "On Approval of the Procedure for Providing Medical Care in the Profile 'Obstetrics and Gynecology'" (Registered with the Ministry of Justice of Russia on November 12, 2020, No. 60869).
2) Serov V.N., Sukhikh G.T. Clinical Guidelines. Obstetrics and Gynecology // Moscow: GEOTAR-Media. - 4th ed. - 2017. Moscow: Problems of Reproduction.
3) National Guideline Alliance (UK). Evidence reviews for management of heavy menstrual bleeding: Heavy menstrual bleeding (update). London: National Institute for Health and Care Excellence (NICE); March 2018. Last updated: 24 May 2021.
Appendix A3.1 FIGO Classification (PALM-COEIN)
Table 1. FIGO Classification (PALM-COEIN), 2018 Revision:
Category | Modification |
|---|---|
AUB-A | Ultrasound diagnostic criteria for adenomyosis are presented |
AUB-L | Definition of type 3 myoma as a submucosal uterine fibroid Introduction of the definition and distinction between nodes: • Types 0 and 1; 6 and 7 • Types 2 and 3; 4 and 5 |
AUB-C | AUB associated with anticoagulant use are excluded |
AUB-I | AUB associated with any iatrogenesis are included, including the use of anticoagulants – according to the ATC classification (Antithrombotic agents) |
AUB-O | Ovulatory disorders of iatrogenic origin are excluded |
AUB-N | Category name changed from "Not yet classified" to "Not otherwise classified" |
Categories not related to visually identifiable structural changes:
Coagulopathy: von Willebrand disease or syndrome, thrombocytopathies (Glanzmann thrombasthenia and Bernard-Soulier syndrome), thrombocytopenias, including idiopathic thrombocytopenic purpura (Werlhof disease) and Gaucher disease; less commonly, acute leukemia.
Ovulatory dysfunction: resulting from progesterone deficiency and excessive estrogen secretion. These forms of AUB can occur in adolescence, perimenopause, during lactation, in conditions accompanied by hyperandrogenism (polycystic ovary syndrome, congenital adrenal hyperplasia, or androgen-producing tumors), hypothalamic dysfunction, high prolactin levels, thyroid pathology, premature ovarian insufficiency, and iatrogenic causes (radiation exposure or chemotherapy).
Endometrial disorders: most often a diagnosis of exclusion, typically occurring against the background of a regular menstrual rhythm as a result of angiogenesis activation, increased production of proinflammatory cytokines, enhanced local fibrinolysis, and prostaglandin imbalance.
Iatrogenic category: continuous use of progestins/COCs or an intrauterine system, which can affect the endometrium, coagulation processes, and ovulation; treatment with systemic antibacterial drugs such as rifampicin** and griseofulvin, antidepressants, tamoxifen**, systemic corticosteroids; and the use of antithrombotic agents (anticoagulants).
Not otherwise classified (AUB-N): arteriovenous malformations, myometrial hypertrophy, cesarean scar niche, as well as other endometrial abnormalities that currently cannot be established using standard diagnostic methods [2].
Table 2. Normal and abnormal uterine bleeding: FIGO 2018 revision.
Category | Characteristics |
|---|---|
Frequency | Absence of menstruation or bleeding – amenorrhea Frequent (<24 days) Normal (24 to 38 days) Infrequent (>38 days) |
Regularity | ● Regular (cycle variability ≤9 days) ● Irregular (cycle variability >9 days) |
Duration | ● Normal: ≤8 days ● Prolonged: >8 days |
Volume | Definition of volume/heavy bleeding ● Heavy ● Normal ● Scanty ● According to NICE recommendations, heavy menstrual bleeding (HMB) is a volume of blood loss that has a negative impact on a woman's quality of life |
Intermenstrual bleeding | Definition of intermenstrual bleeding symptoms ● Random ● Cyclic (beginning, middle, or end of the cycle) |
Appendix B. Physician Action Algorithms
Management algorithms for patients with AUB in the reproductive period
Management algorithms for adolescent patients with AUB
Management algorithms for postmenopausal AUB
Appendix C. Patient Information
Uterine bleeding is bleeding from the uterus that can be either physiological (normal menstruation) or abnormal. A normal menstrual cycle lasts 24-38 days, blood loss per cycle is 5 to 80 ml, and the duration of menstruation is 4.5 to 8 days.
Causes of abnormal uterine bleeding: polyps (growths in the uterine cavity or cervical canal), adenomyosis, myoma, atypical transformation of endometrial cells in the uterine cavity, endometrial thickening, blood clotting disorders (e.g., von Willebrand disease, hemophilia, thrombocytopenia, excluding medications that impair blood clotting), ovulation disorders due to polycystic ovary syndrome, obesity, anorexia, stress, rapid weight loss, severe physical exertion, thyroid disorders, hyperprolactinemia, endometritis, or infection. A link has been established between Chlamydia trachomatis infection and abnormal uterine bleeding.
Bleeding may occur as a result of medications affecting the endometrium, as well as anticoagulants (ATX: Antithrombotic agents) or medications affecting ovulation (combined oral contraceptives [ATX: Progestogens and estrogens, fixed combinations], progestogens).
Acute uterine bleeding is an episode of heavy bleeding requiring urgent medical intervention to prevent further profuse blood loss. It may occur against the background of chronic uterine bleeding.
Chronic uterine bleeding differs from normal menstruation in volume, regularity, and/or duration and has been present for the last 3 months or more. It does not require immediate medical intervention, but may progress to acute bleeding.
Diagnosis of uterine bleeding
In case of uterine bleeding, one should first consult an obstetriciangynaecologist for a gynaecological examination. Blood pressure is measured. A comprehensive pelvic ultrasound, complete blood count, blood ferritin level, and hCG level (serum human chorionic gonadotropin [free beta-subunit] level) are performed. Hysteroscopy with uterine (endometrial) tissue biopsy is performed in the following situations: acute uterine bleeding and endometrial changes on ultrasound (polyps, endometrial hyperplasia, uterine fibroids, menopausal bleeding). Pelvic MRI provides a more detailed image and clear outlines of pelvic organs in the presence of mass lesions.
Treatment of uterine bleeding
Treatment of uterine bleeding is divided into surgical and medical. Medical treatment can be hormonal (combined oral contraceptives [ATX: Progestogens and estrogens, fixed combinations], vaginal rings [ATX: Intravaginal contraceptives], progestogens, progestogen-releasing intrauterine systems) and non-hormonal (non-steroidal anti-inflammatory and antirheumatic drugs, tranexamic acid**).
For acute uterine bleeding and for women aged 40 and older, surgical treatment is preferred: hysteroscopy with uterine tissue biopsy (which also serves as a diagnostic research method), diagnostic curettage of the uterine cavity and cervical canal, and endometrial ablation (complete destruction of the endometrium).
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Not required.