List of Abbreviations
BP – blood pressure
EP – ectopic pregnancy
PID – pelvic inflammatory disease
HES – Hydroxyethyl starch**
MRI – magnetic resonance imaging
RUOG – Russian Association of Obstetricians and Gynecologists
TVS – transvaginal scan (comprehensive pelvic ultrasound (transvaginal and transabdominal))
US – ultrasound examination
hCG – human chorionic gonadotropin
ACOG – American College of Obstetricians and Gynecologists
AEPU – Association of Early Pregnancy Unit
ASRM – American Society for Reproductive Medicine
NICE – National Institute for Clinical Excellence
Terms and Definitions
Ectopic pregnancy (EP) – a pregnancy in which the implantation of the fertilized ovum occurs outside the uterine cavity [1].
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Ectopic pregnancy (EP) – a pregnancy in which the implantation of the fertilized ovum occurs outside the uterine cavity [1], [2].
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
Pathogenesis: impaired transport of the fertilized ovum followed by abnormal implantation of the blastocyst. Risk factors for ectopic pregnancy include: tubal surgery, previous ectopic pregnancies, PID, intrauterine contraception, intrauterine interventions, infertility, maternal age over 35, smoking [3], [4], use of combined oral contraceptives (according to the Anatomical Therapeutic Chemical (ATC) classification – Progestogens and estrogens, fixed combinations) [3], genital malformations (pregnancy in a rudimentary horn), endometriosis, presence of a uterine scar after Cesarean section [5].
1.3 Epidemiology of the Disease or Condition
In Russia in 2017, according to Rosstat data, ectopic pregnancy accounted for 8.1% of the maternal mortality structure; currently, there is a downward trend – 4.97% in 2020, and 2.94% in 2022 [6].
Early diagnosis and timely treatment of EP reduce the maternal mortality rate. In addition, early diagnosis allows for the use of minimally invasive and organ-sparing treatment methods [1], [7], [8], [9].
The incidence of rare forms of ectopic pregnancy reaches 5–8.3% of all ectopic pregnancies, and their course is characterized by massive bleeding, often with a fatal outcome [10].
According to the nomenclature of terms of the European Society of Human Reproduction and Embryology (ESHRE, 2018) and the clinical guidelines (treatment protocol) «Early Pregnancy Loss» approved by the Russian Ministry of Health and RUOG (2024), in the absence of ultrasound signs of intrauterine or ectopic pregnancy with a positive hCG test, the diagnosis of «Pregnancy of unknown location» should be made [2].
«Pregnancy of unknown location» [2], [11] – a condition in which the blood beta-hCG level is at least 1000 IU/L, and no gestational sac is visualized in the uterus outside its cavity upon transvaginal ultrasound – patients are indicated for a transvaginal pelvic ultrasound and monitoring of blood beta-hCG levels (according to ATC – Assay of human chorionic gonadotropin (free beta-subunit) in blood serum) after 48 hours [11].
Risk factors for ectopic pregnancy: age >35 years, smoking, documented tubal pathology, infertility, PID, pregnancy with an intrauterine device (IUD) in the uterine cavity, previous ectopic pregnancy, tubal surgery. See Appendix A3.2.
One previous ectopic pregnancy increases the risk of a recurrent ectopic pregnancy by 10%, and two previous ectopic pregnancies increase it by 25% [12].
The incidence of heterotopic EPs increases with the use of assisted reproductive technologies (ART): 1/100 pregnancies in in vitro fertilization (IVF) and 1/7000 pregnancies in ART with ovulation induction [13].
1.4 Features of Coding the Disease or Condition
Ectopic pregnancy (O00):
O00.0 Abdominal pregnancy.
O00.1 Tubal pregnancy.
(1) Pregnancy in the fallopian tube.
(2) Rupture of the fallopian tube due to pregnancy.
(3) Tubal abortion.
O00.2 Ovarian pregnancy.
O00.8 Other forms of ectopic pregnancy.
(1) Cervical.
(2) In the uterine horn.
(3) Intraligamentary.
(4) Mural.
O00.9 Ectopic pregnancy, unspecified.
Complicated forms (ICD-10):
O08.0 Genital tract and pelvic infection following abortion and ectopic and molar pregnancy.
O08.1 Delayed or excessive hemorrhage following abortion and ectopic and molar pregnancy.
O08.2 Embolism following abortion and ectopic and molar pregnancy.
O08.3 Shock following abortion and ectopic and molar pregnancy.
O08.4 Renal failure following abortion and ectopic and molar pregnancy.
O08.5 Metabolic disorders following abortion and ectopic
and molar pregnancy.
O08.6 Damage to pelvic organs and tissues following abortion and ectopic and molar pregnancy.
O08.7 Other venous complications following abortion and ectopic
and molar pregnancy.
O08.8 Other complications following abortion and ectopic and molar pregnancy.
O08.9 Unspecified complication following abortion and ectopic and molar pregnancy.
1.5 Classification of the disease or condition
1.5.1 Anatomic classification of EP (See Appendix A3.8)
Tubal (interstitial, isthmic, ampullary, fimbrial)
Ovarian
Cervical
Abdominal
Heterotopic pregnancy (coexistence of intrauterine pregnancy and ectopic pregnancy)
Cesarean scar pregnancy — rare; modern data indicate an incidence of 1 in 1,800 to 1 in 2,500 of all cesarean deliveries [14]. See Appendix A3.9.
Rudimentary horn pregnancy
Mural (intramural)
1.5.2 Clinical classification of ectopic pregnancy
By clinical course:
Progressive.
Ruined (ruptured/aborted).
By presence of complications:
Complicated.
Uncomplicated.
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 ectopic pregnancy is established based on complaints, medical history, physical examination, comprehensive pelvic ultrasound (transvaginal and transabdominal), quantitative serum human chorionic gonadotropin (free beta-subunit) testing, and/or positive qualitative urine pregnancy test for human chorionic gonadotropin.
Upon establishing the diagnosis of ectopic pregnancy, the patient must be hospitalized on an emergency basis to determine further management strategy and perform surgical treatment.
2.1 Complaints and Anamnesis
Symptoms of ectopic pregnancy [9]: pain in the lower abdomen and lower back, potentially radiating to the rectum, typically against the background of menstrual irregularities (amenorrhea) and scant bloody vaginal discharge («spotting»). The nature of pain is variable in both intensity and radiation. In a ruptured ectopic pregnancy, pain may be accompanied by dizziness, syncope, nausea, vomiting, and peritoneal irritation signs [15]. See Appendix A3.1.
2.2 Physical Examination
It is recommended that all patients with suspected ectopic pregnancy undergo abdominal palpation (physical examination of the anterior abdominal wall and abdominal cavity by palpation, percussion, and auscultation) to verify the diagnosis [3].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: In progressive ectopic pregnancy, the abdomen is soft and non-tender; in ruptured ectopic pregnancy, abdominal tenderness is detected above the pubic symphysis or in the iliac regions, percussion reveals dullness in dependent areas, and peritoneal signs appear.
It is recommended that all patients with suspected ectopic pregnancy undergo bimanual vaginal examination to verify the diagnosis [9].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: Vaginal examination reveals lower abdominal tenderness, an ovoid soft-consistency mass in the adnexal region, an enlarged uterus, cervical motion tenderness, and fullness (or bulging) of the posterior vaginal fornix in the presence of free fluid (blood) in the peritoneal cavity (rectouterine pouch / pouch of Douglas). In cervical pregnancy, physical examination reveals altered cervical configuration (barrel-shaped). In some cases, a rectovaginal examination is performed.
2.3 Laboratory Diagnostics
It is recommended for diagnosing pregnancy in all patients:
to perform a urine test for human chorionic gonadotropin [16], [17].
Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).
and/or quantitative serum human chorionic gonadotropin (free beta-subunit) testing (if available) [18].
GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).
Comments: Serum beta-hCG is the sole biochemical marker for diagnosing pregnancy, including ectopic pregnancy [19], [20].
It is recommended to determine and evaluate serial serum human chorionic gonadotropin (free beta-subunit) levels in patients with suspected ectopic pregnancy [21], [22], [23].
GOM ALOE 1Grade of Recommendation A (Level of Evidence – 1).
Comments: If the beta-hCG level is less than 1,000 IU/L, repeat blood beta-hCG testing is recommended in 48 hours, provided the patient is in a stable condition.
Quantitative assessment of beta-hCG kinetics. Normally, the increase in beta-hCG levels every 48 hours in an intrauterine pregnancy is greater than 50% (on average 63–66%) [7], [9], [11], [24]. Only 17% of ectopic pregnancies show an increase in serum beta-hCG similar to that of a normal intrauterine pregnancy [7]. A decrease or a small (diagnostically insignificant) rise in beta-hCG levels (below 53%) combined with the absence of an intrauterine pregnancy on ultrasound indicates an ectopic pregnancy [20]. Insufficient beta-hCG rise can also occur in missed (non-viable) intrauterine pregnancy [2]. Beta-hCG levels have limited value in the diagnosis of heterotopic pregnancy (coexistence of intrauterine and ectopic pregnancy) [7].
2.4 Instrumental Diagnostics
It is recommended that all patients with suspected ectopic pregnancy undergo inspection of the cervix and vagina using specula to verify the diagnosis [25].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: Speculum examination reveals cervical cyanosis (bluish discoloration) and bloody discharge (scant, moderate, or heavy).
In cervical pregnancy, asymmetry of the cervix and vaginal fornices and an altered (barrel-shaped) cervical configuration are observed.
It is recommended to perform comprehensive pelvic ultrasound (transvaginal and transabdominal) (ultrasonography) in all patients with suspected ectopic pregnancy to confirm the diagnosis and determine the precise location of the gestational sac [7], [17], [26], [27], [28].
GCR ALEL 1Grade of Recommendation A (Level of Evidence – 1).
Comments: Ultrasound signs of ectopic pregnancy: absence of a gestational sac in the uterine cavity; enlargement of the uterine appendages or fluid accumulation in the pouch of Douglas; signs of decidual endometrial hyperplasia (detection of an ectopically located embryo is an important but rare diagnostic sign). Tubal pregnancy can be diagnosed if a mass is visualized in the adnexal region, which moves separately from the ovary during transvaginal ultrasound [7]. Ultrasound criteria for diagnosing cervical ectopic pregnancy: barrel-shaped cervix, gestational sac located below the level of the internal os of the cervix, absence of blood flow around the gestational sac on color Doppler ultrasound, and the transvaginal "sliding sign" that helps distinguish cervical pregnancy from spontaneous abortion. When pressure is applied to the cervix using a probe in cases of abortion, the gestational sac slides along the endocervical canal, whereas in cervical pregnancy this does not occur [7], [29]. Ultrasound criteria for diagnosing pregnancy in a rudimentary uterine horn: a single interstitial part of the fallopian tube is visualized in the uterine cavity; the gestational sac is mobile, separated from the uterus, and completely surrounded by myometrium; a vascular pedicle adjoins the gestational sac located in the uterine horn [7]. Ultrasound criteria for diagnosing interstitial pregnancy: no gestational sac in the uterine cavity, the gestational sac is located externally in the interstitial (intramural) part of the fallopian tube and surrounded by a myometrial layer of less than 5 mm, and the "interstitial line sign" with a sensitivity of 80% and specificity of 98% for diagnosing interstitial pregnancy [29], [30]. To avoid errors (early pregnancy or implantation in the tubal cornua of the uterine cavity), two-dimensional ultrasound results should be supplemented with three-dimensional ultrasound whenever possible. Pelvic magnetic resonance imaging (MRI) may be useful in diagnosing interstitial pregnancy [7]. Heterotopic pregnancy presents with ultrasound signs of both intrauterine and ectopic pregnancies [7]. There are no specific ultrasound criteria for diagnosing ovarian pregnancy [7].
In the presence of a Cesarean scar pregnancy (or after myomectomy (enucleation of myoma nodes)) with the formation of a "niche" during healing, an gestational sac is identified with invasion into the scar to a depth determined by ultrasound (invasion up to the serosal layer or adjacent organs is possible) [9], [31]. The most informative method is 3/4D technology, which provides additional information in the coronal scanning plane regarding the depth of invasion and changes in surrounding tissues. Color Doppler mapping can be additionally used to assess blood flow.
It is recommended to prescribe pelvic MRI as a second-line diagnostic method in the presence or suspicion of rare forms of ectopic pregnancy (cesarean scar pregnancy, cervical, and abdominal pregnancies) provided the conditions for the procedure are met (patient hemodynamic stability, availability of equipment and personnel) to verify the diagnosis [7], [32].
Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).
Comments: Ultrasound is the primary diagnostic method for ectopic pregnancy. The use of pelvic MRI for rare forms of ectopic pregnancy, combined with other gynecological and extragenital diseases, makes it possible to verify the diagnosis and rule out pathology of adjacent organs.
2.5 Other Procedures
It is recommended to perform differential diagnosis of progressive tubal pregnancy with early intrauterine pregnancy by re-evaluating the serum human chorionic gonadotropin level (free beta-subunit) (after 48 hours) and comprehensive pelvic ultrasound (transvaginal and transabdominal) [22], [24], [17]. See Appendix A3.3.
GOM ALOE 1Grade of Recommendation A (Level of Evidence – 1).
Comments: In early stages, including after the use of ART methods, diagnosing the disease presents certain difficulties.
In some cases, a combination of intrauterine and ectopic pregnancies is possible (1 in 30,000 pregnancies).
It is recommended to perform differential diagnosis of aborted tubal pregnancy (by the type of tubal abortion or rupture of the fallopian tube) with ovarian apoplexy, miscarriage, exacerbation of chronic salpingo-oophoritis, abnormal uterine bleeding, gastric and duodenal ulcer perforation, liver and spleen rupture, torsion of an ovarian cyst or tumor pedicle, acute appendicitis, acute pelvioperitonitis, and other surgical pathologies [7], [17].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: In aborted tubal pregnancy of the tubal abortion type, an atypical clinical picture may occur – masked clinical symptoms: slow development of the abortion presentation, absence of an acute onset of the disease. Any form of ectopic pregnancy, as well as suspicion thereof, requires inpatient monitoring and treatment.
In cases of pregnancy of unknown location, according to the pathomorphological examination of the uterine cavity scrapings, the absence of chorionic villi in the specimen in the presence of a decidual reaction and/or the Arias-Stella phenomenon may indicate an ectopic pregnancy.
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1 Surgical treatment of tubal pregnancy
Surgical treatment is the main method of treatment for any form of ectopic pregnancy. The extent and approach are determined based on the clinical situation and the conditions of the performed surgery [7], [20]. Surgical treatment is performed for both disrupted and progressive tubal pregnancies [2], [10], [12].
It is recommended to perform surgical treatment of tubal pregnancy via laparoscopic or laparotomic approaches [33].
GCR BLEL 2Grade of Recommendation B (Level of Evidence – 2).
Comments: Laparotomic salpingectomy or salpingostomy with removal of the gestational sac (according to the NOM - Removal of the gestational sac from the fallopian tube) is performed depending on the clinical situation, visual assessment of the degree of tubal destruction, the state of the contralateral fallopian tube, and reproductive plans [2], [7], [10].
In the presence of hemorrhagic shock, the laparotomy method is advisable as a method contributing to faster hemostasis [34]. However, if the patient is hemodynamically stable, a laparoscopic approach to the surgical treatment of ruptured tubal pregnancy is preferable to open surgery, provided technical feasibility, hospital tier, and the availability of an appropriate specialist [7], [34], [17], [35].
Laparoscopic interventions contribute to rapid rehabilitation, reduce the duration of hospitalization, and provide a better cosmetic result [35].
In the presence of a healthy contralateral fallopian tube, salpingectomy is preferred [2]. Informed voluntary written consent of the patient must be obtained for the removal of the fallopian tube. However, the final choice is determined by the conditions and clinical situation.
Indications for salpingectomy: 1) disrupted tubal pregnancy; 2) recurrent tubal pregnancy in a previously operated fallopian tube; 3) primary treatment method for progressive tubal pregnancy.
Salpingostomy may be performed under the following conditions: 1) absence of a rupture of the gestational sac wall, 2) absence of hemorrhagic shock, 3) the need to preserve reproductive function, 4) in patients with a history of infertility, tubal-peritoneal risk factor for reproductive disorders (ectopic pregnancy, absence or disease of the contralateral fallopian tube, previous abdominal surgeries, history of pelvic inflammatory disease) combined with the desire to preserve reproductive function [7]. Informed voluntary written consent of the patient must be obtained for salpingostomy.
The patient must be informed about the need for dynamic monitoring after salpingostomy (assay of serum human chorionic gonadotropin (free beta-subunit), comprehensive pelvic ultrasound (transvaginal and transabdominal)) due to the potential for pregnancy progression, development of intra-abdominal hemorrhage, and recurrent ectopic pregnancy in the preserved tube [7].
3.2. Diagnostics at the treatment stage
It is recommended to test serum human chorionic gonadotropin (free beta-subunit) levels after salpingostomy (removal of the gestational sac from the fallopian tube) within 7 days after surgical treatment of ectopic pregnancy, and then once a week until a negative result is obtained to monitor treatment efficacy [9].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).
Comments: The lack of a decrease in blood beta-hCG levels or its concentration above 3000 IU/L and the presence of active blood flow in the fallopian tube in the postoperative period are signs of progressive pregnancy (non-radical removal of the gestational sac during salpingostomy or the presence of a pregnancy of another location) [7].
3.3 Conservative treatment of tubal pregnancy.
It is recommended for the conservative treatment of tubal pregnancy (as an alternative method), by decision of a medical board in Tier 3 hospitals, to administer a single dose of #methotrexate** in hemodynamically stable women planning to realize reproductive function, provided the patient is willing to undergo dynamic monitoring [36], [28], [37].
GOM ALOE 1Grade of Recommendation A (Level of Evidence – 1).
Comments: Conservative treatment is drug therapy with #methotrexate** or #methotrexate** in combination with folinic acid (according to the ATC - Detoxicants for antineoplastic treatment) used in accordance with ACOG (2018); RCOG (2016) recommendations [7], [11], [38]. In the Russian Federation, the instructions for use of #methotrexate** do not provide for indications and treatment regimens for ectopic pregnancy; therefore, its use can only be considered as an alternative to organ-removing surgery when planning to preserve reproductive function after a decision by a medical commission exclusively in gynecological departments of Tier 3 medical organizations, and after obtaining the patient's informed voluntary consent. The choice of conservative tactics is decided collectively (by a medical board).
Candidates for #methotrexate** treatment: *hemodynamic stability; *low serum beta-hCG (up to 5000 IU/L); *absence of embryonic cardiac activity on ultrasound; *certainty of the absence of intrauterine pregnancy; *patient willingness for subsequent monitoring; *absence of hypersensitivity to #methotrexate** [2], [36].
Contraindications to #methotrexate** administration: *hemodynamically unstable patients, *presence of intrauterine pregnancy, *chronic liver diseases, *chronic lung diseases, *immunodeficiency, *peptic ulcer disease, *blood disorders (severe anemia, leukopenia, thrombocytopenia), *hypersensitivity to #methotrexate**, *inability to monitor, etc. [3].
Relative contraindications to the use of #methotrexate** (due to reduced efficacy) include: high initial beta-hCG level above 5000 IU/L, and gestational sac diameter greater than 4 cm [3].
On the first day, an injection of #methotrexate** is administered at a dose of 50 mg/m2 intramuscularly or intravenously. Beta-hCG levels are monitored on days 4 and 7. If the beta-hCG level decreases by less than 15% over 4–7 days, a repeat transvaginal sonography and #methotrexate** 50 mg/m2 are performed if there are signs of ectopic pregnancy. If the beta-hCG level decreases by more than 15% over 4–7 days, beta-hCG tests are repeated once a week until the level drops below 15 IU/L. To minimize adverse effects of #methotrexate**, folinic acid (ATC: Detoxifying agents for antineoplastic treatment) is administered at 6 mg daily. The use of #methotrexate** does not rule out subsequent surgical treatment [39], [40].
The NICE clinical guideline (2019) recommends #methotrexate** as a first-line treatment for women managed in an outpatient setting (electively), which ensures careful monitoring and timely detection of potential complications during follow-up, provided that they meet the following criteria [9]: no significant pain; progressive ectopic pregnancy with a gestational sac diameter of less than 35 mm and no visible heartbeat on ultrasound; serum beta-hCG level between 1,500 and 5,000 IU/L; and no intrauterine pregnancy (as confirmed by ultrasound).
It is not recommended to prescribe #methotrexate** at the initial visit before the diagnosis of ectopic pregnancy is definitively confirmed, except in cases where the diagnosis of ectopic pregnancy is established and a viable intrauterine pregnancy has been ruled out [7].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to administer anti-Rhesus Rh0(D) human immunoglobulin** to Rhesus-negative women with a confirmed ectopic pregnancy in accordance with the product instructions to prevent Rhesus alloimmunization [3], [7], [38], [41].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: Patients with Rhesus-negative blood and a miscarried ectopic pregnancy have a high risk of alloimmunization—fetal cells are detected in maternal blood in 25% of cases [7], [41].
3.4 Treatment of Rare Forms of Ectopic Pregnancy.
Surgical treatment of rare forms of ectopic pregnancy must be performed in Level 3 hospitals (hospitals providing specialized, including high-tech, medical care to women during pregnancy and developing new diagnostic and treatment methods for obstetric and gynecological conditions) due to the high risk of surgical complications, as well as intra- and postoperative complications [2], [42].
Surgical treatment is recommended for cervical pregnancy due to the high risk of life-threatening hemorrhage for the patient (absolute indication) [17], [43], [44], [45], [46].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: Surgical treatment for cervical pregnancy can be either fertility-preserving or a total hysterectomy. The scope of surgery and surgical access depend on the clinical situation, hemodynamic stability, degree of trophoblast invasion, age, and reproductive plans. Hysteroresectoscopic removal of the gestational sac combined with cytostatic therapy using #methotrexate** and folinic acid (ATC: Detoxifying agents for antineoplastic treatment), and in some cases uterine artery embolization, preserves reproductive function and avoids hysterectomy.
Dynamic monitoring of the patient's condition is recommended following hysteroresectoscopic removal of the gestational sac combined with cytostatic therapy using #methotrexate** – testing for chorionic gonadotropin (beta-subunit), complete blood count, general biochemical blood test, and coagulogram (exploratory hemostasis screening), performed every 2–3 days before surgery and for 7 days until beta-hCG levels decrease and paraclinical parameters normalize [43], [44], [45], [47].
Level of Recommendations CLevel of Evidence 4Level of recommendations C (Level of evidence – 4).
Comments: The evaluation of patients with cervical pregnancy may include pelvic MRI and ultrasound with color Doppler mapping [43].
It is recommended to perform surgical treatment in patients with a cesarean scar pregnancy [7], [9].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: In cases of cesarean scar pregnancy, either fertility-preserving surgery (hysteroresectoscopy, removal of the gestational sac; in cases of pronounced destructive changes in the uterine wall at the scar site, laparotomic metroplasty is indicated if fertility preservation is desired) or a fertility-sacrificing surgery—total hysterectomy (if no further pregnancies are planned)—can be performed [2]. In patients with a cesarean scar pregnancy, surgical intervention combined in some cases with uterine artery embolization can be performed, which preserves reproductive function and avoids hysterectomy [28]. In the postoperative period, serial serum chorionic gonadotropin (free beta-subunit) levels must be monitored (in cases of fertility-preserving surgeries).
The choice of treatment method depends on the gestational age, hemodynamic stability, condition of the scar and uterine wall, and the patient's age.
It is recommended to perform the removal of a rudimentary uterine horn or wedge resection of the uterine cornu in pregnancy within a rudimentary horn via laparotomy or laparoscopy with subsequent uterine reconstruction to preserve reproductive function [2], [7], [48].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
It is recommended to perform ovarian resection and/or oophorectomy and/or salpingo-oophorectomy in cases of ovarian pregnancy (depending on the location and degree of destructive changes) via laparotomic or laparoscopic access (using video-endoscopic technologies) for therapeutic purposes [7].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to resect the organ where the pregnancy implanted, depending on the gestational age and the size of the gestational sac; in advanced pregnancies, abdominal delivery with umbilical cord ligation close to the placenta should be performed to prevent hemorrhage [26].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: It is necessary to include allied specialists in the surgical team.
It is recommended to perform hysteroresectoscopic and/or laparoscopic removal of the gestational sac from the fallopian tube in cases of interstitial tubal pregnancy (when feasible and in the absence of bleeding) with the goal of preserving reproductive function [49], [50].
GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).
Comments: In some cases, when preserving reproductive function is necessary, hysterotomy (via laparotomic or laparoscopic access) with removal of the gestational site (including curettage or vacuum aspiration) followed by serial postoperative serum chorionic gonadotropin (free beta-subunit) monitoring may be considered as a treatment method for interstitial tubal and wall (intramural) pregnancy [2].
4. Medical Rehabilitation and Sanatorium-Resort Treatment
In the postoperative period, a physical therapist consultation is recommended to determine the appropriateness and select rehabilitation methods [48].
LoR CGoE 5Level of Recommendation C (Grade of Evidence - 5)
5. Prevention and Dispensary Observation
At the level of primary specialized healthcare, it is indicated to identify women at risk: those with sexually transmitted infections, a history of tubal surgery, a history of ectopic pregnancy, chronic inflammatory diseases of the uterine appendages, and tubal-peritoneal infertility [51].
6. Organization of Medical Care
All patients with a suspected ectopic pregnancy must be transported by an ambulance crew. Self-transportation is not permitted.
If hemorrhagic shock is identified at the pre-hospital stage, the receiving hospital should be notified in advance so that preparations can be made for surgical treatment and intensive care.
If the patient's condition is severe due to hemorrhagic shock, she must be hospitalized in the nearest surgical department.
Upon admission to the hospital in the presence of hemorrhagic shock, the patient must be transferred directly to the operating room.
If cervical ectopic pregnancy is suspected, a speculum and bimanual pelvic examination must be performed in a fully equipped operating room (it is not performed at the pre-hospital stage or in the hospital admission ward).
Upon admission to the inpatient facility, the mandatory emergency examination algorithm in accordance with the Order of the Russian Ministry of Health dated October 20, 2020, No. 1130n includes: complete blood count (CBC), determination of antibodies to Treponema pallidum in the blood, determination of human immunodeficiency virus HIV-1 IgM and IgG antibodies in the blood, determination of human immunodeficiency virus HIV-2 IgM and IgG antibodies in the blood, determination of hepatitis B virus surface antigen (HBsAg) in the blood, determination of antibodies to hepatitis C virus in the blood, coagulogram (exploratory hemostasis assessment), general general-practice blood biochemistry assay, determination of ABO blood groups and Rh factor (D antigen), determination of human chorionic gonadotropin (free beta-subunit) levels in blood serum, ECG (in the absence of massive bleeding), urinalysis.
Criteria for patient discharge: Clinical recovery.
7. Additional Information
The prevalence of ectopic pregnancy in ART programs is approximately 2.5%, which is comparable to the incidence of ectopic pregnancies following natural conception in the general female population (1-2%) [52], [24], [53].
To date, ectopic pregnancy ranks second among acute gynecological conditions and first – among nosological entities accompanied by intra-abdominal bleeding.
7.1 Anesthesia and intensive care
It is recommended that patients with ectopic pregnancy and massive blood loss adhere to the following principles to stop bleeding and stabilize their condition:
— the damage control principle (obstetrician-gynecologist, surgeon),
— the resuscitation control principle (anesthesiologist-intensivist),
— the hemostasis control principle (anesthesiologist-intensivist, transfusiologist) [54], [55].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments:
Assessment of blood loss severity and coagulopathy
To assess the severity of blood loss, the American College of Surgeons Advanced Trauma Life Support (ATLS) scale (Appendix G1) is traditionally used [39].
Definition of massive blood loss:
— Blood loss exceeding 30% of circulating blood volume (CBV) or 1.5 L
— Bleeding exceeding 150 mL per minute with the loss of more than half of the CBV
— Systolic blood pressure below 90 mm Hg and/or the use of vasopressors (according to the Anatomical Therapeutic Chemical (ATC) classification – Adrenergic and dopaminergic agents) in suspected hemorrhagic shock
— Replacement of 50% of CBV within three hours
— Replacement of one CBV within 24 hours
— Need for transfusion of more than 4 units of red blood cells within 1 hour and anticipated ongoing transfusion
— Anticipated transfusion of more than 10 units of red blood cells within 24 hours
In patients with ectopic pregnancy, in addition to standardized laboratory tests—coagulogram (exploratory hemostasis assessment) (fibrinogen, INR, APTT), complete blood count (CBC), determination of blood D-dimer concentration—it is advisable to use thromboelastography/tromboelastometry (TEG/ROTEM) to diagnose DIC syndrome (coagulopathy), which provides monitoring of the hemostatic system during bleeding [56], [57], [58], [59], [60], [61]. See Appendix A3.7.
In an emergency situation, it is necessary to use the generally accepted set of laboratory tests for assessing the hemostatic system [62], [63], [64], [65], [66] to enable prompt decision-making regarding replacement therapy (Appendix G2 Scale for diagnosing overt (bleeding) DIC syndrome).
The severity of DIC syndrome during blood loss is assessed using the generally accepted International Society on Thrombosis and Haemostasis 2001 scale (Appendix G2) [47]–[50].
Basic intensive care methods
Prehospital stage interventions:
At the prehospital stage, for a patient with bleeding due to ectopic pregnancy, the primary intervention is medical evacuation to the nearest healthcare facility capable of providing surgical treatment and ensuring the "damage control" principle [54], [67]. Any diagnostic and therapeutic measures must not prolong the time of medical evacuation to the stage of surgical hemostasis [54], [55], [68], [69]. If hemorrhagic shock is identified, the receiving hospital where the patient will be hospitalized must be notified in a timely manner to prepare for surgical treatment and intensive care.
The following must be performed at the prehospital stage:
Clinical assessment of blood loss (skin color and temperature, microcirculatory disorders, mucous membranes, blood pressure [via medical service nomenclature - Measurement of blood pressure on peripheral arteries], heart rate [via medical service nomenclature - Measurement of heart rate]).
Peripheral vein catheterization and initiation of infusion therapy: crystalloids (per ATC – Solutions affecting the water-electrolyte balance) 500 mL [8]. See Appendix A3.4.
In cases of baseline arterial hypotension (systolic blood pressure below 90 mm Hg), it is inadvisable to raise blood pressure above 100 mm Hg prior to stopping the bleeding.
In severe hemorrhagic shock and ineffective infusion therapy (no increase in blood pressure), the use of vasopressors (per ATC - Adrenergic and dopaminergic agents) is permissible.
Hemostatic therapy includes the intravenous administration of 1 g of tranexamic acid** upon suspicion or diagnosis of massive blood loss and hemorrhagic shock [54], [70].
Oxygen inhalation or, as clinically indicated, respiratory therapy (ranging from non-invasive to invasive mechanical ventilation) must be ensured.
Medical evacuation to the hospital is carried out on a gurney.
Medical evacuation of patients with ongoing bleeding (or suspected bleeding) to another hospital is contraindicated.
Upon admission to the hospital admission ward:
All measures listed above are performed (if not completed at the prehospital stage).
A patient with internal bleeding (or suspected bleeding) must undergo rapid clinical, laboratory (complete blood count [CBC], determination of prothrombin time in blood or plasma, determination of international normalized ratio [INR], coagulogram [exploratory hemostasis assessment], thromboelastography/thromboelastometry), and functional (ultrasound – comprehensive pelvic ultrasound [transvaginal and transabdominal] examinations to assess the severity of blood loss [Table 1] [54], [71]) evaluations, and the need for surgical treatment must be determined.
If the patient's condition is severe—grade III and IV hemorrhagic shock—all examinations are performed in the operating room simultaneously with ongoing intensive care.
The primary objective in treating blood loss and hemorrhagic shock: stopping the bleeding!
In any situation, the time between diagnosis and the initiation of surgical hemostasis must be minimized, and this principle is critically important to strictly observe at both the prehospital and hospital stages of care. Surgical treatment must be initiated under any conditions—hemorrhagic shock, DIC syndrome, etc.—and no circumstances can prevent surgical hemostasis [54]. Gynecological and surgical inpatient departments of any tier (from first to third) must be prepared to provide emergency surgical care and ensure conservative hemostasis.
In severe hemorrhagic shock and technical difficulties with surgical hemostasis, it is necessary to use the “damage control surgery” principle, which includes the following stages:
Stage 1 – obstetrician-gynecologist, surgeon: following laparotomy, bleeding is stopped by any means: compression, application of clamps, ligatures, packing, or even aortic cross-clamping.
Stage 2 – anesthesiologist-intensivist: stabilization of basic body functions, which occurs significantly faster and more effectively once bleeding has stopped than under conditions of ongoing bleeding.
Stage 3 – after the resolution of shock, the obstetrician-gynecologist, in a clinically stable situation, provides the definitive surgical hemostasis required for the case [35], [72], [73].
During intensive care for massive blood loss, the principle of “damage control resuscitation” must be observed [67], [74], [75], [76].
In the acute period—at the peak of blood loss—infusion therapy is required to control cardiac output and restore circulating blood volume [67], [74], [75], [76], [77], [78], [79], [80], [81].
In the acute period at the peak of blood loss, cardiac output and organ perfusion can be supported only by the infusion of plasma volume expanders (ATC: Blood substitutes and perfusion solutions). Restoration of blood volume and maintenance of cardiac output are primarily ensured (starting solution) by crystalloids (ATC: Solutions affecting the water-electrolyte balance) – optimally polyelectrolyte and balanced solutions (Table 4), and if ineffective, by synthetic (hydroxyethyl starch** and/or modified gelatin) and/or natural (human albumin** (ATC: Blood substitutes and plasma protein fractions)) colloids (see Appendix A3.5) [8], [77], [78]. In massive blood loss and hemorrhagic shock, infusion therapy at a volume of 30–40 ml/kg should be administered at the maximum possible rate. Crystalloids (ATC: Solutions affecting the water-electrolyte balance) should be used either solely in combination with blood components (ATC: Blood and blood products) or in a volume 3 to 4 times exceeding the volume of synthetic colloids plus blood components (ATC: Blood and blood products).
When blood loss is up to 1500 ml and bleeding has ceased, infusion therapy is administered in a restrictive mode and, together with blood components, should not exceed 200% of the blood loss volume. The starting solution is a crystalloid (ATC: Solutions affecting the water-electrolyte balance), and if ineffective, synthetic colloids (ATC: Blood substitutes and plasma protein fractions). Blood components are used only in case of confirmed coagulopathy (fibrinogen less than 1.0 g/l, INR, aPTT greater than 1.5 times the upper limit of normal, platelets less than 50,000/µl, hypocoagulation on TEG/ROTEM) and ongoing bleeding.
In massive, critical blood loss, along with infusion therapy, it is necessary to follow the massive transfusion protocol [82], [83], [84], [85], [86], [87], [88], [89].
In massive, critical blood loss exceeding 1500–2000 ml, along with infusion therapy, the massive transfusion protocol [82], [83], [84], [85], [86], [87] must be initiated as early as possible (within minutes) by starting the administration of blood components (fresh frozen plasma, packed red blood cells, platelets, and #coagulation factor VIII**) even without laboratory confirmation, since the infusion of plasma expanders alone (ATC: Blood substitutes and plasma protein fractions) in a volume greater than 30–40 ml/kg at such a volume of blood loss already causes dilutional coagulopathy and increases blood loss, the incidence of multiple organ failure, and mortality [74], [77], [90], [91], [92].
Hypervolemia with crystalloids (ATC: Solutions affecting the water-electrolyte balance) or colloids (ATC: Blood substitutes and plasma protein fractions) exceeding the steady-state interstitial space and optimal cardiac preload should be avoided [91], [92], [93].
In this situation, the use of coagulation factor concentrates or individual factors significantly reduces the time required to correct coagulopathy.
Hemodynamic parameters are regulated, when necessary, by the early use of vasopressors (ATC: Adrenergic and dopaminergic agents) (norepinephrine**, epinephrine**, dopamine**, phenylephrine**).
In ongoing bleeding and arterial hypotension, systolic blood pressure should not be raised above 90–100 mm Hg, as this will lead to increased bleeding. The optimal mean arterial pressure is 65 mm Hg [74].
Perioperative normothermia should be maintained, as this measure reduces blood loss and transfusion requirements.
Central venous pressure should not be used to select the volume of infusion therapy and optimize preload in severe bleeding [78]: instead, dynamic assessment of fluid responsiveness and non-invasive cardiac output measurement should be considered [94].
When blood loss exceeds 30–40% of the circulating blood volume, correction of hypocalcemia will be required [54].
Use of blood components and the "hemostatic control" principle
Blood components are used in accordance with Order No. 797 of the Russian Ministry of Health dated June 22, 2019, "On approval of the Rules for the procurement, storage, transportation, and clinical use of donor blood and its components and on invalidating certain acts of the Government of the Russian Federation".
When bleeding has ceased, blood transfusion is performed at a hemoglobin level of less than 70 g/l, but indications are determined individually [95], [96], [97], [98].
There are no indications for blood transfusion when hemoglobin is above 100 g/l. In general, indications for red blood cell transfusion are based on the nature of the underlying disease, symptoms of impaired oxygen delivery, and laboratory parameters.
The optimal option for correcting anemia is intraoperative autologous blood salvage. The use of intraoperative cell salvage reduces the volume of postoperative transfusion and shortens hospital stay [95], [98], [99], [100].
The "coagulation control" principle in blood loss. Conservative hemostasis in blood loss should include (see Appendix A3.6):
Antifibrinolytics (ATC: Antifibrinolytic agents) (tranexamic acid**).
Blood components (ATC: Blood and blood products): fresh frozen plasma, cryoprecipitate, platelet concentrate, and coagulation factors (factor concentrates).
Specific features of the use of blood components (ATC: Blood products) are presented in Tables 6 and 7 [77], [82], [83], [84], [85], [86], [87], [95], [96], [98], [101].
The advantages of coagulation factors and factor concentrates include [95], [96], [102], [103], [104]:
— Ability to administer immediately (outperforming the effect of fresh frozen plasma by 30–40 min)
— For #eptacog alfa (activated)** – more localized action at the site of injury (The dose is selected individually, the recommended starting dose is 90 µg/kg) [38], [105], [106].
— Immunological and infectious safety
— Reduced amount of replacement therapy products (fresh frozen plasma, coagulation factor VIII**, platelet concentrate, red blood cells).
— Reduced incidence of transfusion-related acute lung injury (TRALI)
— Administration of antithrombotic agents
There is no evidence base regarding the hemostatic effect of etamsylate**, menadione sodium bisulfite**, and calcium chloride.
Anesthetic management
As the method of choice in massive blood loss and hemorrhagic shock, general anesthesia with mechanical ventilation is performed [79], [81], [80].
After surgery, prolonged mechanical ventilation is indicated:
— In unstable hemodynamics with a tendency to arterial hypotension (systolic BP less than 90 mm Hg, need for vasopressors (ATC: Adrenergic and dopaminergic agents)) – insufficient restoration of blood volume.
— Ongoing bleeding.
— Hemoglobin level less than 70 g/l and the need to continue blood transfusion.
— Mixed venous oxygen saturation less than 70%.
— Persistent coagulopathy (INR and aPTT more than 1.5 times the upper limit of normal, fibrinogen less than 1.0 g/l, platelet count less than 50,000/µl) and the need for replacement therapy.
The duration of mechanical ventilation depends on the rate of achieving the criteria for a positive effect in massive blood loss and hemorrhagic shock.
Treatment goals and the post-hemorrhagic period
With effective cessation of bleeding and intensive care, the criteria for a positive effect in massive blood loss and hemorrhagic shock are achieved within 3–4 hours:
— Absence of hemorrhagic syndrome of any localization, nature, and intensity.
— Systolic blood pressure greater than 90 mm Hg without the use of vasopressors (ATC: Adrenergic and dopaminergic agents), mean arterial pressure greater than 65 mm Hg.
— Hemoglobin level greater than 70 g/l.
— Absence of clinical and laboratory signs of coagulopathy.
— Urine output rate greater than 0.5 ml/kg/h.
— Mixed venous oxygen saturation greater than 70%.
— Restoration of consciousness and adequate spontaneous breathing.
If the goals of treatment for blood loss are not achieved within the next 3–4 hours, and arterial hypotension, anemia, or oliguria persist or recur, it is first necessary to rule out ongoing bleeding: repeat examination, comprehensive ultrasound of the abdominal cavity and pelvic organs (transvaginal and transabdominal).
In the post-hemorrhagic period, the following diagnostic measures should be strongly performed to timely correct potential complications [79], [81], [80]:
— Clinical monitoring of bleeding (arterial hypotension, pallor, oliguria, microcirculatory disorders, drains, and puncture sites).
— Laboratory monitoring – complete (clinical) blood count (hemoglobin, platelets), coagulogram (screening hemostasis test) (fibrinogen, INR, aPTT), thrombelastography/thrombelastometry.
When bleeding has ceased, blood components are used only for absolute indications with laboratory and clinical confirmation of coagulopathy and/or anemia (there is usually a need for red blood cells)
Considering hemodynamic disturbances and blood component transfusion following massive blood loss, pharmacological thromboprophylaxis (heparin group within the first 12 hours provided surgical and conservative hemostasis is certain) and non-pharmacological thromboprophylaxis (elastic compression of the lower extremities, intermittent pneumatic compression of the lower extremities) are absolutely essential [79], [81], [80].
Criteria for Evaluating the Quality of Medical Care
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Appendix A1. Working Group Composition
Leyla V. Adamyan – Academician of the Russian Academy of Sciences, Deputy Director for Research at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health; Head of the Department of Operative Gynecology at the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health; Head of the Department of Obstetrics, Gynecology and Reproductive Medicine at the Russian University of Medicine of the Russian Ministry of Health; Chief freelance Specialist in Gynecology of the Russian Ministry of Health; Vice President of the Russian Society of Obstetricians and Gynecologists (Moscow).
Natalya V. Artymuk – MD, Professor, Head of the Professor G.A. Ushakov Department of Obstetrics and Gynecology at 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 of the Russian Ministry of Health, Board Member of the Russian Society of Obstetricians and Gynecologists, President of the Kemerovo Regional Public Organization "Association of Obstetricians and Gynecologists" (Kemerovo).
Vitaly F. Bezhenar – MD, Professor, Head of the Department of Obstetrics, Gynecology and Neonatology, Department of Obstetrics, Gynecology and Reproductology, Head of the Clinic of Obstetrics and Gynecology at the First Pavlov State Medical University of St. Petersburg of the Russian Ministry of Health. Chief freelance Specialist in Obstetrics and Gynecology of the Health Committee of the Government of St. Petersburg, Board Member of the Russian Society of Obstetricians and Gynecologists.
Tatyana E. Belokrinitskaya – MD, Professor, Head of the Department of Obstetrics and Gynecology of the Faculty of Additional Professional Education at Chita State Medical Academy of the Russian Ministry of Health, Honored Doctor of the Russian Federation, Chief freelance Specialist in Obstetrics of the Russian Ministry of Health, Chief freelance Specialist in Gynecology of the Russian Ministry of Health, Chief freelance Specialist in Women's Reproductive Health in the Far Eastern Federal District (Chita).
Yulia E. Dobrokhotova – MD, Professor, Honored Doctor of the Russian Federation, Honored Worker of Science of the Russian Federation, Laureate of the Government Prize of the Russian Federation, Head of the Department of Obstetrics and Gynecology at the Institute of Clinical Medicine of the Pirogov Russian National Research Medical University.
Stanislav I. Kiselev – MD, Professor of the Department of Obstetrics, Gynecology and Reproductive Medicine at the Russian University of Medicine of the Russian Ministry of Health, City Clinical Hospital No. 15 named after O.M. Filatov.
Andrey V. Kozachenko – MD, Professor of the Russian Academy of Sciences, Leading Researcher at the Department of Operative Gynecology of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health (Moscow).
Denis N. Protsenko – MD, Head of the Department of Anesthesiology and Intensive Care of the Faculty of Additional Professional Education at the Pirogov Russian National Research Medical University, Director of the Kommunarka Moscow Multidisciplinary Clinical Center of the Moscow Healthcare Department, Chief freelance Anesthesiologist-Intensivist of the Moscow Healthcare Department.
Aleksey V. Pyregov – MD, Head of the Department of Anesthesiology and Intensive Care of the V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health (Moscow).
Rogachevsky Oleg Vladimirovich – D.Sc. in Medicine, Leading Researcher at the Department of Blood Gravitational Surgery, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).
Silaev Borislav Vladimirovich - Head of the Anesthesiology and Intensive Care Department, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology; Leading Researcher at the Department of Analysis and Development of Regional Healthcare, National Medical Research Center for Anesthesiology and Intensive Care for Pregnant Women; Ph.D. in Medicine, Associate Professor at the Department of Anesthesiology and Intensive Care, I.M. Sechenov First Moscow State Medical University; Expert in Medical Care Quality, National Medical Research Center for Anesthesiology and Intensive Care for Adults, I.M. Sechenov First Moscow State Medical University.
Suturina Larisa Viktorovna – D.Sc. in Medicine, Professor, Head of the Department of Reproductive Health Protection, Scientific Centre for Family Health and Human Reproduction Problems (Irkutsk).
Filippov Oleg Semenovich – D.Sc. in Medicine, 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 Scientific and Clinical Center of Children and Adolescents of FMBA of Russia, Professor at the Department of Obstetrics, Gynecology and Reproductive Medicine, Russian University of Medicine.
Shifman Efim Munevich – D.Sc. in Medicine, Professor at the Department of Anesthesiology and Intensive Care, Faculty of Advanced Medical Training, Moscow Regional Research Clinical Institute named after M.F. Vladimirsky (MONIKI), President of the Association of Obstetric Anesthesiologists-Intensivists, Presidium Member of SIVA, Honored Doctor of the Republic of Karelia, Expert in Anesthesiology and Intensive Care of the Federal Service for Surveillance in Healthcare (Moscow).
Kulikov Alexander Veniaminovich – D.Sc. in Medicine, Professor at the Department of Anesthesiology, Intensive Care and Transfusiology, Faculty of Advanced Training and Professional Retraining, Ural State Medical University of the Russian Ministry of Health (Yekaterinburg). Member of the Federation of Anesthesiologists and Intensivists and the Association of Obstetric Anesthesiologists-Intensivists.
Tonoyan Narine Marzpetunovna – Obstetrician-Gynecologist, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow).
Yarmolinskaya Maria Igorevna - Head of the Department of Gynecology and Endocrinology, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology; Head of the Center for Diagnosis and Treatment of Endometriosis; Professor at the Department of Obstetrics and Gynecology, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health; Professor of the Russian Academy of Sciences; D.Sc. in Medicine, Professor; President of the Society of Obstetricians and Gynecologists of Saint Petersburg and the North-Western Federal District; Board Member of the Russian Society of Obstetricians and Gynecologists.
Conflict of interest:
All members of the working group declare no conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
Obstetricians-gynecologists,
General physicians,
General practitioners.
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 | There is only a rationale for the mechanism of action or expert opinion |
Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)
LoE | Definition |
|---|---|
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 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) |
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:
Serov V. N., Sukhikh G. T. Clinical Guidelines. Obstetrics and Gynecology // M: GEOTAR-Media. – 4th ed. – 2017. Moscow: Problemy Reproduktsii.
Savelieva G. M. et al. National Guidelines // Obstetrics. – M.: Geotar-Media. – 2015.
Clinical Guidelines of the Russian Society of Obstetricians and Gynecologists (ROAG), approved by the Ministry of Health of the Russian Federation, "Miscarriage (Spontaneous Abortion)". ID: 670. 2024. – 49 p.
Procedure for the Provision of Medical Care to the Adult Population in the Profile "Anesthesiology and Intensive Care", approved by Order of the Ministry of Health of the Russian Federation No. 919n dated 2012.
American College of Obstetricians and Gynecologists et al. ACOG Practice Bulletin No. 193: tubal ectopic pregnancy //Obstet Gynecol. – 2018. – Vol. 131. – No. 3. – P. e91-e103.
Diagnosis and Management of Ectopic Pregnancy Green-top Guideline No. 21 RCOG/AEPU Joint Guideline.
Loss E. P. ACOG Practice Bulletin No. 150: Early Pregnancy Loss. – 2015.
Early pregnancy loss. Queensland Clinical Guideline. MN11.29-V2-R16. 2022
National Clinical Practice Guideline the Diagnosis and Management of Ectopic Pregnancy. Institute of Obstetricians and Gynaecologists, Royal College of Physicians of Ireland and Directorate of Clinical Strategy and Programmes. Health Service Executive №3. 2017
Medical management of ectopic pregnancy. Guideline Summary NGC-6533. 2012
National C. G. C. U. K. Intravenous Fluid Therapy: Intravenous Fluid Therapy in Adults in Hospital. – 2013.
Webster K. et al. Ectopic pregnancy and miscarriage: diagnosis and initial management: summary of updated NICE guidance //Bmj. – 2019. – Vol. 367.
RCOG. The management of tubal pregnancy. RCOG Clinical Guideline No 21.
Guideline No. 414: Management of Pregnancy of Unknown Location and Tubal and Nontubal Ectopic Pregnancies. J Obstet Gynaecol Can. 2021
Appendix A3.1. Clinical presentation is determined by the course of ectopic pregnancy [1].
Clinical course | Symptoms |
|---|---|
By type of gestational sac rupture | · Sudden onset · Abdominal pain – pronounced · Peritoneal signs – markedly positive · Vaginal fornices bulging – pronounced · Sharp tenderness upon cervical motion · Clinical presentation of hemorrhagic shock |
By type of abortion (tubal abortion) | · Abdominal pain mild / absent · Peritoneal signs weakly positive / absent |
Cervical ectopic pregnancy | · Absence of spotting from the genital tract · Scanty spotting from the genital tract · Heavy bleeding from the genital tract (profuse hemorrhage, clinical presentation of hemorrhagic shock) · Pain syndrome is absent in all cases |
Cases of pregnancy of unknown location | · β-hCG level 1000–1500 IU/L in the absence of a gestational sac visualized by transvaginal probe |
Appendix A3.2 Risk factors for ectopic pregnancy [4], [107].
№ | Factor | Risk increase factor (fold) |
|---|---|---|
1 | History of fallopian tube surgery | 21.0 |
2 | Sterilization | 9.3 |
3 | History of ectopic pregnancies | 8.3 |
4 | Intrauterine contraception | 5.0 |
5 | Pelvic inflammatory disease in medical history | 3.4 |
6 | Infertility for 2 years or more | 2.7 |
7 | Maternal age: | |
– over 40 years | 2.9 | |
– 35–39 years | 1.4 | |
8 | Smoking: | |
≥ 20 cigarettes per day | 3.9 | |
10–19 cigarettes per day | 3.1 | |
1–9 cigarettes per day | 1.7 | |
Ex-smokers | 1.5 |
Appendix A3.3 Recommendations for assessing the ratio of β-hCG levels to ultrasound results in clinically stable patients
(Good practice points, Queensland Clinical Guidelines, 2014) [4].
β-hCG and TVS (according to medical service nomenclature – comprehensive pelvic ultrasound (transvaginal and transabdominal)) | Management |
|---|---|
Beta-hCG level less than 2000 IU/L | Repeat comprehensive pelvic ultrasound (transvaginal and transabdominal) and determine beta-hCG level (according to medical service nomenclature – determination of human chorionic gonadotropin (free beta-subunit) level in blood serum) in 48–72 hours |
Beta-hCG level greater than 2000 IU/L i TVS: no intrauterine pregnancy, adnexal enlargement and/or free fluid in the abdominal cavity | High probability ectopic pregnancy |
Beta-hCG level greater than 2000 IU/L i TVS: no intrauterine pregnancy, no pathological changes detected in the abdominal cavity | Repeat TVS and beta-hCG level determination in 48–72 hours |
Decreased or small increase in β-hCG level (diagnostically insignificant) | Non-progressing pregnancy (intrauterine or ectopic) Ensure proper evaluation to clarify the diagnosis and subsequent measures for pregnancy termination |
Appendix A3.4 Characteristics of certain crystalloid solutions (by ATC: Electrolytes) for infusion therapy*
Solution | Content in 1000 ml, mmol/L | Osmo- larity, (mOsm) | |||||
|---|---|---|---|---|---|---|---|
Na | K | Ca | Mg | Cl | Reserve alkalinity carriers | ||
Blood plasma | 136-143 | 3,5-5 | 2,38-2,63 | 0,75-1,1 | 96-105 | - | 280-290 |
Interstitial fluid | 145 | 4 | 2,5 | 1 | 116 | - | 298 |
Sodium chloride** 0.9% | 154 | - | - | - | 154 | - | 308 |
Compound sodium chloride solution [Potassium chloride+Calcium chloride+Sodium chloride]** | 147 | 4 | 6 | 155 | - | 309 | |
Compound sodium lactate solution [Potassium chloride+Calcium chloride+Sodium chloride+Sodium lactate]** | 130 | 4 | 3 | - | 109 | Lactate 28 | 273 |
Potassium chloride+Calcium chloride+Magnesium chloride+Sodium acetate+Sodium chloride | 131 | 4 | 2 | 1 | 111 | acetate 30 | 280 |
Potassium chloride+Calcium chloride+Magnesium chloride+Sodium acetate+Sodium chloride+Malic acid** | 140 | 4 | 2,5 | 1 | 127 | malate 5.0, acetate 24 | 304 |
Potassium acetate+Calcium acetate+Magnesium acetate+Sodium acetate+Sodium chloride | 137 | 4 | 1.65 | 1,25 | 110 | acetate 3.674 | 291 |
Potassium chloride + Magnesium chloride + Sodium acetate + Sodium gluconate + Sodium chloride | 140 | 5 | - | 1,5 | 98 | Malate, acetate 27 each | 294 |
– Note: * - Other crystalloids may also be used if available (according to ATC – Solutions affecting the water-electrolyte balance)
Appendix A3.5 Characteristics of synthetic colloids* (according to ATC – Plasma substitutes and plasma protein fractions)
Indicator | Modified gelatin** | HES** 6% |
|---|---|---|
Molecular weight (Mw), Da | 45000 | 130000 |
Molar substitution (Ds) | 0,42/0,4 | |
Osmolarity, mOsm/L | 320 | 308/308 |
COP, mmHg | 33 | 36/36 |
Volumizing effect, % | 100 | 100/100 |
Duration of volume effect, h | 3-4 | 4-6/6 |
Maximum dose, mL/kg/day | 200 | 50/50 |
Effect on coagulation | 0 + | 0 + |
Note: Hydroxyethyl starch preparations** are used only at the height of shock and hypovolemia at a dose of no more than 30 mL/kg. Infusion must be discontinued once hemodynamics are stabilized.
Appendix A3.6 Doses of drugs for conservative hemostasis in acute hemostatic disorders
Drug | Dose |
|---|---|
Fresh frozen plasma | 15-20 mL/kg body weight |
Coagulation factor VIII** | 1 unit per 10 kg of body weight (Dose and duration of therapy depend on the degree of factor VIII deficiency, location and severity of bleeding, as well as the patient's objective condition) |
Platelet suspension | 1 unit per 10 kg of body weight |
Platelet concentrate | 1-2 units |
Prothrombin complex concentrate | In acute bleeding 50 IU/kg; if no effect is observed within 20 minutes, repeat at the same dose. |
#Coagulation factor VII** | 90 mcg/kg, repeated every 3 h if necessary |
Tranexamic acid** | 15 mg/kg IV followed by continuous infusion until bleeding stops |
Appendix A3.7 Management of clinical and laboratory parameters of coagulopathy and DIC syndrome
Parameter change | Value | Correction | Target value |
|---|---|---|---|
Platelets less than 50×109/L | Main component of the thrombus | Platelet suspension (ATC – Blood and blood products) Platelet concentrate (ATC – Blood and blood products) | More than 50×109/L |
Fibrinogen less than 1.0 g/L | Main component of the thrombus | Fibrinogen concentrate, coagulation factor VIII**, fresh frozen plasma (FFP) – ATC: Blood and blood products | More than 1.0 g/L Optimally more than 2.0 g/L |
aPTT more than 1.5 times the upper limit of normal | Decreased levels of intrinsic pathway factors Effect of heparin | FFP (ATC – Blood and blood products), coagulation factor VII** (ATC – Blood coagulation factors) Inactivation of heparin with protamine sulfate** | Normal |
INR more than 1.5 times the upper limit of normal | Decreased levels of extrinsic pathway factors Effect of VKAs (Warfarin**) | FFP (ATC – Blood and blood products), Coagulation factors II, VII, IX, and X in combination [Prothrombin complex]** | No more than 1.3 |
Hypocoagulation on TEG/ROTEM | Platelet and/or coagulation factor deficiency. Effect of antiplatelet agents (ATC – Antithrombotic agents: antiplatelet agents excluding heparin) or antithrombotic drugs | All available Blood and blood products or antidotes depending on the cause. Antifibrinolytic agents | Normocoagulation or hypercoagulation |
Diffuse bleeding | Cessation of bleeding |
Appendix A3.8 Epidemiology and characteristics of various types of EP [13]
Ectopic pregnancy type | Description | Incidence | Characteristics |
|---|---|---|---|
Tubal | Implantation of the ovum in the fallopian tube | 95% | – |
Interstitial | Implantation in the interstitial part of the fallopian tube with invasion into the myometrium of the uterine fundus | 2%–4% | May manifest in late pregnancy 1 |
Cesarean scar | Implantation into the anterior wall of the lower uterine segment within a previous cesarean section scar | <1% | Treatment has high efficacy and a high complication rate |
Heterotopic | Combined intrauterine pregnancy (IUP) and ectopic pregnancy | 1%–3% | Difficult to manage if it is necessary to preserve the IUP |
Cervical | Implantation into the endocervical canal mucosa | <1% | Dilation and curettage in a previous pregnancy in 70% of cases |
Ovarian | Ovarian implantation | <3% | Associated with IUD use in 81% of cases |
Abdominal | Abdominal implantation | ~1% | There are reports of several cases of term delivery of healthy infants |
Appendix A3.9 Clinical classification of cesarean scar pregnancy [108]
A – C. Type I. Implantation of the gestational sac into a previous Cesarean scar with an anterior myometrial thickness of more than 3 mm, regardless of the size of the gestational sac.
D – F. Type IIa. Anterior myometrial thickness of 1 to 3 mm and mean diameter of the gestational sac or mass of 30 mm or less.
G – I. Type IIb. Anterior myometrial thickness of 1 to 3 mm and mean diameter of the gestational sac or mass greater than 30 mm.
J – L. Type IIIa: the gestational sac bulges beneath the Cesarean scar with an anterior myometrial thickness of 1 mm or less and a mean diameter of the gestational sac or mass of 50 mm or less.
M – O. Type IIIb. With an anterior myometrial thickness of 1 mm or less and a mean diameter of the gestational sac or mass greater than 50 mm.
Appendix B. Physician Action Algorithms
Single-dose regimen algorithm for #methotrexate** (RCOG (2016)), [12].
Appendix C. Patient Information
Ectopic pregnancy is a pathological pregnancy condition in which the fertilized ovum implants outside the uterine cavity. Ectopic pregnancy is classified as a high-risk condition for a woman's health and can be fatal without medical intervention.
At the slightest suspicion of an ectopic pregnancy, immediate referral to a gynecology department is required.
According to statistics, the increasing incidence of ectopic pregnancy is associated with a rise in inflammatory diseases of the internal genitalia, an increase in the number of surgical procedures for birth control, the use of IUDs, the treatment of certain forms of infertility, and assisted reproductive technologies.
In cases of delayed diagnosis and without adequate treatment, ectopic pregnancy can be life-threatening for a woman. Furthermore, ectopic pregnancy can lead to infertility. Every 4th patient develops a recurrent ectopic pregnancy, every 5th to 6th develops pelvic adhesions, and 3/4 of women develop secondary infertility after surgical treatment.
Prevention of ectopic pregnancy is impossible, but regular visits to an obstetrician-gynecologist can reduce the risk of a fatal outcome. Pregnant women in the high-risk category should undergo a comprehensive evaluation to rule out delayed identification of an ectopic pregnancy.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Appendix G1. Assessment of blood loss severity
Russian title: Assessment of blood loss severity.
Source (official developer website, validated publication): American College of Surgeons Advanced Trauma Life Support (ATLS).
Type (underline): rating scale
Purpose: To assess the severity of blood loss.
Content (template): The table consists of 5 columns: the left column lists the parameters being evaluated, and columns 2–5 indicate the severity grades of blood loss.
Indicator | Grade I | Grade II | Grade III | Grade IV |
|---|---|---|---|---|
Blood loss, mL | <750 | 750–1500 | 1500–2000 | >2000 |
Pulse, bpm | <100 | ≥100 | >120 | >140 |
Blood pressure | normal | normal | decreased | decreased |
Pulse pressure, mm Hg | normal | decreased | decreased | decreased |
Respiratory rate, per min | 14–20 | 20–30 | 30–40 | >40 |
Diuresis, mL/h | >30 | 20–30 | 5–15 | Anuria |
Consciousness | Mild anxiety | Moderate anxiety | Anxiety, confusion | Drowsiness |
Key: The severity of blood loss is determined based on the indicators (volume of blood loss, hemodynamic parameters, respiratory rate, diuresis, consciousness).
Notes: The obtained data allow for assessing the severity of blood loss.
Appendix G2. Scale for diagnosing overt (bleeding) DIC syndrome
Russian title: Diagnostic scale for overt (bleeding) DIC syndrome.
Source (official developer website, validated publication): Assessment of DIC severity in blood loss is performed using the standard International Society on Thrombosis and Haemostasis scale, 2001 [47]–[50]
Type (underline): rating scale
Purpose: Diagnosis of DIC syndrome
Content (template): The table consists of 2 columns: column 1 lists the parameters being evaluated, and column 2 indicates the scores corresponding to these parameters.
Does the patient have an underlying disease associated with DIC?
If yes, proceed to the scale:
Parameter | Points |
|---|---|
Platelet count greater than 100*109 50-100*109 less than 50*109 | 0 1 2 |
Soluble fibrin monomers / fibrin degradation products No increase Moderate increase Significant increase | 0 2 3 |
Prolongation of prothrombin time Less than 3 s 3 to 6 s More than 6 s | 0 1 2 |
Fibrinogen More than 1 g/L Less than 1 g/L | 0 1 |
Total score > 5 – overt DIC | |
Key: The severity of blood loss is determined based on the parameters (platelet count, soluble fibrin monomers, prothrombin time prolongation, fibrinogen).
Notes: A total score of more than 5 is an absolute indication for replacement therapy with blood components and coagulation factors (factor concentrates).
When diagnosing DIC syndrome with clinical bleeding, there are absolute indications for replacement therapy with blood components and coagulation factors (factor concentrates).