List of Abbreviations
PID | pelvic inflammatory disease |
|---|---|
IM | infected miscarriage |
STI | sexually transmitted infections |
CRL | crown-rump length |
EM | early pregnancy loss |
RPL | recurrent pregnancy loss |
FHR | palpitations |
TM | threatened miscarriage |
ultrasound | ultrasound examination |
CA | chromosomal aneuploidy |
CH | chorionic gonadotropin |
Cx | cervix |
Terms and Definitions
Anembryony is a condition in which the gestational sac and its structures develop, but an embryo fails to form and is not visualized on ultrasound examination (ultrasonography).
Biochemical pregnancy is a pregnancy diagnosed solely by detecting chorionic gonadotropin (CG) in blood serum or urine.
Clinical pregnancy - a pregnancy diagnosed by visualization of one or more gestational sacs/embryos on ultrasound, or by the presence of definitive clinical signs of pregnancy. The term applies to both intrauterine and ectopic pregnancies.
Pregnancy of unknown (unclear) location is the absence of signs of intrauterine or ectopic pregnancy on ultrasound with a positive urine pregnancy test or blood test for the β-subunit of CG.
Pregnancy of uncertain (unclear) viability is an intrauterine pregnancy in which the mean internal diameter of the gestational sac is <20 mm on ultrasound, or the yolk sac and/or embryo are not visualized, or the crown-rump length (CRL) of the embryo is <6 mm in the absence of embryonic heart rate (FHR).
Miscarriage (spontaneous abortion) is the spontaneous termination of pregnancy (expulsion or extraction of the embryo/fetus) prior to 22 weeks of gestation.
Infected (septic) miscarriage (IM) is a miscarriage accompanied by signs of infection/inflammation of the reproductive system organs.
Inevitable miscarriage is an irreversible state of pregnancy loss in which the gestational sac/fetus is in the process of being expelled from the uterine cavity.
Incomplete miscarriage is the incomplete expulsion of the gestational sac/fetus from the uterine cavity.
Complete miscarriage is the complete expulsion of the gestational sac/fetus from the uterine cavity.
Recurrent miscarriage (RPL) is defined as the occurrence of two or more consecutive spontaneous pregnancy losses prior to 22 weeks of gestation.
Threatened miscarriage (TM) is a condition of a developing pregnancy up to 22 weeks characterized by genital bleeding or signs of chorionic/placental detachment on ultrasound.
Early pregnancy loss (EPL) is the cessation of development (absence of FHR) of the embryo/fetus prior to 22 weeks of gestation without expulsion of the gestational sac/fetus.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Miscarriage (spontaneous abortion) is the spontaneous termination of pregnancy (expulsion or extraction of the embryo/fetus) prior to 22 weeks of gestation. The definition also includes early pregnancy loss (EPL).
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
Chromosomal aneuploidy (CA) in the embryo/fetus is the most common cause of miscarriage in the 1st trimester of pregnancy [1], [2], [3]. The earlier in pregnancy a miscarriage occurs, the higher the probability that the embryo/fetus had CA. The number of miscarriages caused by CA in the 1st trimester is 41–50%. The most common types of CA in early miscarriages are autosomal trisomies (52%), monosomy X (19%), and polyploidies (22%). Other forms account for 7%. The risk of trisomy in the embryo/fetus resulting from chromosomal aberrations increases with maternal age. The most prevalent CAs are trisomy 16 and trisomy 22. Triploidy is detected in ≈15% of embryos/fetuses. Monosomy X accounts for ≈20% of miscarriages occurring in the 1st trimester of pregnancy. No correlation has been established between maternal age and monosomy X, polyploidy, or structural chromosomal anomalies [4].
Other causes of miscarriages include anatomical, infectious, endocrine, immunological, and other factors.
Risk factors for miscarriage include [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]:
maternal age >35 years, paternal age >40 years;
number of prior pregnancy losses: the risk of pregnancy loss after a 1st miscarriage is 13–17%, which corresponds to the population miscarriage rate, whereas after 2 prior miscarriages the risk increases more than twofold to 36–38% (Table 1);
obesity or underweight (>30 kg/m2 or <18.5 kg/m2);
excessive caffeine intake (>5 cups of coffee per day or >100 g of caffeine/day);
alcohol and substance use;
adverse occupational conditions (exposure to mercury, lead, benzene vapor, cyclohexane, nitro paint, resin, dust, pesticides, noise, vibration), as well as prolonged exposure to chemical and/or physical factors unrelated to occupation;
chronic diseases: antiphospholipid syndrome, high-risk thrombophilia for thromboembolic complications, polycystic ovary syndrome, thyroid disorders, decompensated diabetes mellitus, celiac disease;
acute and chronic infectious diseases: listeriosis, syphilis, chlamydia, toxoplasmosis, acute respiratory viral infections, human immunodeficiency virus infection, tuberculosis;
medication use: itraconazole, methotrexate**, paroxetine**, venlafaxine, etc.;
uterine disorders: uterine developmental anomalies, uterine fibroids, cervical surgery, intrauterine synechiae;
fever >380C;
folic acid deficiency.
Table 1
Miscarriage risk, maternal age, and history of prior miscarriages [10]
Number of prior miscarriages | Maternal age | |||
|---|---|---|---|---|
25-29 years | 30-34 years | 35-39 years | 40-44 years | |
1 miscarriage | 15% | 16-18% | 21-23% | 40% |
2 miscarriages | 22-24% | 23-26% | 25-30% | 40-44% |
≥3 miscarriages | 40-42% | 38-40% | 40-45% | 60-65% |
1.3 Epidemiology of the Disease or Condition
Miscarriage occurs in 15–20% of clinically recognized pregnancies [21], [22]. Of these, 80% of miscarriages happen before 12 weeks of gestation [23]. Among miscarriages, 1/3 of pregnancies terminate before 8 weeks in the form of anembryony. In 80% of miscarriages, embryonic death occurs first, followed by expulsion of the gestational sac. The incidence of IM is ≈5% of all miscarriages. For TM, the likelihood of a favorable prognosis reaches up to 85%, but depends on gestational age, patient age, and other factors [18], [24].
1.4 Features of Coding the Disease or Condition
O02 (O02.0 - O02.9) Other abnormal products of conception
O03 (O03.0 – O03.1, O03.3 – O03.6, O03.8 - O03.9) Spontaneous abortion
O05 (O05.0 – O05.1, O05.3 – O05.6, O05.8 - O05.9) Other types of abortion
O20 (O20.0 - O20.9) Bleeding in early pregnancy
N85.3 Uterine subinvolution
N85.7 Hematometra
1.5 Classification of the disease or condition
Classification of miscarriage by gestational age [25]:
early (up to 96 weeks of gestation);
late (from 10 to 216 weeks of gestation).
Classification of miscarriage by the developmental stage of the gestational sac [25]:
pre-embryonic (up to 46 weeks of gestation);
embryonic (from 5 to 96 weeks of gestation);
fetal (from 10 to 216 weeks of gestation).
1.6 Clinical presentation of the disease or condition
The most common clinical manifestations of miscarriage are lower abdominal or lower back pain of a spastic nature and vaginal bleeding against the background of delayed menstruation. The patient may also experience a sensation of pelvic pressure and vaginal discharge, which may be clear with pink or bloody streaks (typically after 12 weeks of gestation).
The following clinical manifestations are characteristic of different stages of miscarriage:
Threatened miscarriage – lower abdominal and lumbar pain, vaginal bleeding. Uterine tone is increased, the uterine body corresponds to gestational age, the cervix is not shortened. Ultrasound reveals embryonic cardiac activity (starting from 5–6 weeks of gestation or with a CRL ≥7 mm) / fetal cardiac activity. The following obstetric complications must be excluded: placenta previa or low-lying chorion/placenta, bleeding from a rudimentary uterine horn in uterine malformations, demise of one gestational sac in a multiple pregnancy.
Inevitable miscarriage – the uterine body is generally smaller than the expected gestational age, regular labor-like myometrial contractions are observed, amniotic fluid leakage is possible. The internal and external os are open, the cervical canal is dilated throughout its length, and products of conception are located in the cervical canal or vagina.
Incomplete miscarriage – pregnancy has terminated, but products of conception are identified within the uterine cavity. The lack of adequate uterine contraction and closure of its cavity leads to ongoing bleeding.
Septic miscarriage – pregnancy termination accompanied by fever, chills, malaise, lower abdominal pain, and bloody, sometimes purulent vaginal discharge. Physical examination reveals tachycardia, tachypnea, abdominal wall muscle rigidity; bimanual pelvic examination reveals a tender, soft-consistency uterus, with a dilated cervical canal. If untreated, generalized infection is possible.
Missed miscarriage – death of the embryo or fetus at <22 weeks of gestation without expulsion of the products of conception from the uterine cavity. The diagnosis is established based on ultrasound findings.
2. Diagnostics, medical indications and contraindications for diagnostic methods
* Applies to all patients with miscarriage unless otherwise specified
** Examination during pregnancy is carried out in accordance with the clinical guidelines "Normal Pregnancy" (2023) [26].
Diagnostic criteria
The diagnosis is suspected based on the patient's complaints of lower abdominal and/or lower back pain and vaginal bleeding against the background of a previously confirmed clinical pregnancy. The diagnosis is confirmed by ultrasound of the uterus and adnexa (up to 96 weeks of gestation) or fetal ultrasound (after 10 weeks of gestation), during which concordance of the gestational sac/embryo/fetus with the gestational age, presence of embryonic/fetal cardiac activity, and signs of expulsion of the gestational sac/fetus from the uterine cavity are established (Table 2).
Table 2
Ultrasound diagnostic criteria for miscarriage [23], [27], [28]
Definition | Ultrasound findings |
|---|---|
TM | The external cervical os is closed, embryonic cardiac activity (starting from 5–6 weeks of gestation or with a CRL ≥7 mm) / fetal cardiac activity is visualized, there are signs of chorionic/placental detachment with hematoma formation: retrochorionic, retroplacental, retroamniotic, or vaginal bleeding. |
Inevitable miscarriage | The cervical canal is dilated, the gestational sac is deformed and located in the lower uterine cavity or cervical canal, embryonic/fetal cardiac activity is not visualized, and there are signs of total or subtotal chorionic/placental detachment. |
Anembryony | A gestational sac with a mean diameter >13 mm without a yolk sac, or >18 mm without an embryo, or an amniotic cavity without a yolk sac and embryo at a gestational age of >6 weeks is identified in the uterus. |
Incomplete miscarriage | Ultrasound reveals heterogeneous and/or hyperechoic inclusions along the endometrium or the cervical canal (fragments of the gestational sac or chorionic tissue). |
Complete miscarriage | No products of conception are detected in the uterine cavity. |
Missed miscarriage [29], [30] | The external os of the cervix is closed, embryonic/fetal heartbeat is not visualized. Diagnostic criteria for missed miscarriage: · Absence of embryonic heartbeat with a CRL ≥7 mm. · Absence of an embryo with a mean gestational sac diameter ≥25 mm. · Absence of an embryo and heartbeat ≥14 days after an ultrasound that visualized a gestational sac without a yolk sac. · Absence of an embryo and heartbeat ≥10 days after an ultrasound that visualized a gestational sac and a yolk sac. Suspicious signs of missed miscarriage: · Absence of embryonic heartbeat with a CRL <7 mm. · Absence of an embryo with a mean gestational sac diameter of 16-24 mm. · Absence of an embryo and heartbeat <14 days after an ultrasound that visualized a gestational sac without a yolk sac. · Absence of an embryo and heartbeat <10 days after an ultrasound that visualized a gestational sac and a yolk sac. · Absence of an embryo at a gestational age ≥6 weeks from the first day of the last menstrual period in patients with a regular menstrual cycle. · Empty gestational sac (without a yolk sac and embryo). · Enlarged yolk sac >7 mm or decreased <2 mm. · Relatively small size of the gestational sac compared to the size of the embryo (<5 mm difference between the mean gestational sac diameter and the embryonic CRL). |
2.1 Complaints and Anamnesis
It is recommended to evaluate miscarriage risk factors in order to eliminate them during threatened miscarriage or to plan the next pregnancy in inevitable or complete miscarriage [18], [23], [21], [31].
GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).
2.2 Physical Examination
It is recommended to perform a physical general examination, general thermometry, heart rate measurement, respiratory rate measurement, and peripheral blood pressure measurement to assess the patient's general condition [18], [23].
RG CLE 5Recommendation Grade C (Level of Evidence 5).
It is recommended to perform abdominal palpation and percussion to detect tenderness, anterior abdominal wall muscle guarding, peritoneal irritation signs, abdominal distension, and free fluid in the abdominal cavity [18], [31].
GGR CLEL 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) level C (Level of evidence - 5).
It is recommended to perform a speculum examination of the cervix to assess the condition of the vaginal portion of the cervix, bleeding intensity, and the presence of products of conception in the vagina [18].
GGR CLEL 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) level C (Level of evidence - 5).
Comment: The volume and nature of discharge (bloody, mucosanguineous, purulent), expulsion of products of conception, bulging of the amniotic sac, cervical anatomy, and the condition of the external os and cervical canal are evaluated.
It is recommended to perform a bimanual pelvic examination for differential diagnosis with ectopic pregnancy, determination of uterine size and its correspondence to gestational age, as well as the condition and tenderness of the adnexa and vaginal fornices [18], [31].
GGR CLEL 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) level C (Level of evidence - 5).
Comment: If intrauterine pregnancy is confirmed by ultrasound and the risk of miscarriage is high (presence of a hematoma, moderate to heavy vaginal bleeding, increased uterine tone), the examination may be limited to a speculum examination of the cervix.
2.3 Laboratory Diagnostics
It is recommended to test for serum human chorionic gonadotropin (hCG) (free β-subunit) levels, or urine hCG testing if blood testing is unavailable, to diagnose pregnancy [18], [23], [31], [32].
GGR CLEL 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) level C (Level of evidence - 5).
Comment: This recommendation applies regardless of the date of the last menstruation, the patient's report of contraception, sterilization, or absence of sexual activity.
It is recommended to repeat the serum hCG (free β-subunit) test after 48 hours in cases of pregnancy of unknown location to rule out ectopic pregnancy and determine pregnancy progression [33], [34], [35].
LoR BGoE 1Level of Recommendation B (Grade of Evidence - 1).
Comment: When repeating the test, the ratio of the repeat hCG level (hCG2) to the initial hCG level (hCG1) is calculated, which determines the diagnosis and management strategy. If the hCG2/hCG1 ratio >0.8, provided that the hCG level is ≥1000 IU/L, transvaginal pelvic ultrasound (or transabdominal pelvic ultrasound if transvaginal is not feasible) is recommended to determine the localization of the gestational sac. If the hCG2/hCG1 ratio ≥2, the prognosis for pregnancy development is favorable. If the hCG2/hCG1 ratio <0.5, monitoring should be discontinued. If the hCG2/hCG1 ratio is 0.5–0.7, ultrasound monitoring should be discontinued, but hCG testing should be continued until the level drops to ≤100 IU/L, with a frequency depending on the baseline hCG level. If the hCG2/hCG1 ratio does not decrease and complaints of bleeding and pain persist, diagnostic laparoscopy may be performed to establish the diagnosis [35].
It is recommended to perform a blood serum C-reactive protein test in the presence of complaints of fever, chills, or purulent vaginal discharge for the diagnosis of IAB [18], [36], [37].
GPP ALOE 1Grade of Recommendation A (Level of Evidence - 1).
It is recommended to determine Rh antibodies in Rh-negative patients pregnant by a partner with Rh-positive or unknown Rh blood type if this test has not been performed during the current pregnancy, in order to select the correct screening algorithm for the prevention of fetal hemolytic disease in the event of pregnancy continuation, or to administer Rh isoimmunization prophylaxis in the event of termination [38], [39], [40].
LeR ALoE 1Level of Evidence Recommendation A (Level of Evidence - 1).
Comment: For evaluation and management upon detection of fetal hemolytic disease, see the clinical guidelines "Rh Isoimmunization. Fetal Hemolytic Disease" [41].
It is recommended to perform microscopic examination of vaginal smears and determine the hydrogen ion concentration (pH) of the vaginal mucosa discharge in cases of TAB when preserving the pregnancy, for the diagnosis and treatment of infectious-inflammatory and dysbiotic conditions [18], [42], [43], [44].
LoR CGoE 4Level of Recommendation C (Grade of Evidence - 4).
It is recommended to perform molecular biological testing of female genital mucous membrane discharge for sexually transmitted infection (STI) pathogens (Neisseria gonorrhoeae, Trichomonas vaginalis, Chlamydia trachomatis, Mycoplasma genitalium) in cases of TAB when preserving the pregnancy and in cases of IAB for the diagnosis and treatment of STIs [31], [45].
GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).
It is recommended to perform microbiological (culture) examination of female genital discharge for aerobic and facultatively anaerobic microorganisms in cases of IAB [46].
GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).
Comment: Biological material should be collected from the cervical canal, uterus, placenta, blood, urine, and other sites using a cotton swab into a sterile tube with transport medium or with a syringe into a sterile laboratory container (for tissues and fluids) [46].
It is recommended to perform an amniotic fluid leakage test (determination of hydrogen ion concentration (pH) of vaginal mucosal discharge, determination of phosphorylated insulin-like growth factor-binding protein 1 (phIGFBP-1) in cervical mucus, and determination of placental alpha-microglobulin-1 (PAMG-1) in cervical mucus) during a speculum examination of the cervix in cases of TAB in the 2nd trimester of pregnancy when premature rupture of membranes is suspected [47], [48–53].
LeR ALoE 1Level of Evidence Recommendation A (Level of Evidence - 1).
Comment: The false-negative rate of the cytological test (ferning test) is >20%, and the false-positive rate of the nitrazine test (pH) is 5–30% [48–53].
2.4 Instrumental Diagnostics
It is recommended to perform ultrasound of the uterus and appendages (up to 96 weeks of gestation) or fetal ultrasound (from 100 weeks of gestation) for the diagnosis of pregnancy, its location, determination of whether the gestational sac/embryo/fetus corresponds to the gestational age, presence of embryonic/fetal heartbeat, signs of expulsion of the gestational sac/fetus from the uterine cavity, and the ratio of the uterine body to the cervix (presence of hyper-ante- or retroflexion) [54, 55], [56].
GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).
Comments: Transvaginal ultrasound of the uterus and appendages is the method of choice. If transvaginal ultrasound of the uterus and appendages is unavailable, transabdominal ultrasound of the uterus and appendages may be used; however, this method is not as accurate as transvaginal ultrasound for diagnosing early pregnancy complications [31].
It is recommended to perform a repeat ultrasound of the uterus and appendages after 7–10 days when missed miscarriage is suspected, in order to confirm an evolving pregnancy or the diagnosis of missed miscarriage [21], [27], [29], [30], [31], [57].
GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).
Comment: Transvaginal ultrasound is the ultrasound method of choice. If transvaginal ultrasound of the uterus and appendages is unavailable, transabdominal ultrasound of the uterus and appendages may be used, although this method is not as accurate as transvaginal ultrasound for diagnosing early pregnancy complications. When possible, the diagnosis of missed miscarriage should be confirmed by two ultrasound diagnosticians [23], [32]. Special caution should be exercised when diagnosing missed miscarriage prior to 8 weeks of gestation, particularly in women with no clinical symptoms.
It is recommended to perform ultrasound of the uterus and appendages 7–14 days after a miscarriage to confirm complete miscarriage [21], [23], [32], [58].
GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).
Comment: Transvaginal ultrasound is the ultrasound method of choice. If transvaginal ultrasound of the uterus and appendages is unavailable, transabdominal ultrasound of the uterus and appendages may be used, but this method is not as accurate as transvaginal ultrasound for diagnosing complications.
2.5 Other Procedures
It is recommended to perform pathomorphological examination of early and late miscarriage material, or pathomorphological examination of missed miscarriage material, or pathomorphological examination of placental biopsy (surgical) material (obtained via vacuum aspiration of the endometrium (uterine cavity contents) resulting from a miscarriage) to confirm the fact of pregnancy and/or rule out gestational trophoblastic disease [31], [59].
GPP CLOE 5 Grade of Recommendation C (Level of Evidence - 5).
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
*Applies to all patients with miscarriage unless otherwise specified
** Non-pharmacological and pharmacological methods for managing pregnancy-related complaints, as well as the prescription of vitamins and dietary supplements during pregnancy, must comply with the clinical guidelines "Normal Pregnancy" [26].
3.1. Non-pharmacological treatments
A patient with TAB is recommended a restful regimen with activity restriction in order to preserve the pregnancy [18].
GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).
Comment: The restful regimen includes limiting physical activity, maintaining a proper sleep-wake schedule, and restricting sexual activity. There is no convincing evidence that bed rest prevents pregnancy loss [17], [23], [60]; however, adhering to a restful regimen, avoiding physical activity and sexual activity in the presence of TAB provides the necessary conditions to prolong a viable pregnancy [18].
3.2. Pharmacotherapy
A patient with TAB is recommended to be prescribed dydrogesterone** or progesterone preparations** in order to preserve the pregnancy [18], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74].
GGR ALEL 1Grading of Recommendations Assessment, Development and Evaluation (GRADE) level A (Level of evidence - 1).
Comment: The safety profile of dydrogesterone** and progesterone** at recommended doses in early pregnancy has been well studied and is favorable (there is no evidence of an increased incidence of adverse events in the mother and fetus compared to no treatment/placebo, or upon direct comparison of these drugs) [61], [62], [63], [64], [65], [67], [68], [75], [76], [77], [78], [79], [80], [81], [82].
A patient with TAB, in the presence of indications according to the drug's prescribing information, is recommended to be prescribed drotaverine** as needed when complaints arise, in order to reduce smooth muscle spasms [18].
GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).
A patient with TAB presenting with heavy vaginal bleeding is recommended to be prescribed tranexamic acid** according to the dosing schedule in the drug's prescribing information, in order to stop the bleeding [18].
GCP CLEL 5Level of Evidence C (Level of Likelihood of Evidence - 5).
In cases of IAB, a patient in an inpatient setting is recommended to be prescribed systemic antibacterial therapy for the treatment of the infectious and inflammatory process [83].
GCR ALeE 1Grade of Recommendation A (Level of Evidence - 1).
Comments: Broad-spectrum antibacterial drugs are prescribed empirically; adjustment is made based on culture results 48–72 hours after treatment initiation if there is no improvement in clinical and laboratory parameters indicating a positive trend in the disease course and/or pathogen resistance to the administered therapy [46], [83], [84].
Possible empirical antibiotic therapy regimens involving intravenous administration of medicinal products according to the instructions for use:
- gentamicin** and clindamycin** with or without beta-lactam antibacterial drugs, penicillins (J01C);
- beta-lactam antibacterial drugs, penicillins (J01C), and gentamicin** with metronidazole**;
- second-generation cephalosporins (J01DC) or third-generation cephalosporins (J01DD) with metronidazole**;
- piperacillin+[tazobactam];
- carbapenems and other reserve drugs are prescribed according to the patient's severity by a medical board.
In cases of missed miscarriage or incomplete miscarriage in the 1st trimester (up to 12 weeks of gestation) without signs of anemia, infection, bleeding, or hemodynamic instability, it is recommended to prescribe #misoprostol** [23], [32], [85], [86] or #mifepristone followed by #misoprostol** [87], [88], [89], [90] to evacuate the uterine cavity.
LeR ALoE 1Level of Evidence Recommendation A (Level of Evidence - 1).
Comment: For administration regimens, see Appendix A3. In the 1st trimester (up to 12 weeks of gestation), in the absence of bleeding and signs of infection, there are 3 management options for patients: expectant management for 7–14 days, medical uterine evacuation, and surgical management [23]. Expectant management is an option if the patient is located close to a medical facility and has provided informed voluntary consent. It is not recommended for patients with bleeding, coagulopathy, severe anemia, signs of infection, hemodynamic instability, or a previous negative experience with expectant management [23], [21], [32].
For missed miscarriage in the 2nd trimester (after 12 weeks of gestation) with intact fetal membranes and a closed cervix, it is recommended to administer #mifepristone followed by #misoprostol** to evacuate the uterine cavity [31], [91].
GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).
Comment: For administration regimens, see Appendix A3.
For missed miscarriage in the 2nd trimester with ruptured or leaking amniotic membranes and a dilated cervical canal, it is recommended to administer #misoprostol** to evacuate the uterine cavity [31], [91].
GPP CLoE 5Level of Evidence/Grade of Recommendation C (level of evidence - 5).
Comment: For administration regimens, see Appendix A3.
Following a 2nd-trimester miscarriage, on the day of pregnancy termination (but no earlier than 4 hours later), it is recommended to prescribe bromocriptine** in accordance with the manufacturer's instructions or #cabergoline at a single dose of 1 mg to prevent lactation [92], [93].
LeveL of Recommendation BGrade of Evidence 2LeveL of Recommendation B (Grade of Evidence - 2).
For patients undergoing medical termination of a missed miscarriage, it is recommended to prescribe nonsteroidal anti-inflammatory drugs (from the M01A group) for pain relief and an anti-inflammatory effect [86], [94].
GPP BLE 2Grade of Recommendations B (Level of Evidence 2).
Patients with incomplete miscarriage or missed miscarriage undergoing surgical treatment are recommended to receive antibiotic prophylaxis to prevent infectious and inflammatory complications [23].
GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).
Comment: For antibiotic prophylaxis, 1 hour before the procedure or immediately after it, prescribe either doxycycline** in accordance with the drug's instructions, or #azithromycin 500–1000 mg orally once [95], or #metronidazole** (500 mg orally before the abortion, 500 mg orally 4 and 8 hours after) [95], [96].
Patients who are Rhesus (D) negative, pregnant by a Rhesus (D) positive partner or whose partner's Rhesus blood group is unknown, in the absence of Rhesus (D) isoimmunization, are recommended to receive anti-Rhesus Rho[D] human immunoglobulin** within 72 hours after the first dose of #misoprostol** or after surgical treatment of the miscarriage, as well as patients with signs of chorionic/placental abruption or uterine bleeding [23], [32], [39], [40], [41].
Level of recommendation 1 (level of evidence - A).
Comment: For evaluation and management upon detection of fetal hemolytic disease, see the clinical guidelines "Rh Isoimmunization. Fetal Hemolytic Disease" [41].
It is recommended to administer 5 IU of oxytocin** intravenously or intramuscularly after surgical removal of the gestational sac to reduce blood loss volume [97].
GGR BLEL 1Grading of Recommendations Assessment, Development and Evaluation (GRADE) level B (Level of evidence - 1).
3.3 Surgical treatments
In cases of incomplete miscarriage and missed miscarriage, endometrial vacuum aspiration (evacuation of uterine contents) is recommended to remove residual chorionic/placental tissue and stop bleeding [23], [98].
GGR ALEL 1Grading of Recommendations Assessment, Development and Evaluation (GRADE) level A (Level of evidence - 1).
Comment: Vacuum aspiration is preferred over curettage of the uterine cavity as it is less traumatic, results in less blood loss and less pain intensity, and has a shorter procedure duration [23], [21], [98], [99]. Curettage of the uterine cavity is performed only when vacuum aspiration is not feasible.
Patients with infected miscarriage are recommended to undergo endometrial vacuum aspiration (evacuation of uterine contents) or curettage of the uterine cavity to remove tissues affected by the inflammatory process [23], [21], [98], [99].
GGR ALEL 1Grading of Recommendations Assessment, Development and Evaluation (GRADE) level A (Level of evidence - 1).
For adequate anesthetic management during surgical treatment of missed miscarriage, incomplete miscarriage, and infected miscarriage, the use of general anesthesia methods (predominantly intravenous anesthesia) is recommended [100–104].
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5).
Comments: During general anesthesia, it is recommended to use propofol** (no more than 2.5 mg/kg), sodium thiopental**, fentanyl**, and ketamine**, and to ensure oxygenation via a face mask, laryngeal mask, or endotracheal intubation. Risk stratification and aspiration prophylaxis measures should be based on the gestational age: up to 16 weeks, the risk of complications does not differ from that in non-pregnant individuals. If general anesthesia is not feasible (drug allergies, recent food intake), neuroaxial anesthesia may be used. For spinal anesthesia, small-gauge 25-27G spinal needles are used. Recommended local anesthetics include bupivacaine** (isobaric or hyperbaric solution), levobupivacaine**, and lidocaine** in dosages according to the drug instruction labels.
For a patient with a complete miscarriage, vacuum aspiration of the uterine cavity contents or uterine curettage is not recommended [23], [31], [32].
GGR CLEL 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) level C (Level of evidence - 5).
4. Medical Rehabilitation and Sanatorium-Resort Treatment
Not applicable.
5. Prevention and Dispensary Observation
For prevention methods, see the clinical guidelines "Normal Pregnancy" [26].
6. Organization of Medical Care
Indications for inpatient hospitalization:
Threatened miscarriage.
Inevitable miscarriage accompanied by bleeding.
Incomplete miscarriage accompanied by bleeding.
Infected miscarriage.
Genital tract bleeding accompanied by hemodynamic instability.
Indications for discharge from the hospital:
1. Following miscarriage in the absence of bleeding and signs of infection.
2. After relief of threatened miscarriage symptoms.
7. Additional Information
Not applicable.
Criteria for Evaluating the Quality of Medical Care
№ | Criteria for diagnostic and treatment quality | Yes/No |
|---|---|---|
1. | A repeat blood serum human chorionic gonadotropin (free beta-subunit) test was ordered after 48 hours (for pregnancy of unknown location). | Yes/No |
2. | Transabdominal and/or transvaginal ultrasound of the uterus and appendages (up to 10 weeks of gestation) or fetal ultrasound (after 10 weeks of gestation) was ordered. | Yes/No |
3. | A repeat transabdominal and/or transvaginal ultrasound of the uterus and appendages was ordered in 7–10 days (if missed miscarriage is suspected). | Yes/No |
4. | Transabdominal and/or transvaginal ultrasound of the uterus and appendages was ordered (7–14 days after miscarriage). | Yes/No |
5. | Pathological examination of early and late miscarriage material, or pathological examination of missed miscarriage material, or pathological examination of placental biopsy (surgical) material (obtained via vacuum aspiration of uterine contents) was performed. | Yes/No |
6. | Treatment with systemic antibacterial drugs was performed (in cases of infected miscarriage, depending on medical indications and in the absence of medical contraindications). | Yes/No |
7. | Administration of anti-Rhesus Rho[D] human immunoglobulin was performed (for Rhesus (D) negative patients pregnant by a Rhesus (D) positive partner, in the absence of Rhesus (D) isoimmunization) (within 72 hours after the first dose of misoprostol or surgical treatment, and/or in the presence of signs of chorionic or placental abruption, and/or in the presence of uterine bleeding) (depending on medical indications and in the absence of medical contraindications). | Yes/No |
8. | Prophylaxis of infectious complications with systemic antibacterial drugs was performed (during surgical intervention) (in cases of missed miscarriage or incomplete miscarriage, depending on medical indications and in the absence of medical contraindications). | Yes/No |
9. | Endometrial vacuum aspiration was performed (in cases of incomplete miscarriage, missed miscarriage, and infected miscarriage). | Yes/No |
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Appendix A1. Working Group Composition
Nana K. Tetruashvili – MD, PhD, Head of the 2nd Department of Obstetric Pathology of Pregnancy, Deputy Director of the Institute of Obstetrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). There is no conflict of interest.
Dolgushina Nataliya Vitalievna – D.Sc. (Medicine), Professor, Deputy Director for Research, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Chief Freelance Specialist of the Russian Ministry of Health in Women's Reproductive Health (Moscow). There is no conflict of interest.
Natalia E. Kan – MD, PhD, Professor, Deputy Director for Research – Director of the Institute of Obstetrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). There is no conflict of interest.
Viktor L. Tyutyunnik - MD, PhD, Professor, Leading Researcher at the Department of Innovative Scientific Projects of the Department of Scientific Activity Organization, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). There is no conflict of interest.
Baranov Igor Ivanovich – D.Sc. in Medicine, Professor, Head of the Department of Scientific and Educational Programs, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health. No conflict of interest.
Pyregov Aleksey Viktorovich – D.Sc. in Medicine, Professor, Deputy Chief Physician for Anesthesiology and Intensive Care, Moscow Regional Perinatal Center. Chairman of the Committee on Anesthesiology and Intensive Care in Obstetrics and Gynecology of the Association of Anesthesiologists and Intensivists (Moscow). No conflict of interest.
Viktor E. Radzinsky - Corresponding Member of the RAS, D.Sc. (Medicine), Professor, Head of the Department of Obstetrics and Gynecology with a Course in Perinatology, Peoples' Friendship University of Russia (Moscow). No conflict of interest.
Galina M. Savelieva - Academician of the RAS, MD, Professor, Honored Worker of Science of the RF, Hero of Labour of the Russian Federation (Moscow). No conflict of interest.
Serov Vladimir Nikolayevich - Academician of the RAS, MD, Professor, Chief Researcher, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, President of the Russian Society of Obstetricians and Gynecologists (ROAG) (Moscow). No conflict of interest.
Khodzhaeva Zulfiya Sagdullaevna – D.Sc. in Medicine, Professor, Deputy Director of the Institute of Obstetrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.
Shabanova Natalia Evgenyevna – Candidate of Medical Sciences, Associate Professor, Head of the Department of Clinical Pharmacology of Antimicrobial and Immunobiological Drugs, Institute of Microbiology, Antimicrobial Therapy and Epidemiology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.
Shmakov Roman Georgievich – D.Sc. in Medicine, Professor, Professor of the Russian Academy of Sciences, Director of the Moscow Regional Research Institute of Obstetrics and Gynecology named after Academician V.I. Krasnopolsky, Chief freelance specialist in obstetrics of the Russian Ministry of Health (Moscow). No conflict of interest.
Shifman Efim Munevich – Doctor of Medical Sciences, Professor, 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-Resuscitators (Moscow). No conflict of interest.
Sheshko Elena Leonidovna – Candidate of Medical Sciences, Director of the Department of Pediatric Medical Care, Obstetrical Services and Public Health (Moscow). No conflict of interest.
Chief Freelance Specialists
Artymuk Natalia Vladimirovna – D.Sc. in Medicine, Professor, Head of the Department of Obstetrics and Gynecology named after Professor G.A. Ushakova, Kemerovo State Medical University of the Russian Ministry of Health, Chief freelance specialist in obstetrics 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 Siberian Federal District (Kemerovo). No conflict of interest.
Bashmakova Nadezhda Vasilevna – D.Sc. (Medicine), Professor, Chief Researcher, Ural Research Institute of Maternity and Infancy Welfare of the Russian Ministry of Health, Chief Freelance Specialist of the Russian Ministry of Health in Obstetrics, Chief Freelance Specialist of the Russian Ministry of Health in Gynecology, Chief Freelance Specialist in Women's Reproductive Health in the Ural Federal District. There is no conflict of interest.
Bezhenar Vitaly Fedorovich – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics, Gynecology and Reproductology, Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the Northwestern Federal District (Saint Petersburg). No conflict of interest.
Belokrinitskaya Tatiana Evgenievna – D.Sc. in Medicine, Professor, Head of the Department of Obstetrics and Gynecology, Faculty of Additional Professional Education, Chita State Medical Academy of the Russian Ministry of Health, Honored Doctor of the Russian Federation, Chief freelance specialist in obstetrics of目 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). No conflict of interest.
Kalugina Alla Stanislavovna – D.Sc. (Medicine), Professor, Professor at the Department of Obstetrics, Gynecology and Neonatology, First Pavlov State Medical University of St. Petersburg of the Russian Ministry of Health (Saint Petersburg), Chief Freelance Specialist in Women's Reproductive Health in the Northwestern Federal District. There is no conflict of interest.
Kogan Igor Yuryevich – Doctor of Medical Sciences, Professor, Corresponding Member of the RAS, Director of the Ott Research Institute of Obstetrics, Gynecology and Reproductology (Saint Petersburg), Chief Freelance Specialist in Reproductive Health of the Healthcare Committee of Saint Petersburg. No conflict of interest.
Krasnopolskaya Ksenia Vladislavovna – Corresponding Member of the Russian Academy of Sciences, D.Sc. in Medicine, Professor, Head of the Department of Reproductology at MONIIAG, Chief freelance specialist in women's reproductive health of the Ministry of Health of the Moscow Region (Moscow). No conflict of interest.
Malyshkina Anna Ivanovna – Doctor of Medical Sciences, Professor, Director of the Ivanovo Research Institute of Motherhood and Childhood named after V.N. Gorodkov, Head of the Department of Obstetrics and Gynecology, Medical Genetics, Faculty of General Medicine, Ivanovo State Medical Academy of the Russian Ministry of Health, 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 Central Federal District (Ivanovo). No conflict of interest.
Mikhailov Anton Valerievich – MD, Professor, Chief Physician, Maternity Hospital No. 17 of St. Petersburg, Professor of the Department of Obstetrics and Gynecology, North-Western State Medical University named after I.I. Mechnikov of the Russian Ministry of Health, and the Department of Obstetrics, Gynecology and Perinatology, First Saint Petersburg State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics and Gynecology of the Russian Ministry of Health in the North-Western Federal District (St. Petersburg). No conflict of interest.
Moiseeva Irina Valerievna – D.Sc. (Medicine), Head of the Department of Assisted Reproductive Technologies, Samara Regional Medical Center "Dynasty", Chief Freelance Specialist in Reproductive Health of the Ministry of Health of the Samara Region, Chief Freelance Specialist in Women's Reproductive Health in the Privolzhsky Federal District (Samara). There is no conflict of interest.
Anton S. Olenev – PhD, Chief freelance specialist in obstetrics and gynecology of the Moscow Healthcare Department, Head of the Perinatal Center branch of City Clinical Hospital No. 24, Associate Professor of the Department of Obstetrics and Gynecology with a Course in Perinatology, Medical Institute of RUDN University. No conflict of interest.
Popandopulo Victoria Alexandrovna – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology, Maykop State Technological University, Professor of the Department of Obstetrics and Gynecology, Faculty of General Medicine, Astrakhan State Medical University of the Russian Ministry of Health, Chief Medical Officer of Kuban Medical Center LLC, 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 Southern Federal District (Krasnodar). No conflict of interest.
Fatkullin Ildar Faridovich — MD, Professor, Head of the Prof. V.S. Gruздеv Department of Obstetrics and Gynecology, Kazan State Medical University; Chief Freelance Specialist in Obstetrics of the Russian Ministry of Health; Chief Freelance Specialist in Gynecology of the Russian Ministry of Health in the Privolzhsky Federal District (Kazan). No conflict of interest.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
1. obstetrician-gynecologists
2. obstetrics and gynecology residents
Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | 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 | 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 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Appendix A3. Reference Materials
Method of medical termination of missed miscarriage
Regimen for #misoprostol** use. Two methods of medical evacuation of the uterine cavity in missed miscarriage are described using #misoprostol** with or without prior use of #mifepristone. The efficacy of the methods ranges from 13% to 96%. The use of #misoprostol** is the most cost-effective intervention for anembryony and early missed miscarriage [17], [23], [86], [94].
Regimen for #mifepristone and #misoprostol** use. The efficacy of oral administration of #mifepristone 200 mg 24 hours prior to vaginal administration of #misoprostol** 800 mcg has been confirmed. This alternative regimen has demonstrated greater efficacy compared to #misoprostol** monotherapy [87], [88], [89], [90].
Regimen for #misoprostol** use in missed miscarriage and incomplete abortion
The initial dose of #misoprostol** is 800 mcg vaginally. If there is no response to the initial dose, a repeat dose may be administered, but no earlier than 3 hours after the first dose and no later than 7 days (optimally after 48 hours) [17], [23], [85], [94].
#Misoprostol** may cause fever within 24 hours after administration, which should not be interpreted as a sign of infection. Severe cramps and bleeding generally occur within two to six hours after #misoprostol** administration [86], [94].
Appendix B. Physician Action Algorithms
Algorithm 1. Physician action algorithm for suspected early pregnancy loss
Algorithm 2. Diagnostic algorithm for pregnancy of unknown (uncertain) location
Appendix C. Patient Information
Early pregnancy losses are the most common complication of pregnancy, occurring in 15–20% of all established pregnancies. Currently, examination methods are so sensitive and precise that they allow establishing the fact of pregnancy at a very early stage, before the gestational sac appears in the uterine cavity or outside it. If symptoms such as severe lower abdominal pain, back pain, shoulder pain, or vaginal bleeding occur during pregnancy, you must consult a doctor immediately. The doctor will perform an examination, including blood tests and an ultrasound scan, to determine the location of the gestational sac (inside or outside the uterine cavity) and embryo viability. Sometimes observation is required to make a correct diagnosis, since it is not always possible to clearly determine the location or viability of the embryo during the initial examination. In this case, the doctor may suggest hospitalization (if ectopic pregnancy is suspected or in case of heavy bleeding) or home monitoring in the absence of heavy spotting/bleeding. According to the doctor's recommendations, in some cases it is necessary to test blood for β-hCG several times with a 48-hour interval to determine whether the pregnancy is developing. Once the gestational sac is detected in the uterine cavity, you may be offered a repeat ultrasound to assess embryo viability.
The doctor may recommend medications to support the pregnancy, but if the pregnancy still cannot be saved, the cause in most cases is fetal developmental disorders (chromosomal abnormalities or fetal developmental anomalies). Usually, such a situation does not recur in the future, however, if this is not your first pregnancy loss, you will be offered a special examination to identify risk factors and causes of pregnancy losses.
In missed miscarriage or incomplete abortion, there are several options for evacuating the non-viable gestational sac from the uterine cavity. One tactic is expectant management, where you wait for 7–14 days for a complete miscarriage to occur, after which an ultrasound is performed. If heavy bleeding starts during the waiting period, you must immediately contact a medical facility, ensuring that you can do so around the clock.
Another tactic is medical termination of the non-viable pregnancy. In this case, after the examination, the doctor will give you pills that accelerate the miscarriage process and minimize blood loss. You may experience pain (you can take a painkiller) and a possible rise in body temperature to low-grade fever.
And finally, the third method is surgical. It is preferred if you have low hemoglobin, significant blood loss, an inflammatory process, or if it is impossible to quickly and round-the-clock access a medical facility, for example, due to its remoteness from your place of residence. For the duration of the procedure, you will be hospitalized (in a hospital or a day-care facility), and using one of the anesthesia methods, the surgeon will empty the uterine cavity using one of the methods – a vacuum device or special surgical instruments. You can discuss a particular method of terminating a missed miscarriage with your doctor after the fact of early pregnancy loss is established. Following surgical treatment, antibacterial therapy and pain relief may be prescribed.
After pregnancy termination, sexual intercourse is not recommended for 2 weeks; thereafter, contraception methods must be used for several months. You can ask your obstetrician-gynecologist all your questions regarding planning your next pregnancy.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Not applicable.