Multiple pregnancy: clinical guidelines

List of Abbreviations

Terms and Definitions

Twin-twin transfusion syndrome is a complication of monochorionic multiple pregnancy caused by unbalanced placental anastomoses, leading to polyhydramnios in the recipient fetus and anhydramnios in the donor fetus.

Selective fetal growth restriction is a complication of multiple pregnancy characterized by growth restriction in one of the fetuses (estimated fetal weight below the 3rd percentile) or a combination of two of the following parameters: estimated fetal weight discordance $\ge$25%, estimated fetal weight of one of the fetuses below the 10th percentile, abdominal circumference below the 10th percentile (only for monochorionic multiples), and abnormal umbilical artery blood flow.

Twin-reversed arterial perfusion sequence is a complication of monochorionic multiple pregnancy characterized by the absence of a functioning heart in one of the fetuses, leading to severe developmental anomalies.

Twin anemia-polycythemia sequence is a complication of monochorionic multiple pregnancy characterized by unidirectional small-diameter placental anastomoses, leading to chronic anemia in the donor fetus and polycythemia in the recipient fetus, without significant differences in amniotic fluid volumes.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

A multiple pregnancy is a pregnancy in which two or more fetuses develop within the mother's body.

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

Dizygotic multiple pregnancy is the result of fertilization of two or more oocytes maturing during a single menstrual cycle; each embryo develops a separate placenta and amniotic cavity.

Monozygotic multiple pregnancy is the result of the fertilization of a single oocyte and its subsequent division. Approximately 30% of monozygotic twins are dichorionic, and 70% are monochorionic. Division at the morula stage (days 0–3 after fertilization) forms a dichorionic diamniotic (DCDA) twin pregnancy; division at the blastocyst stage (days 4–8 after fertilization) forms a monochorionic diamniotic (MCDA) twin pregnancy. If the embryo divides on days 9–12 after fertilization, both embryos develop within a single gestational sac, sharing both chorionic and amniotic membranes—forming a monochorionic monoamniotic (MCMA) twin pregnancy (1–5% of all monozygotic twins). In rare cases, division occurs after the 12th day of embryonic development, resulting in conjoined (siamese) twins.

1.3 Epidemiology of the Disease or Condition

In recent decades, the incidence of multiple pregnancy has increased significantly, varying from 3 to 40 cases per 1000 births depending on the region of the world, prevailing race, prevalence of assisted reproductive technology (ART) methods, and regulation of the number of transferred embryos in ART cycles.

In multiple pregnancies, perinatal risks are significantly higher than in singleton pregnancies. Therefore, multiple pregnancies and deliveries are classified as complicated pregnancies. Maternal mortality in multiple pregnancy is 2.5 times higher, and perinatal loss is 9–11 times higher than in singleton pregnancy [1–4].

For spontaneous multiple pregnancy (without ART), Hellin's law applies: the ratio of twin pregnancies to all multiple pregnancies is 1:89, triplets 1:89² = 1:7910, quadruplets 1:89³ = 1:704,969, etc. Spontaneous triplet pregnancy occurs in 1 case per 7,000–10,000 births, and quadruplet pregnancy in 1 per 700,000 births. Monoamniotic twins are quite rare, occurring in 1 per 10,000 pregnancies. Conjoined (siamese) twins are characteristic only of MCMA twins, with an incidence of 1 per 200 MCMA pregnancies (1 per 50,000 pregnancies). The incidence of dizygotic twins reaches up to 70% of all multiple pregnancies, and its probability depends on heredity, maternal age and parity, use of ART, and the number of transferred embryos in ART cycles. Dizygotic twins can be of the same sex (in 75% of cases) or different sexes.

1.4 Features of Coding the Disease or Condition

O30 – Multiple gestation

O30.0 – Twin pregnancy

O30.1 – Triplet pregnancy

O30.2 – Quadruplet pregnancy

O30.8 – Other multiple pregnancies

O30.9 – Multiple pregnancy, unspecified

O31 – Complications specific to multiple pregnancy

O31.0 – Fetus papyraceus

O31.1 – Continuing pregnancy after abortion of one or more fetuses

O31.2 – Continuing pregnancy after intrauterine death of one or more fetuses

O31.8 – Other complications specific to multiple pregnancy

O32.5 – Multiple pregnancy with malpresentation of one or more fetuses, requiring maternal care

O33.7 – Maternal care for other fetal disproportion (conjoined twins)

O43.0 – Placental transfusion syndromes

O63.2 – Delayed delivery of second twin, triplet, etc.

O84 – Multiple delivery

O84.0 – Multiple delivery, all spontaneous

O84.1 – Multiple delivery, all forceps and vacuum extractor

O84.2 – Multiple delivery, all cesarean section

O84.8 – Other multiple delivery

O84.9 – Multiple delivery, unspecified

1.5 Classification of the disease or condition

Classification of multiple pregnancy based on fetal number, chorionicity, and amnionicity

Twins

Dichorionic diamniotic (DCDA) twins: each fetus has its own placenta and amniotic cavity.

Monochorionic diamniotic (MCDA) twins: the placenta is shared between both fetuses, with two amniotic cavities.

Monochorionic monoamniotic (MCMA) twins: the fetuses share both the placenta and the amniotic cavity.

Triplets

Trichorionic triamniotic (TCTA) triplets: each fetus has its own placenta and amniotic cavity.

Dichorionic triamniotic (DCTA) triplets: one fetus has its own placenta, while the second placenta is shared by the other two fetuses. Each fetus has its own amniotic cavity.

Dichorionic diamniotic (DCDA) triplets: one fetus has its own placenta and amniotic cavity, while the other placenta and amniotic cavity are shared by the remaining two fetuses.

Monochorionic triamniotic (MCTA) triplets: the placenta is shared by all three fetuses, but each fetus has its own amniotic cavity.

Monochorionic diamniotic (MCDA) triplets: the placenta is shared by all three fetuses, one fetus has a separate amniotic cavity, and the other two share a common amniotic cavity.

Monochorionic monoamniotic (MCMA) triplets: all three fetuses share a common placenta and amniotic cavity.

Quintero et al. staging system for twin-to-twin transfusion syndrome (TTTS), 1999 [5]

Stage I: oligohydramnios in the donor fetus (maximum vertical pocket (MVP) <2 cm) and polyhydramnios in the recipient fetus (MVP >8 cm before 20 weeks and >10 cm after 20 weeks of gestation), with the donor's urinary bladder still visible.

Stage II: marked discrepancy in amniotic fluid volume without visualization of the donor twin's urinary bladder filling.

Stage III: in the presence of polyhydramnios/oligohydramnios, blood flow abnormalities are diagnosed in one or both fetuses: absent or reversed end-diastolic flow in the umbilical arteries, reversed a-wave in the ductus venosus, or pulsatile flow in the umbilical vein (various combinations of blood flow abnormalities detected by color Doppler mapping (CDM) are possible). As a rule, umbilical artery flow abnormalities are more frequently detected in the donor fetus, whereas the recipient fetus more commonly shows abnormal blood flow in the ductus venosus or pulsatile flow in the umbilical vein, indicating developing heart failure.

Stage IV: fetuses with TTTS (more commonly the recipient) develop ascites, pericardial effusion, pleural effusion, and generalized edema of the head and body (hydrops fetalis).

Stage V: demise of one or both fetuses. 0.

Classification of selective fetal growth restriction (sFGR) based on umbilical artery Doppler assessment in the growth-restricted fetus (Gratacos et al. 2007) [6]

Type I: positive diastolic blood flow in the umbilical artery of the growth-restricted fetus;

Type II: absent or reversed end-diastolic flow in the umbilical artery;

Type III: intermittent umbilical artery blood flow (absent or reversed end-diastolic flow periodically alternating with a positive diastolic component on the spectral waveform).

Stages of twin anemia-polycythemia sequence (TAPS) [7]

Stage I: increased peak systolic velocity in the middle cerebral artery (MCA-PSV) of the donor fetus >1.5 MoM and decreased MCA-PSV of the recipient <1.0 MoM;

Stage II: increased MCA-PSV of the donor fetus >1.7 MoM and decreased MCA-PSV of the recipient <0.8 MoM;

Stage III: signs of heart failure in the donor fetus (absent or reversed umbilical artery flow, pulsatile umbilical venous flow, increased pulsatility index, or reversed flow in the ductus venosus);

Stage IV: hydrops fetalis in the donor;

Stage V: intrauterine demise of one or both fetuses.

1.6 Clinical presentation of the disease or condition

See Section 2.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Diagnostic criteria:

Multiple pregnancy is diagnosed when two or more viable embryos/fetuses (demonstrating cardiac activity) are visualized within the uterine cavity by pelvic and fetal ultrasound (US).

2.1 Complaints and Anamnesis

Symptom evaluation and medical history taking are performed in accordance with the 2023 clinical guidelines "Normal Pregnancy" [8].

2.2 Physical Examination

Physical examination is performed in accordance with the 2023 clinical guidelines "Normal Pregnancy" [8]. Gestational age is determined as follows.

• Patients with a multiple pregnancy are recommended to use the crown-rump length (CRL) of the fetuses based on first-trimester ultrasound to determine gestational age and expected date of delivery [9–11]. It is recommended to use fetal head circumference measurements to determine gestational age and delivery date on later-stage ultrasounds (when CRL >84 mm) [11, 12].

GSI CLEL 4Grade of Recommendations C (Level of Evidence – 4).

Comments: If there is a discrepancy between the gestational age estimated by the last menstrual period and ultrasound data, the gestational age should be established based on the ultrasound. To determine gestational age by ultrasound, the largest embryonic CRL must be used to avoid errors related to the developmental differences of one of the fetuses [13]. If first-trimester ultrasound data are not available, fetometry of the larger fetus during the second ultrasound at 18–22 weeks of gestation should be used to determine gestational age [11].

• In patients with multiple pregnancies resulting from assisted reproductive technology (ART), it is recommended to use the date of intrauterine embryo transfer and the duration of embryo culture to determine gestational age [10].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: When pregnancy results from ART, the expected date of delivery should be calculated based on the embryo transfer date (transfer date plus 266 days (38 weeks) minus the number of days corresponding to the embryo culture stage).

2.3 Laboratory Diagnostics

Laboratory screening is performed in accordance with the 2023 clinical guidelines "Normal Pregnancy" [8}.

2.4 Instrumental Diagnostics

Comments: Multiple pregnancy is diagnosed when ultrasound imaging reveals 2 or more embryos [1]. In multiple pregnancies, the ultrasound specialist additionally determines the chorionicity and amnionicity (number of chorions and amniotic cavities) (Appendix B). The number of yolk sacs generally corresponds to the number of amniotic cavities. The dichorionic type of placentation is characterized by the presence of the λ-sign, while the monochorionic type is characterized by the T-sign. The absence of visualization of the interamniotic membranes between the embryos indicates monochorionic monoamniotic multiple pregnancy. Color Doppler mapping (CDM) can be used to diagnose umbilical cord entanglement, which serves as additional confirmation of an MCMA twin pregnancy [12–14]. The diagnosis of conjoined twins is also established during the 1st trimester ultrasound [13]. It must be taken into account that the rate of false-positive results in 1st trimester screening is higher in multiple pregnancies than in singleton pregnancies [1, 19]. The risk of fetal anomalies in twin pregnancies is higher than in singleton pregnancies [13]. When performing 1st trimester ultrasound, it is also recommended to measure the pulsatility index (PI) in the uterine arteries to predict early preeclampsia.

• If it is impossible to unambiguously determine chorionicity in order to decide on further obstetric management, it is recommended to manage a multiple pregnancy as monochorionic until proven otherwise [1, 11].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• For the purpose of timely diagnosis of complications, it is recommended to refer a patient with a monochorionic multiple pregnancy for fetal ultrasound and color Doppler ultrasound of uteroplacental, fetoplacental, and fetal blood flow every 2 weeks starting from 16 weeks of gestation [Appendix A 3.1.] [11].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: During Doppler ultrasound of blood flow, blood flow is assessed in the umbilical cord artery, ductus venosus, and fetal middle cerebral artery (MCA). The most informative assessment is that of umbilical cord artery blood flow, which utilizes the PI value and the presence, absence, or reversal of the end-diastolic flow velocity waveform.

• For the purpose of timely diagnosis of complications, it is recommended to refer a patient with a dichorionic/trichorionic multiple pregnancy for fetal ultrasound every 4 weeks starting from 16 weeks of gestation [Appendix A 3.1.] [11].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• For the purpose of timely diagnosis of complications, it is recommended to refer a patient with a dichorionic/trichorionic multiple pregnancy for Doppler ultrasound of uteroplacental, fetoplacental, and fetal blood flow during fetal ultrasound at 18–20⁶ weeks of gestation and in the 3rd trimester of gestation (at 30–34 weeks of gestation) [Appendix A 3.1.] [20].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• For the purpose of timely diagnosis of complications, it is recommended to refer the patient for a screening ultrasound examination at nineteen to twenty-one weeks of gestation to assess antenatal fetal development in order to detect chromosomal abnormalities, malformations, risks of fetal growth restriction, preterm birth, and preeclampsia in multiple pregnancy (second-trimester screening), as well as to assess extraembryonic structures (localization, thickness, structure of the placenta, amount of amniotic fluid) and cervical ultrasound (cervicometry) at a medical organization providing expert-level prenatal diagnostics [Appendix A 3.1.] [21, 22].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• For the purpose of timely diagnosis of complications in pregnant women with multiple gestations, it is recommended to assess discordance in estimated fetal weight (EFW) starting from 20 weeks of gestation [Appendix A 3.1.] [23–25].

GSI CLEL 4Grade of Recommendations C (Level of Evidence – 4).

• In dichorionic/trichorionic multiple pregnancies, to determine further management tactics, it is recommended to verify the diagnosis of fetal growth restriction (FGR) based on fetal ultrasound revealing an estimated weight of one or both (several) fetuses below the 10th percentile and an EFW discordance of 25% or more [26–28].

GSI CLEL 4Grade of Recommendations C (Level of Evidence – 4).

• To determine further management tactics, it is recommended to refer a patient with a dichorionic/trichorionic multiple pregnancy and FGR for Doppler ultrasound of uteroplacental, fetoplacental, and fetal blood flow with a frequency depending on the degree of blood flow changes in the umbilical arteries: with a positive diastolic component of the blood flow velocity waveform in the umbilical arteries, every 1–2 weeks; with a absent or reversed diastolic component of the blood flow velocity waveform in the umbilical arteries, up to 26 weeks, weekly, and then twice a week with mandatory assessment of PI in the ductus venosus, as well as peak systolic velocity (PSV) and PI in the MCA [Appendix A 3.1.] [20].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: Criteria for worsening fetal condition include changes in blood flow in the ductus venosus, oligohydramnios, and centralization of fetal circulation [29]. Pregnancy with FGR in dichorionic/trichorionic multiple gestations may be prolonged to term only in cases of impaired umbilical artery blood flow with a positive diastolic component in the presence of positive fetal growth dynamics.

Diagnosis of twin-to-twin transfusion syndrome

• To diagnose twin-to-twin transfusion syndrome (TTTS) in pregnant women with monochorionic multiple pregnancy based on fetal ultrasound, it is recommended to rely on the presence of oligohydramnios in one fetus and polyhydramnios in the other; fetal biometry parameters have no diagnostic value in this case [20].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment: Oligohydramnios is diagnosed when the maximum vertical pocket (MVP) of amniotic fluid decreases below 2 cm in the donor fetus; polyhydramnios is diagnosed when the MVP increases above 8 cm before 20 weeks of gestation and above 10 cm after 20 weeks in the recipient fetus [20, 32].

• In pregnant women with monochorionic multiple pregnancies where a normal amount of fluid is diagnosed in one fetus and polyhydramnios (MVP greater than 8–10 cm) or oligohydramnios (MVP less than 2 cm) in the other, for the timely diagnosis of TTTS, it is recommended to assess the amount of amniotic fluid weekly during fetal ultrasound, as well as fetal blood flow Doppler parameters up to 26 weeks of gestation [11].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment: The diagnosis of TTTS is not established in this case. The risk of developing TTTS is 14% [33].

Diagnosis of selective fetal growth restriction syndrome

• In pregnant women with multiple pregnancies, for the purpose of diagnosing selective fetal growth restriction (sFGR), it is recommended to calculate EFW discordance using the formula: (weight of the larger fetus - weight of the smaller fetus) / weight of the larger fetus * 100 [6, 11, 28, 34, 35].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: The diagnosis of FGR can be made based on ultrasounds performed every 2 weeks, which reveal a decrease in the estimated weight of one of the fetuses below the 3rd percentile. Selective FGR can also be established based on a combination of several parameters: EFW deviation of one of the fetuses below the 10th percentile, a difference in EFW between the fetuses of 25% or more, abdominal circumference deviation below the 10th percentile (can be used in monochorionic pregnancy), and altered umbilical artery blood flow [36].

• In monochorionic multiple pregnancies complicated by sFGR, to improve perinatal outcomes, it is recommended to perform fetal ultrasound every 2 weeks, and Doppler ultrasound of uteroplacental, fetoplacental, and fetal blood flow weekly [37].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: Blood flow is assessed in the umbilical artery, ductus venosus, and fetal MCA [6]. In monochorionic pregnancy complicated by sFGR, blood flow in the umbilical artery of the growth-restricted fetus depends on the type and diameter of vascular anastomoses, which affect the umbilical artery blood flow waveform. This contributes to the appearance of a unique type of blood flow found only in monochorionic twins, called intermittent flow. It occurs in the presence of a large-diameter arterio-arterial anastomosis and uncoordinated heartbeats of both fetuses. Absent or reversed umbilical artery blood flow is an unfavorable prognostic factor for fetal condition compared to positive end-diastolic flow.

Diagnosis of twin anemia-polycythemia sequence

• To determine further management tactics for twin anemia-polycythemia sequence (TAPS) in monochorionic multiple pregnancy, it is recommended to diagnose it upon detecting anemia in one fetus and polycythemia in the other during fetal blood flow Doppler ultrasound (assessment of fetal MCA PSV) performed every two weeks starting from 20 weeks of gestation [7, 35].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: TAPS is characterized by a significant difference in hemoglobin levels between the twins in the absence of differences in amniotic fluid volume [36]. Diagnosis is based on the absence of ultrasound signs of TTTS. An increase in MCA-PSV (more than 1.5 MoM) in the donor fetus indicates anemia, while a decrease in MCA-PSV (less than 0.8 MoM) in the recipient fetus indicates polycythemia; a difference in MCA-PSV of 1 MoM or more also has diagnostic significance [35]. This complication of monochorionic multiple pregnancy may occur spontaneously or as a complication of laser coagulation of placental vascular anastomoses in TTTS. The spontaneous form of TAPS occurs in 3–5% of monochorionic multiple pregnancies, while the iatrogenic form occurs in 2–13% of cases following laser coagulation of anastomoses in TTTS [7]. Diagnosis of TAPS in the early neonatal period involves determining the hemoglobin and reticulocyte concentrations of the twins. The differences in hemoglobin and reticulocyte concentrations between the twins are evaluated (not compared to standard values!): $\geq$80 g/L and $\geq$1.7, respectively, which indicates TAPS. In uncomplicated monochorionic twins, a difference in newborn hemoglobin concentration may occur due to acute intrapartum TTTS or acute fetofetal transfusion after delivery of the first fetus. An increased reticulocyte ratio between the twins is considered an additional criterion for the differential diagnosis of TAPS and acute intrapartum TTTS: if it exceeds 1.7, this is a pathognomonic sign of TAPS [36]. Determining the staging of TAPS allows for the evaluation of treatment efficacy and the analysis of pregnancy outcomes complicated by TAPS [38].

Diagnosis of twin reversed arterial perfusion sequence

• To determine further management tactics, it is recommended to diagnose twin reversed arterial perfusion (TRAP) sequence in pregnant women with monochorionic multiples by fetal ultrasound visualization of gross developmental anomalies in one of the fetuses (underdevelopment of the head and upper body, soft tissue edema, absent functioning heart with fetal movements present, rudimentary heart) and reversed blood flow direction in the umbilical artery on color Doppler imaging (CDI) in the malformed fetus [39].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• To decide on further management tactics, pregnant women with TRAP sequence are recommended to be referred for echocardiographic evaluation of the pump fetus's heart (cardiothoracic ratio, ventricular wall thickness, ductus venosus blood flow) and measurement of the amniotic fluid volume (progression of polyhydramnios) of the pump fetus [40].

GCR BLOE 3Grade of Recommendation B (Level of Evidence – 3).

Diagnosis of complications of MCMA multiple pregnancy

• In monochorionic monoamniotic (MCMA) multiple pregnancy, for the timely diagnosis of complications, it is recommended to perform dynamic monitoring of fetal condition starting from 28 weeks of gestation using fetal cardiotocography every 3 days [41], and ultrasound Doppler velocimetry of fetoplacental blood flow [11, 42].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: Monoamniotic twins are associated with the highest risk of perinatal complications. In most cases, pregnancy loss is due to spontaneous miscarriage, fetal death (15–40%) [43, 44], or developmental anomalies (38–50%) [45]. Due to the free movement of the fetuses within a single amniotic cavity, their umbilical cords become entangled in the majority of cases.

Diagnosis of death of one or more fetuses

• A patient with a multiple pregnancy with suspected intrauterine death of one or more fetuses is recommended to undergo ultrasound examination with fetal blood flow Doppler velocimetry [46–51].

GCR BLEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade B (Level of Evidence – 2).

Comments: Death of one or more fetuses in multiple pregnancies occurs more frequently than in singleton pregnancies (5–7%). In dichorionic placentation, the pregnancy is managed as a singleton (the risk of death for the second twin is 3%, and the risk of neurological impairment is 2%). In monochorionic pregnancies, the risks of injury to the second twin are significantly higher (due to functioning placental anastomoses). The death of one of the fetuses in a monochorionic twin pregnancy can lead to the death (15%) or neurological impairment of the surviving child (26%) [6].

• Following the death of one of the fetuses in a monochorionic multiple pregnancy, it is recommended to assess the condition of the surviving fetus using ultrasound, CTG, and fetal blood flow ultrasound Doppler velocimetry with evaluation of MCA-PSV to diagnose potential anemia [41, 52–54].

GSI CLEL 4Grade of Recommendations C (Level of Evidence – 4).

• Following the death of one of the fetuses in a monochorionic multiple pregnancy, to exclude structural brain damage, it is recommended to perform fetal neurosonography [55].

GCR BLOE 3Grade of Recommendation B (Level of Evidence – 3).

• Following the death of one of the fetuses in a monochorionic multiple pregnancy, to rule out structural brain damage, it is recommended to consider the possibility of magnetic resonance imaging (MRI) of the brain of the second developing fetus after 32–34 weeks of gestation, but no earlier than 4 weeks after the death of the first fetus [36].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

2.5 Other Procedures

• Pregnant women with monochorionic multiples, for the timely diagnosis of obstetric complications, are recommended to have an appointment (examination, consultation) with an obstetrician-gynecologist once every 2 weeks starting from 16 weeks of gestation (including monitoring blood pressure, weight gain, and laboratory parameters) [56].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• Pregnant women with di/trichorionic multiples, for the timely diagnosis of obstetric complications, are recommended to have an appointment (examination, consultation) with an obstetrician-gynecologist once every 4 weeks from 16 to 34 weeks of gestation, and thereafter once every 2 weeks (including monitoring blood pressure, weight gain, and laboratory parameters) [56].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: To rule out fetal aneuploidy, the patient may be offered non-invasive prenatal testing (cell-free fetal DNA testing via maternal blood) after 10 weeks of gestation [57–59].

• In the event of the death of one of the fetuses after 10 weeks of gestation, for chromosomal disorder screening, it is recommended to use only fetal ultrasound data with nuchal translucency (NT) measurement, as hCG and PAPP-A levels will not objectively reflect the condition of the living fetus [19, 60].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• In the event of the death of one of the fetuses prior to 10 weeks of gestation, for chromosomal disorder screening, it is recommended to use a combination of fetal ultrasound results and serum levels of pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin ($\beta$-hCG), just as in a singleton pregnancy [56].

GCR CLEL 5Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade C (Level of Evidence – 5).

• In multiple pregnancies with three or more embryos, it is recommended to consider embryo reduction at 10–12 weeks of gestation [61, 62].

GCR ALEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade A (Level of Evidence – 2).

Comment: Second-trimester biochemical screening may be prescribed if first-trimester screening results are unavailable [65].

• For the diagnosis of chromosomal abnormalities, it is recommended to refer a patient with a high risk of fetal/fetal aneuploidy based on first- and second-trimester screening and/or NIPT, and/or fetal developmental anomalies detected on first- and second-trimester ultrasound, for medical genetic counseling. In cases of high risk for fetal malformations, the patient is recommended to undergo invasive prenatal diagnostics (chorionic villus sampling, placental biopsy, amniocentesis) with cytogenetic analysis (karyotyping) of the obtained material [66–69]. If invasive prenatal testing is prescribed, it is recommended to perform the procedure on both fetuses regardless of the type of placentation [13].

GCR CLEL 2Grade of recommendation C (level of evidence – 2).

Comments: Chorionic villus sampling is performed at 10–14 weeks of pregnancy. Amniocentesis is performed at a gestational age of >15 weeks. An individual high risk of fetal chromosomal disorders according to 1st-trimester screening is ≥1/100. Contraindications to invasive prenatal diagnosis include: infectious and inflammatory diseases of any localization, threatened miscarriage. In cases of Rh(D) sensitization, the potential benefit/risk ratio of invasive diagnosis must be weighed [66]. Research methods for fetal material after invasive prenatal diagnosis are determined by a geneticist. Currently, cytogenetic analysis (karyotype analysis) of fetal material is the most widespread. Molecular cytogenetic analysis (FISH method) (Fluorescence in Situ Hybridization, FISH) is used to detect chromosomal abnormalities. High-resolution chromosomal microarray analysis (CMA) makes it possible to analyze both aneuploidies, including mosaic forms, and copy number variations (CNVs) – microdeletions, microduplications, unbalanced translocations [19]. The risk of pregnancy loss after invasive prenatal diagnosis in multiple pregnancy is higher than in singleton pregnancy; after chorionic villus sampling in twins it is 2–3.8%, after amniocentesis – 1.5–3.1% [13, 15–17].

• When performing invasive prenatal diagnosis, a chorionic villus/placental biopsy is recommended for the patient at 11–14 weeks of gestation, since earlier diagnosis of chromosomal diseases allows for pregnancy termination or selective fetal reduction with a lower risk of complications [13].

GCR CLEL 2Grade of recommendation C (level of evidence – 2).

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

3.1 Non-pharmacological methods for symptom management

Non-pharmacological methods for correcting complaints in patients with multiple pregnancy are carried out in accordance with the 2023 clinical guidelines "Normal Pregnancy" [8].

3.2 Pharmacological methods for symptom management

Pharmacological methods for correcting complaints, the administration of vitamins and dietary supplements to patients with multiple pregnancy are carried out in accordance with the 2023 clinical guidelines "Normal Pregnancy" [8].

3.3 Treatment of complications of multiple pregnancy

Treatment of twin-to-twin transfusion syndrome

• Pregnant women with TTTS are recommended the following treatment methods: serial amnioreduction; fetoscopic laser coagulation of placental vascular anastomoses (selective/non-selective/Solomon technique) [70].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

Comments: Serial amnioreduction consists of repeatedly reducing the volume of amniotic fluid via a transabdominal approach in the recipient twin and prolonging the pregnancy. The method is used in stage I TTTS diagnosed at a gestation of more than 26 weeks, as well as in cases of syndrome recurrence after fetoscopic laser coagulation of placental anastomoses (FLCP) and when there is no technical capability to perform laser coagulation of anastomoses.

• Pregnant women with stage II–IV TTTS, in the absence of contraindications at a gestational age of 16–26 weeks, are recommended to undergo laser coagulation of placental vascular anastomoses [45, 71, 72].

GCR ALEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade A (Level of Evidence – 2).

Comments: There are differences in the surgical technique; the intervention is performed with varying degrees of selectivity. The use of the Solomon technique reliably increases survival and reduces the recurrence rate of TTTS, but increases the risk of placental abruption [73]. To improve perinatal prognosis, performing FLCP before 28 weeks of gestation may be considered in the absence of contraindications and with the patient's consent [74].

• Following intrauterine intervention, due to the risk of pregnancy loss, it is recommended to provide inpatient treatment under the control of sonographic and laboratory parameters [75].

GCR CLEL 5Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade C (Level of Evidence – 5).

Comments: The choice of drugs, dosage, and duration of therapy are determined individually, according to existing protocols. Progesterone** is used at a dose of 200 mg daily vaginally [76]. Hexoprenaline** is prescribed according to the instructions; the drug dosage is selected individually. Intravenous tocolysis is performed with the woman lying on her left side, preferably under cardiac monitoring [77–79]. Atosiban** (oxytocin receptor blocker) is administered intravenously in 3 consecutive steps according to the instructions. Re-administration can be started at any time after the first use of the drug, and can be repeated for up to 3 cycles [77–79]. #Nifedipine** is not registered as a tocolytic agent and is used off-label, therefore, prior to its use, a conclusion of the medical commission (head of the department and 2 obstetrician-gynecologists) and the patient's written informed consent are required. Regimen: 20 mg orally, then if uterine contractions persist, repeat 20 mg after 30 minutes, then 20 mg every 3–8 hours for 48 hours as indicated; maximum dose 160 mg/day [73, 74, 76]. #Indomethacin** (nonsteroidal anti-inflammatory drug) is prescribed based on the conclusion of the medical commission, after obtaining the patient's consent to use the drug off-label [81]. It is used starting with 50–100 mg rectally or orally, then 25 mg every 6 hours (no more than 48 hours) [77, 78, 80, 82].

• In case of successful antenatal treatment of TTTS, patients with multiple pregnancy are recommended delivery at 35–36 weeks of gestation for the prevention of perinatal complications [83]

GSI CLEL 4Grade of Recommendations C (Level of Evidence – 4).

• Pregnant women with TTTS are recommended to undergo fetoscopic laser coagulation of placental vascular anastomoses via a transabdominal approach under intravenous, local, or regional anesthesia, with antibiotic prophylaxis (cefoxitin**, cefuroxime**, cefamandole**, cefaclor**, cefotaxime**, ceftazidime**, ceftriaxone**, ceftizoxime**, cefixime**, cefoperazone**) and tocolysis (#indomethacin, #nifedipine**, atosiban**, hexoprenaline**). The choice of drugs is made individually) [84, 85]. The operation is completed with amnioreduction until a normal amount of amniotic fluid is achieved (maximum vertical pocket 4–6 cm) [86].

GSI CLEL 4Grade of Recommendations C (Level of Evidence – 4).

Comments: The complication rate after FLCP remains quite high: premature rupture of membranes – 34–42%, pregnancy termination – 17%, recurrence of TTTS – 1.5–9%, twin anemia-polycythemia sequence (TAPS) development – 3–16%, placental abruption – 1%, septostomy – 10–15%, chorioamnionitis – 0–1%, membrane separation – 5–10%, bleeding during coagulation – 2–7%. Survival of one or both twins after FLCP is 70–88% [87].

• In pregnant women with multiple pregnancy, selective fetal reduction (fetocide) (cessation of cardiac activity) is recommended in the presence of gross structural malformations in one of the fetuses, a combination of TTTS with selective fetal growth restriction (sFGR) of one of the fetuses with discordance greater than 40% (up to 22 weeks of gestation), or in stage IV TTTS when FLCP is technically unfeasible. Laser coagulation of the umbilical cord vessels of one of the fetuses is performed via fetoscopic or puncture approach [88].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: The decision on the intervention is made in each case by a medical board after discussion with the patient and her husband/partner and obtaining their informed voluntary consent.

• Pregnant women after intrauterine surgery are recommended to undergo ultrasound dopplerography of feto-placental and fetal blood flow for the timely diagnosis of possible antenatal fetal death, assessment of visualization of the donor twin's urinary bladder, and measurement of the maximum vertical pocket of the fetuses. [89–92]

GCR ALEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade A (Level of Evidence – 2).

Comments: Intrauterine treatment of patients with complicated monochorionic multiples requires monitoring of the patient's comprehensive laboratory examination parameters (complete blood count, biochemical blood test, microbiological (culture) and microscopic examination of vaginal smears) [93, 94].

• Pregnant women in the event of the death of one of the fetuses after treatment are recommended to continue expectant management in order to prolong the pregnancy [56, 95].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: Pregnancy is managed under the control of the mother and fetus condition, fetal ultrasound parameters, fetal blood flow ultrasound dopplerography, detailed complete blood count, C-reactive protein, and coagulogram parameters. In the absence of leukocytosis and elevated C-reactive protein levels, antibacterial therapy is not indicated. If there is no deterioration in the condition of the second twin according to functional examination methods, delivery is performed at term. After any type of surgical intervention, ultrasound and blood flow dopplerography monitoring is carried out at intervals of 1–2 weeks until the time of delivery [36].

Treatment of selective fetal growth restriction syndrome

• In pregnant women with monochorionic multiple pregnancy complicated by sFGR, decompensation of the growth-restricted fetus's condition, and visualization of a reverse a-wave in the ductus venosus after 28 weeks of gestation, it is recommended to consider this as an indication for early delivery via Cesarean section following fetal respiratory distress syndrome (RDS) prophylaxis [11, 96].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment: The question of the timing of delivery is decided individually after fetal respiratory distress syndrome (RDS) prophylaxis (#betamethasone**, #dexamethasone** in a total dose of 24 mg [4 mg every 8 hours #6, 12 mg every 24 hours #2] is prescribed according to the conclusion of the medical commission, after previously obtaining the patient's consent for the off-label use of the drug) [81, 96].

• In pregnant women with monochorionic multifetal gestation complicated by selective fetal growth restriction (SFGR), due to the high risk of fetal demise in type I SFGR, delivery is recommended at 34–35 weeks, and in types II and III at 30–32 weeks of gestation [6, 97, 98].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Treatment of twin anemia-polycythemia sequence

• In pregnant women with monochorionic multifetal gestation complicated by twin anemia-polycythemia sequence (TAPS), in the absence of signs of severe donor-twin anemia (MCA-PSV less than 1.6 MOM, absence of hydrops), it is recommended to manage the pregnancy conservatively with regular fetal ultrasound at least once every 2 weeks [7, 38].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• If severe fetal anemia is detected between 16 and 26 weeks of gestation, fetoscopic laser coagulation of placental vascular anastomoses is recommended [7].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• If fetoscopy and laser coagulation of placental vascular anastomoses are not feasible in pregnant women with severe TAPS between 16 and 32 weeks of gestation, surgical treatment in the form of intrauterine blood transfusion to the anemic fetus is recommended [38].

GSI CLEL 4Grade of Recommendations C (Level of Evidence – 4).

• Delivery in monochorionic multifetal gestation complicated by TAPS is recommended before 36 weeks of gestation [99, 100].

GCR ALEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade A (Level of Evidence – 2).

Treatment of twin reversed arterial perfusion sequence

Comments: Delivery is performed electively at term in a Level III obstetric hospital.

• In pregnant women with monochorionic multifetal gestation and progression of TRAP sequence (increase in the mass of the acardiac twin; increase in its dimensions exceeding 50% of the size of the pump twin; presence of blood flow in its vessels; decompensation of the pump twin—presence of ultrasound signs of cardiomyopathy and polyhydramnios), intrauterine surgical intervention aimed at stopping the blood supply to the acardiac twin via laser coagulation of the umbilical cord vessels is recommended [101, 102], [102–106].

GCR ALEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade A (Level of Evidence – 2).

• In pregnant women with monochorionic multifetal gestation complicated by TRAP sequence, interstitial or fetoscopic laser coagulation of the umbilical cord vessels of the acardiac twin under ultrasound guidance is recommended [101, 102].

GCR ALEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade A (Level of Evidence – 2).

• In monoamniotic twins, to prevent umbilical cord entanglement, fetoscopic laser coagulation of the umbilical cord vessels of the acardiac twin followed by its transection is recommended [39, 107].

GCR ALEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade A (Level of Evidence – 2).

Comments: The medical birth record in TRAP sequence is executed as the birth of a single newborn. The acardiac twin is evaluated as a conceptus (due to the absence of cardiac activity).

Management of death of one or more fetuses

• In pregnant women with monochorionic multifetal gestation and single fetal demise, to prevent perinatal and neonatal complications, emergency delivery is not recommended in the absence of other obstetric indications and data indicating compromise of the second fetus [6, 11, 28, 34].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: In the event of single fetal demise in a monochorionic twin pregnancy, it is recommended to observe the pregnant woman in a hospital setting for 7–14 days under strict monitoring of clinical and laboratory parameters (complete blood count, C-reactive protein, coagulopathy markers) and fetal condition [3]. In the absence of signs of inflammation (leukocytosis, elevated C-reactive protein levels), antibacterial therapy is not recommended [36]. Subsequently, the patient is monitored on an outpatient basis, with fetal ultrasound performed once every 2 weeks.

• In the event of single fetal demise in a monochorionic twin pregnancy, delivery of the pregnant woman is recommended at 34–36 weeks after fetal RDS prophylaxis [36].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• In the event of single fetal demise in a dichorionic twin pregnancy, in the absence of other obstetric indications and data indicating compromise of the second fetus, it is recommended to manage the pregnancy expectantly under strict monitoring of fetal condition via ultrasound and the pregnant woman's laboratory test parameters [6, 11, 28, 34].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: It is recommended to observe the pregnant woman in a hospital setting for 7–14 days, monitoring clinical and laboratory parameters (complete blood count, serum C-reactive protein level, coagulogram [screening hemostasis test]), and fetal condition. Subsequently, fetal ultrasound is performed once every 4 weeks. In the absence of leukocytosis and elevated C-reactive protein levels, antibacterial therapy is not indicated. Demise of one of the fetuses in a dichorionic twin pregnancy generally poses no threat to the surviving twin, since the dichorionic placentation type lacks vascular anastomoses between the fetal blood circulation systems. In the event of single fetal demise in a dichorionic twin pregnancy, prolongation of pregnancy is possible until term [6, 11, 28, 34].

3.4 Delivery in multiple pregnancy

• It is recommended to discuss the timing of delivery and possible delivery methods with patients pregnant with twins or triplets at the beginning of the 3rd trimester of pregnancy [108, 109].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• In uncomplicated monochorionic twin pregnancy, delivery is recommended at 36–37 weeks, dichorionic twin pregnancy at 37–38 weeks, and triplet pregnancy at 35–36 weeks [1, 108, 110].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: Elective delivery of a monochorionic twin pregnancy from 36 weeks 0 days, a dichorionic twin pregnancy from 37 weeks 0 days, and a triplet pregnancy from 35 weeks 0 days is associated with the lowest risks of complications. Prolongation of an uncomplicated twin pregnancy beyond 38 weeks increases the risk of intrauterine fetal demise. In pregnant women with triplets, risks increase after 36 weeks of gestation [1]. Patients who refuse elective delivery at the specified times are advised to receive counseling regarding the risks, execute an informed refusal of intervention, and schedule weekly physician visits for ultrasound and fetal condition assessment [36].

• In uncomplicated monochorionic monoamniotic (MCMA) twin pregnancy, delivery via Cesarean section at 32–34 weeks is recommended [1, 108, 110].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Mode of delivery

• To choose the method of delivery, it is recommended to take into account the following factors: gestational age, degree of perinatal risk, number of fetuses, chorionicity and amnionicity, fetal lie and presentation, estimated fetal weights, presence of obstetric complications, maternal status (extragenital diseases), and the presence of the patient's informed voluntary consent [71, 98, 111, 112].

GCR BLEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade B (Level of Evidence – 2).

• At a gestational age of 32 weeks or more with cephalic presentation of the first twin, the patient should be informed that vaginal delivery is not associated with an increased risk of complications for the mother and newborns [111, 112].

GCR BLEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade B (Level of Evidence – 2).

Comments: In an uncomplicated twin pregnancy with cephalic presentation of the first twin at 32–38 weeks of gestation, vaginal delivery does not increase the risk of perinatal complications [111, 112]. When planning a vaginal delivery at 32 weeks or more, the success rate of vaginal delivery is 65%–75%; the probability of Cesarean section for the delivery of the second twin after vaginal delivery depends on staff experience and ranges from 3% to 10% [111, 112]. Based on the counseling results, a medical board decision with a delivery plan and the patient's signature is documented in the pregnancy medical record. Vaginal twin delivery is classified as a high-risk delivery, and the patient must be informed of this.

Comments: With careful patient selection, survival of the second twin following delayed-interval delivery of more than 24 hours can significantly improve perinatal outcomes [114]. Given the certain risk of potential complications for both the mother and the second twin (primarily associated with the likelihood of infectious complications), delayed-interval delivery of the second twin is possible only in a Level III facility against the background of antibacterial therapy, provided that an interdisciplinary medical board is organized and the patient's informed voluntary consent is obtained.

• To improve perinatal outcomes and reduce the risk of fetal trauma during delivery in preterm birth with an estimated fetal weight of less than 1,500 g, patients carrying twins are recommended to consider Cesarean section [71, 111].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: Indications for cesarean section: monoamniotic twins; conjoined twins at any gestational age; non-cephalic presentation of the 1st fetus; three or more fetuses; standard indications for singleton pregnancy [1, 36, 71, 111, 112, 115]. There are no reliable data on the safety and potential success of vaginal delivery after a previous cesarean section in twin pregnancies. The rate of uterine rupture in the presence of a lower uterine segment scar in women with multiple pregnancies is no higher than in singleton pregnancies; therefore, the choice of delivery method is decided on an individual basis in each case. If a woman wishes to give birth via the natural birth canal, counseling regarding the risks is required, and informed voluntary consent must be obtained [114].

Comment: Studies conducted have not obtained reliable data on the improvement of perinatal outcomes with operative delivery in women with DCDA twins [116–118].

• Preparation of the soft birth canal for labor in multiple pregnancies is recommended to be carried out using mechanical and pharmacological methods [119, 120].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: Labor preinduction is performed using mechanical methods: hygroscopic dilators, intracervical catheter. Pharmacological methods include mifepristone and dinoprostone** [121]. A prerequisite for cervical ripening and labor induction is obtaining the patient's informed voluntary consent.

Vaginal delivery

• To assess the progress of labor in a patient with a multiple pregnancy, fetal monitoring using fetal cardiotocography is recommended [122, 123].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• In a patient with a multiple pregnancy, induction of labor and oxytocin** labor augmentation are recommended to be performed according to the same indications and in the same regimen as in singleton pregnancies [119].

GSI CLEL 4Grade of Recommendations C (Level of Evidence – 4).

- separate CTG registration for each fetus;

- the possibility of managing labor under epidural analgesia (ensuring rapid and adequate anesthesia during obstetric procedures);

- the possibility of immediate operative vaginal delivery (vacuum extraction, internal podalic version, breech extraction, cord repositioning in case of cord prolapse);

- the possibility of acute tocolysis (hexoprenaline** 10 mcg intravenously over 5 minutes);

- availability of neonatal resuscitation systems.

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• To prepare for the 2nd stage of labor, it is recommended to ensure [123, 124]:

- team assembly: two obstetrician-gynecologists, a midwife, an anesthesiologist-resuscitologist, an anaesthetic nurse, two neonatologists;

- preparation of necessary obstetric equipment (prepare oxytocin** infusion in advance);

- preparation of necessary anesthetic equipment (general anesthesia and acute tocolysis may be required);

- preparation of neonatal equipment for multiple children.

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment: Management of the 2nd stage of labor during the birth of the first fetus does not differ from that of a singleton pregnancy.

• After the birth of the first fetus, it is recommended to stop the oxytocin** infusion in order to determine the presentation and position of the second fetus (if not done previously) [123].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• In monochorionic twins, the umbilical cord of the first fetus is recommended to be clamped immediately after birth to prevent acute twin-to-twin transfusion syndrome [125].

GSI CLEL 4Grade of Recommendations C (Level of Evidence – 4).

• Following the birth of the first fetus, a patient with a multiple pregnancy is recommended to undergo external obstetric and bimanual vaginal examinations to determine the position, presentation, and station of the presenting part of the second fetus relative to the pelvic inlet [124].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment: If necessary, it is advisable to perform an ultrasound of the second fetus.

Comments: An interval of 30 minutes between the birth of twin fetuses can be considered optimal, as it is associated with the best outcomes for newborns. After this period, the obstetric situation should be carefully evaluated, and a decision on further labor management should be made. If uterine inertia is effectively corrected, the presenting part is progressively advancing, and the condition of the mother and fetus is satisfactory, labor can be continued conservatively. In case of unsatisfactory labor progress, the issue of operative delivery should be considered [2].

• If the position of the second fetus is longitudinal (cephalic or breech presentation), it is recommended to apply the following algorithm of actions [123, 124]:

- in the absence of contractions, start or continue intravenous infusion of oxytocin** at a rate of 5 mIU/min (3 ml/h), gradually increasing until contractions resume;

- continuous CTG monitoring;

- when contractions become regular and the presenting part is pressed against the pelvic inlet, perform amniotomy;

- if contractions weaken, perform amniotomy immediately upon establishing the longitudinal position and pressed presenting part of the 2nd fetus, then start titrated oxytocin induction**;

- if the fetal heart rate is within normal limits, wait for spontaneous birth of the fetus;

- vacuum extraction and application of obstetric forceps are performed according to standard indications;

- in case of fetal heart rate abnormalities and breech presentation, perform breech extraction.

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment: The risk of intrapartum complications for the second fetus during vaginal delivery is higher.

• In case of oblique or transverse lie of the second fetus, it is recommended to perform an external cephalic version under ultrasound guidance [123, 124].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comments: Acute tocolysis may sometimes be required for a more successful version. If the version is successful, labor is managed as in a longitudinal lie. If external version is ineffective, at the time of amniotic fluid leakage/amniotomy, a single attempt at combined internal-external podalic version and (only for emergency indications) breech extraction may be attempted. This procedure requires adequate pain relief (epidural, spinal, or intravenous anesthesia) and uterine relaxation, which is achieved through acute tocolysis. If internal podalic version and breech extraction are impossible, a cesarean section should be performed in the best interest of the 2nd fetus. Such labor is referred to as combined delivery.

- lack of progress in the descent of the presenting part due to uterine inertia unresponsive to medical correction;

- failed attempt at external cephalic version or combined internal-external podalic version and breech extraction;

- fetal distress and lack of conditions for operative vaginal delivery.

Grade of Recommendation CLevel of Evidence 5Grade of Recommendation C (Level of Evidence – 5).

• After the birth of the second fetus, administration of oxytocin** is recommended [123].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• In the early postpartum period, additional administration of oxytocin** infusion is recommended, since the rate of hemorrhage in multiple pregnancies is on average 3 times higher than in singleton deliveries [129].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

• In the early postpartum period, speculum examination of the cervix and vagina, and repair of cervical, vaginal, and perineal tears are recommended [2].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

• In the early postpartum period, careful monitoring of uterine tone, amount of lochia, pulse rate, blood pressure, skin color, and patient complaints is recommended [2].

GR CLEL 5Grade of Recommendation C (Level of Evidence – 5).

Comment: In the absence of contraindications during the early postpartum period, it is advisable to keep the mother and children together, initiate early breastfeeding, and teach the mother techniques for feeding two or more children.

3.5 Anesthesia considerations in multiple pregnancy

• During anesthesia and intensive care in a pregnant woman with a multiple pregnancy, the anesthesiologist-resuscitologist and obstetrician-gynecologist are recommended to take into account the physiological characteristics of a pregnant woman with a multiple pregnancy [130–139].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: Multiple pregnancies are characterized by: an increase in uterine size; enhanced uterine blood flow; cardiovascular changes in the form of increased heart size, greater functional load (contractility, heart rate (HR)); decrease in blood pressure (mean, diastolic) in the 3rd trimester of pregnancy; increased effect of aortocaval compression both during labor and during cesarean section under anesthesia; an increase in circulating blood volume by 500-750 ml, which is accompanied by an additional increase in cardiac output (up to 20%), stroke volume (up to 15%), and HR (up to 4%).

• For patients with multiple pregnancy undergoing invasive procedures, surgeries during pregnancy, and delivery via cesarean section, for adequate anesthetic management, it is recommended to use local, infiltration, and neuraxial anesthesia methods (epidural, spinal, combined spinal-epidural) as well as general anesthesia [56, 62, 122, 140–143].

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

Comments: For minimally invasive endoscopic or puncture-based intrauterine interventions, local, infiltration, or neuraxial anesthesia is used; in other cases, any anesthetic option (inhalation, intravenous, neuraxial) with maintained spontaneous breathing. In certain critical conditions (shock, blood loss, sepsis), anesthesia with mechanical ventilation may be required [144–150].

• For patients with multiple pregnancy during vaginal delivery, it is recommended to use neuraxial anesthesia (epidural, spinal) as the method of labor pain relief in the absence of contraindications [151–153].

GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).

Comments: Given the increased risk of surgical intervention during labor, the use of neuraxial pain relief methods allows for rapid modification of the anesthetic management and reduces the potential need for emergency general anesthesia. Epidural analgesia may also reduce the need for an emergency cesarean section for the 2nd fetus after the vaginal delivery of the 1st fetus [56, 122, 154–158].

• For patients with a multiple pregnancy prior to general anesthesia, prophylaxis of aspiration syndrome is recommended to prevent pulmonary complications [159–161].

Level of Evidence BLevel of Confidence 2Level of recommendation B (level of evidence – 2).

Comments: During vaginal delivery, due to the high risk of aspiration syndrome, fluid intake should be restricted and food intake should be avoided. Aspiration prophylaxis includes a "nil by mouth" policy (clear liquids at least 2 hours, and solids at least 6–8 hours prior to surgery) [162–168].

• For patients with a multiple pregnancy during cesarean section under neuraxial anesthesia (epidural, spinal, combined spinal-epidural), it is recommended to use a lateral tilt position (up to 30^°), [169, 170].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

• For postoperative pain management, it is recommended to use continuous epidural analgesia, regional anesthesia (Transversus Abdominis Plane block – TAP) [171–173].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1).

• For postoperative pain management, the use of paracetamol** is recommended; if breastfeeding is discontinued, opioids and non-steroidal anti-inflammatory drugs may be additionally used [165, 174–179].

GPP ALOE 1Grade of Recommendation A (Level of Evidence – 1).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Not applicable.

5. Prevention and Dispensary Observation

5.1. Recommendations for the prevention of pregnancy complications

Recommendations on eliminating risk factors for the prevention of pregnancy complications are given in accordance with the 2023 clinical guidelines on "Normal Pregnancy" [8].

5.2. Prevention of preeclampsia

• If the patient has risk factors for preeclampsia (age 40 years or older, interpregnancy interval of more than 10 years, body mass index of 35 kg/m² or more at the first visit, history of preeclampsia), the administration of #acetylsalicylic acid** daily from 12 to 36 weeks of pregnancy at 150 mg per day is recommended [180, 181].

GCR ALEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade A (Level of Evidence – 2).

Comments: Multiple pregnancy is classified as a moderate risk factor for the development of preeclampsia.

5.3. Prevention of preterm birth

• For the prevention of preterm birth, it is recommended to perform an ultrasound examination of the uterine cervix (ultrasound cervicometry) at 16–20 weeks of gestation [182].

GCP BLeE 1Grade of recommendation B (Level of evidence – 1).

Comment: A cervical length of 25 mm or less indicates the risk of pregnancy loss and very early preterm birth [182].

• For patients with a multiple pregnancy, prophylactic cervical cerclage is not recommended [185, 186].

GCR ALEL 2Grading of Recommendations Assessment, Development and Evaluation — Recommendation Grade A (Level of Evidence – 2).

Comments: The need for cervical cerclage may be considered on a consultative basis in case of cervical shortening in patients with an burdened obstetric history (pregnancy losses, preterm birth), or pregnancy complicated by TTTS.

• For patients with multiple pregnancy, routine placement of an obstetric support pessary is not recommended as it does not reduce the rate of spontaneous preterm birth [110, 190–194].

GRC ALOE 1Grade of Recommendation A (Level of Evidence – 1)

• If an intrauterine intervention is required and the cervix is shortened, the placement of an obstetric support pessary is recommended, as this reduces the rate of spontaneous preterm birth up to 34 weeks of gestation [110, 190, 191, 195].

GCR ALEL 1Grading of Recommendations Assessment, Development and Evaluation A (Level of Evidence – 1).

5.4. Prevention of venous thromboembolic events

Comments: There is no compelling evidence regarding the necessity of pharmacological thromboprophylaxis during pregnancy, as well as after vaginal delivery in women with a multiple pregnancy without additional significant risk factors. An individual assessment of all risk factors for venous thromboembolic events is required (especially comorbidities, ART, pregnancy and delivery complications, significant thrombophilia) [200].

Comments: The combination of a multiple pregnancy and delivery via cesarean section classifies these patients into the moderate risk group for developing venous thromboembolic events; individual risk factor assessment and, if necessary, prolongation of pharmacological thromboprophylaxis are required [203].

5.5. Prevention of Rhesus isoimmunization

• For a pregnant Rh-negative patient with a negative anti-Rh antibody titer not detected at 28 weeks, the administration of human anti-Rh Rho[D] immunoglobulin** at 28–30 weeks of gestation at a dose according to the product insert, intramuscularly, is recommended [204, 205].

GCR ALEL 1Grading of Recommendations Assessment, Development and Evaluation A (Level of Evidence – 1).

Comments: If the husband's/partner's blood is Rh-negative, the administration of human anti-Rh Rho(D) immunoglobulin** at 28–30 weeks is not performed. In the case of non-invasive determination of fetal Rh-negative blood type using cell-free fetal DNA circulating in maternal blood, the administration of human anti-Rh Rho(D) immunoglobulin** at 28–30 weeks is not performed.

• For a pregnant Rh-negative patient with a negative anti-Rh antibody titer undergoing invasive intrauterine surgeries, the administration of human anti-Rh Rho(D) immunoglobulin** at a dose according to the product insert, intramuscularly, is recommended [66, 206].

ForCLoE 4Level of Evidence C (Level of Likelihood of Evidence – 4).

Comment: Amniocentesis and chorionic villus sampling can lead to maternal Rh sensitization if the mother's blood is Rh-negative and the fetus's blood is Rh-positive [207–210].

5.6. Vaccination during pregnancy

Vaccination during pregnancy is carried out in accordance with the 2023 clinical guidelines on "Normal Pregnancy" [8].

6. Organization of Medical Care

• Pregnant women with an uncomplicated multiple pregnancy should deliver in a level 2 or level 3 obstetrical hospital.

• Pregnant women with MCMA pregnancies should be hospitalized in a level 2 or level 3 obstetrical hospital at 30–32 weeks of gestation.

• Patients with monochorionic multiples complicated by TTTS, sFGR, TRAP, or TAPS should be offered counseling (including via telemedicine) and treatment in a level 3 obstetrical hospital; in cases of sFGR, demise of one or more fetuses in monochorionic multiples, or when embryo reduction in the 1st trimester is required – delivery or embryo reduction in a level 3 obstetrical hospital; in cases of TTTS, TAPS, or TRAP – delivery in a level 3 obstetrical hospital equipped with the capabilities and technical infrastructure for fetoscopic surgeries.

Indications for hospitalization in an obstetric-gynecological hospital:

- Clinical manifestations of threatened miscarriage.

- Cervical shortening to less than 25 mm according to transvaginal ultrasound.

- Development of specific complications of monochorionic multiple pregnancy requiring intrauterine interventions (TTTS, sIUGR, TAPS).

- Patients with selective fetal growth restriction (sIUGR), type I at 33-34 weeks, types II and III at 29-30 weeks.

- Antenatal death of one or both fetuses.

- Clinical manifestations of threatened preterm labor.

- Rupture or leakage of amniotic fluid.

- Clinical manifestations of placental abruption with normally positioned placenta.

- Clinical manifestations of preeclampsia.

- Onset of labor.

7. Additional Information

Not applicable.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Gladkova Kristina Alexandrovna – Candidate of Medical Sciences, Head of the 1st Department of Pregnancy Pathology, Senior Research Fellow at 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

2. Sichinava Lali Grigorievna – Doctor of Medical Sciences, Professor at the Department of Obstetrics and Gynecology, Pediatric Faculty, Pirogov Russian National Research Medical University (Moscow). No conflict of interest

3. Kostyukov Kirill Vitalievich – Doctor of Medical Sciences, Head of the Department of Ultrasound and Functional Diagnostics, Senior Research Fellow at 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.

4. Gorina Ksenia Alekseevna – Candidate of Medical Sciences, Obstetrician-Gynecologist at the 1st Department of Pregnancy Pathology, Researcher at 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.

5. Dolgushina Natalia Vitalievna – Doctor of Medical Sciences, 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). No conflict of interest.

6. Sakalo Victoria Anatolievna – Candidate of Medical Sciences, Obstetrician-Gynecologist at the 1st Department of Pregnancy Pathology, Researcher at 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.

7. Serov Vladimir Nikolaevich – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Honored Scientist of the Russian Federation, President of the Russian Association of Obstetricians and Gynecologists, Chief Researcher, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

8. Tetruashvili Nana Kartlosovna – Doctor of Medical Sciences, Head of the 2nd Department of Pregnancy Pathology, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health (Moscow). No conflict of interest.

9. Shmakov Roman Georgievich – Doctor of Medical Sciences, 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.

10. Natalia V. Artymuk – MD, PhD, Professor, Head of the Department of Obstetrics and Gynecology named after Professor G.A. Ushakova, Kemerovo State Medical University of the Russian Ministry of Health, Chief Freelance Specialist in Obstetrics, Gynecology, and Women's Reproductive Health of the Russian Ministry of Health in the Siberian Federal District (Kemerovo). No conflict of interest.

11. Nadezhda V. Bashmakova – MD, PhD, Professor, Chief Researcher, Ural Research Institute for Maternal and Infant Care of the Russian Ministry of Health, Chief freelance specialist in obstetrics, gynecology, and women's reproductive health of the Russian Ministry of Health in the Ural Federal District. No conflict of interest.

12. Bezhenar Vitaly Fedorovich – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics, Gynecology and Reproductology at the Academician I.P. Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health, Chief Freelance Obstetrician-Gynecologist of the Healthcare Committee of the Government of Saint Petersburg (Saint Petersburg). No conflict of interest.

13. 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.

14. Vagushenko Ulyana Andreevna – Obstetrician-Gynecologist at the Organizational and Methodological Department, Yekaterinburg Clinical Perinatal Center, Assistant at the Department of Obstetrics and Gynecology, Faculty of Medicine and Prophylaxis, Ural State Medical University (Yekaterinburg). No conflict of interest.

15. Guryev Dmitry Lvovich – Candidate of Medical Sciences, Chief Freelance Specialist in Obstetrics and Gynecology of the Department of Health and Pharmacy of the Yaroslavl Region, Chief Medical Officer of the Yaroslavl Regional Perinatal Center, Associate Professor at the Department of Obstetrics and Gynecology, Yaroslavl State Medical University (Yaroslavl). No conflict of interest.

16. Emelyanenko Elena Sergeevna – Candidate of Medical Sciences, Federal Expert in Prenatal Ultrasound Diagnostics, Associate Professor at the Department of Obstetrics, Gynecology and Reproductive Medicine, Faculty for Advanced Training of Medical Personnel, RUDN University (Moscow). No conflict of interest.

17. Kosovtsova Natalia Vladimirovna – Doctor of Medical Sciences, Head of the Department of Biophysical and Radiation Research Methods, Ural Research Institute of Maternity and Infancy Welfare of the Russian Ministry of Health (Yekaterinburg). No conflict of interest.

18. Kostin Igor Nikolaevich – Doctor of Medical Sciences, Professor, Professor at the Department of Obstetrics and Gynecology with the Course of Perinatology, Medical Institute of the Peoples' Friendship University of Russia (Moscow). No conflict of interest

19. Kukarskaya Irina Ivanovna – Doctor of Medical Sciences, Professor, Chief Freelance Specialist in Obstetrics and Gynecology of the Department of Health of the Tyumen Region, Chief Medical Officer of the Tyumen Perinatal Center, Head of the Department of Obstetrics and Gynecology, Faculty for Advanced Training and Professional Retraining, Tyumen State Medical University (Tyumen). No conflict of interest.

20. Kulikov Alexander Veniaminovich – Doctor of Medical Sciences, Professor, Head of the Department of Anesthesiology, Intensive Care, Toxicology and Transfusiology, Ural State Medical University of the Russian Ministry of Health (Yekaterinburg). No conflict of interest.

21. Malgina Galina Borisovna – Doctor of Medical Sciences, Professor, Academic Secretary, Ural Research Institute of Maternity and Infancy Welfare of the Russian Ministry of Health (Yekaterinburg). No conflict of interest.

22. Malyshkina Anna Ivanovna – D.Sc. in Medicine, Professor, Director of the V.N. Gorodkov Ivanovo Research Institute of Motherhood and Childhood, Head of the Department of Obstetrics, Gynecology and Medical Genetics of the 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.

23. Martirosyan Sergey Valerievich – Candidate of Medical Sciences, Associate Professor at the Department of Obstetrics and Gynecology, Faculty of Fundamental Medicine, Lomonosov Moscow State University (Moscow), Expert at the National Institute of Quality of Roszdravnadzor. No conflict of interest.

24. Melkozerova Oksana Alexandrovna – Doctor of Medical Sciences, Deputy Director, Ural Research Institute of Maternity and Infancy Welfare of the Russian Ministry of Health (Yekaterinburg). No conflict of interest.

25. Mikhailov Anton Valerievich – D.Sc. in Medicine, Professor, Chief Physician of Maternity Hospital No. 17 of Saint Petersburg, Professor of the Department of Obstetrics and Gynecology, I.I. Mechnikov North-Western State Medical University of the Russian Ministry of Health, and the Department of Obstetrics, Gynecology and Perinatology, Academician I.P. 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.

26. Tatiana Oboskalova – D.Sc. in Medicine, Professor, Head of the Department of Obstetrics and Gynecology, Faculty of Medicine and Preventive Care, Ural State Medical University (Yekaterinburg). No conflict of interest.

27. Olenev Anton Sergeevich – Doctor of Medical Sciences, Deputy Chief Medical Officer for Obstetric and Gynecological Care, City Clinical Hospital No. 31 named after Academician G.M. Savelieva of the Moscow City Health Department (Moscow), Chief Freelance Specialist in Obstetrics of the Moscow City Health Department. No conflict of interest.

28. Panina Olga Borisovna – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology, Faculty of Fundamental Medicine, Lomonosov Moscow State University (Moscow). No conflict of interest.

29. Perevozkina Olga Vladimirovna – Candidate of Medical Sciences, Head of the Clinical and Expert Work Department, Vorokhobov City Clinical Hospital No. 67 of the Moscow Healthcare Department, Perinatal Center, Assistant at the Department of Obstetrics and Gynecology, Faculty of Fundamental Medicine, Lomonosov Moscow State University (Moscow). No conflict of interest.

30. Victoria Popandopulo – D.Sc. in Medicine, Professor, Head of the Department of Obstetrics and Gynecology, Maykop State Technological University, Professor at the Department of Obstetrics and Gynecology, Faculty of Medicine, Astrakhan State Medical University of the Russian Ministry of Health, Chief Medical Officer, Kuban Medical Center LLC, Chief freelance specialist in obstetrics, gynecology, and women's reproductive health for the Southern Federal District, Ministry of Health of Russia (Krasnodar). No conflict of interest.

31. Pyregov Alexey Viktorovich – Doctor of Medical Sciences, Professor, Deputy Chief Medical Officer for Anesthesiology and Intensive Care, Moscow Regional Perinatal Center, Chief Freelance Specialist in Obstetric Anesthesiology and Intensive Care of the Ministry of Health of the Moscow Region. No conflict of interest.

32. Radzinsky Viktor Evseevich – Corresponding Member of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology with the Course of Perinatology, Peoples' Friendship University of Russia, Honored Scientist of the Russian Federation (Moscow). No conflict of interest.

33. Romanovsky Artem Nikolaevich – Candidate of Medical Sciences, Associate Professor at the Department of Obstetrics, Gynecology and Reproductology, Faculty of Medicine, St. Petersburg State University, Obstetrician-Gynecologist at Maternity Hospital No. 17 (St. Petersburg). No conflict of interest.

34. Savelyeva Galina Mikhailovna – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Hero of Labour of the Russian Federation, Honored Scientist of the Russian Federation (Moscow). No conflict of interest.

35. Semenov Yury Alekseevich – Doctor of Medical Sciences, Director, Ural Research Institute of Maternity and Infancy Welfare of the Russian Ministry of Health (Yekaterinburg). No conflict of interest.

36. Serova Olga Fedorovna – D.Sc. in Medicine, Professor, Chief freelance specialist in obstetrics and gynecology of the Ministry of Health of the Moscow Region, Chief Physician of the Moscow Regional Perinatal Center, Head of the Department of Obstetrics, Gynecology and Perinatology at the Institute of Postgraduate Professional Education of the A.I. Burnasyan Federal Medical Biophysical Center (Moscow). No conflict of interest.

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

38. Filippov Oleg Semenovich – D.Sc. in Medicine, Professor, Honored Doctor of the Russian Federation, Chief freelance obstetrician-gynecologist of the FMBA of Russia, Deputy Director of the Federal Scientific and Clinical Center for Children and Adolescents of the FMBA of Russia, Professor at the Department of Obstetrics, Gynecology and Reproductive Medicine of the Russian University of Medicine (Moscow). No conflict of interest.

39. Shifman Efim Munevich – D.Sc. in Medicine, Professor, Professor at the Department of Anesthesiology and Intensive Care of the Faculty of Postgraduate Education of the Moscow Regional Research Clinical Institute named after M.F. Vladimirsky (MONIKI), President of the Association of Obstetric Anesthesiologists-Resuscitators, Member of the SIVA Presidium, Honored Doctor of the Republic of Karelia, Expert in Anesthesiology and Intensive Care of the Federal Service for Surveillance in Healthcare (Moscow). No conflict of interest.

40. Shman Vera Valerievna – Head of the Maternity Ward at St. Petersburg City Maternity Hospital No. 17 (St. Petersburg). No conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Obstetricians-gynecologists

2. Obstetrician-gynecologist residents

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

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

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

Appendix A3. Reference Materials

Appendix A 3.1. Antenatal management guidelines

*if the pregnant woman declines the proposed delivery method, continued monitoring with weekly ultrasound evaluation of parameters is recommended

Appendix A 3.2. Ultrasound examination protocol in monochorionic pregnancy

Date of examination _______________________________________________

Patient's full name ___________________________________________________________

First day of last menstrual period _________________gestational age __________weeks

Gestational age by first trimester screening ___________________________________weeks

Conclusion: Pregnancy ___ weeks. Monochorionic diamniotic (or monoamniotic) twin pregnancy.

Ultrasonic signs of TTTS detected / not detected, stage ______

FGR type I II III. Discordant fetal growth.

TRAP

Physician ______________(__________________________)

Appendix A 3.3. Ultrasound examination protocol in dichorionic pregnancy

Date of examination _______________________________________________

Patient's full name ___________________________________________________________

First day of last menstrual period _________________gestational age __________weeks

Gestational age by first trimester screening ___________________________________weeks

Conclusion: Pregnancy ___ weeks. Dichorionic diamniotic twin pregnancy.

Physician ______________(__________________________)

Appendix B. Physician Action Algorithms

Appendix B.1 Determination of gestational age and chorionicity

Appendix B.2 Ultrasound examination algorithm in multiple pregnancy

Monochorionic twin pregnancy

Dichorionic twin pregnancy

Appendix B.3 Differential diagnosis of monochorionic pregnancy complications

Appendix B.4 Timing of delivery

Appendix C. Patient Information

The first and most important step at the beginning of any pregnancy, especially a multiple pregnancy, is a consultation with an obstetrician-gynecologist, during which the multiplicity is confirmed, the gestational age is determined, a general and gynecological examination is performed, a plan for further examinations and check-ups is drawn up, and recommendations on lifestyle, nutrition, necessary vitamins, and medications (if required) are provided.

The frequency of visits to an obstetrician-gynecologist for a pregnant woman with an uncomplicated monochorionic twin pregnancy averages 12 visits, and for a dichorionic twin pregnancy, 7 visits. The optimal time for the first visit to a doctor is the 1st trimester of pregnancy (up to 10 weeks).

Pregnant women with multiple pregnancies are recommended additional nutritional support to meet increased demands for energy, protein, carbohydrates, fats, and micronutrients. All medical recommendations must be strictly followed, planned examinations completed on time, and lifestyle guidelines during pregnancy adhered to, namely:

• avoid work involving prolonged standing or excessive physical exertion, night shift work, and work causing fatigue,

• avoid physical exercises that can lead to abdominal trauma, falls, or stress: contact sports, various martial arts, racket and ball sports, scuba diving,

• be sufficiently physically active, walk, and do prenatal exercise for 20-30 minutes a day (in the absence of complaints and contraindications),

• when traveling by plane, especially on long-haul flights, wear compression stockings for the duration of the flight, walk around the cabin, stay well hydrated, and avoid alcohol and caffeine,

• when traveling by car, use a special three-point seat belt,

• eat a proper and regular diet: consume food of adequate caloric value with an optimal content of protein, vitamins, and minerals, with mandatory inclusion of vegetables, meat, fish, legumes, nuts, fruits, and whole-grain products in the diet,

• in addition to a balanced diet, it is necessary to remember anemia prevention starting from 18–20 weeks (a diet based on iron-rich foods and/or iron supplements),

• monitor weight gain (depending on the baseline body mass index), at least 18–20 kg for the pregnancy,

• limit caffeine intake to less than 300 mg/day (1.5 cups of espresso at 200 ml each, or 2 cups of cappuccino/latte/americano at 250 ml each, or 3 cups of instant coffee at 250 ml each),

• if you smoke, try to quit or reduce the number of cigarettes smoked per day,

• avoid alcohol consumption during pregnancy, especially in the first 3 months.

An important factor for a pregnant woman is her emotional state. Throughout your pregnancy, you need to avoid stressful situations and emotional distress.

Sexual intercourse during pregnancy is not contraindicated if you feel well. In case of pain, discomfort, spotting during intercourse, as well as itching or burning in the vagina, you must stop sexual intercourse and consult a doctor.

You should also consult a doctor if you experience the following complaints:

• vomiting >5 times a day,

• weight loss > 3 kg in 1–1.5 weeks,

• blood pressure elevation >135/90 mmHg,

• vision problems such as blurred vision or flashing lights before the eyes,

• severe headache,

• lower abdominal pain of any character (aching, cramping, stabbing, etc.),

• epigastric pain (in the stomach area),

• swelling of the face, hands, or feet,

• appearance of bloody or abundant watery vaginal discharge,

• fever above 37.5 °C,

• sharp increase in abdominal size, rapid weight gain

• absence or alteration of fetal movements for more than 12 hours (after 20 weeks of pregnancy).

If you are Rh-negative, it is advisable for your husband to take a blood test to determine his Rh factor. If your husband's blood is Rh-negative, your further tests for anti-Rh antibodies and administration of anti-Rh immunoglobulin will not be required.

In multiple pregnancies, delivery is carried out according to obstetric indications, meaning spontaneous delivery is not contraindicated and is preferred. However, the timing and method of delivery for each individual woman are determined case-by-case, as delivery should take place before 40 weeks due to the increased risk of complications for both the fetuses and the mother-to-be. Depending on the state of the birth canal, the physician may offer and discuss a particular method of cervical ripening and labor induction.

In the maternity facility, you will be given detailed instructions and help to establish lactation, as breastfeeding is extremely important for newborns.

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

G1. VTE risk assessment during labor and the postpartum period

Source: venous complications during pregnancy and the postpartum period. Obstetric thromboembolism. Clinical guidelines of the Russian Ministry of Health, 2021 (as amended) [1]

Type: rating scale

Indication: assessment of risk factors for thromboembolic complications during pregnancy

Contents and Key:

[1] Clinical guidelines "Prevention of venous thromboembolic complications in obstetrics and gynecology" https://roag-portal.ru/recommendations_obstetrics