INTRODUCTION — Twin-twin transfusion syndrome (TTTS) and twin anemia polycythemia sequence (TAPS) are serious complications of monochorionic (MC) twin gestations. Only MC twins have these complications because, in contrast to dichorionic twins, the circulatory systems of almost all MC twins have placental anastomoses that result in vascular connections between the twins.
●TTTS – TTTS is characterized by relative hypovolemia of one twin (donor) and hypervolemia of the other twin (recipient) as a result of imbalance in the direction of flow through the placental anastomoses. The cardinal prenatal finding is MC placentation with discordant amniotic fluid volumes (maximum vertical pocket <2 cm in one amniotic sac and >8 cm in the other amniotic sac).
●TAPS – TAPS is an atypical chronic form of TTTS caused by slow transfusion of red blood cells through a few very small (<1 mm diameter) placental anastomoses with net increased unidirectional flow, resulting in anemia of one twin and polycythemia of the co-twin . Amniotic fluid volumes are normal. The cardinal prenatal finding is MC placentation with middle cerebral artery-peak systolic velocity greater than 1.5 multiples of median (MoM) in one twin and less than 0.8 MoM in the other twin. TAPS may occur spontaneously or after laser therapy of TTTS. (See "Twin anemia-polycythemia sequence (TAPS)".)
These descriptions reflect the characteristics of each disorder in its classic, pure form. However, diagnosis can be challenging because TAPS, TTTS, and a third disorder, selective fetal growth restriction (sFGR), are not necessarily mutually exclusive of each other and can present together in any combination.
This topic will review screening, prevalence, pathophysiology, and diagnosis of TTTS. Management and outcome of patients with TTTS , including neurodevelopmental outcomes, are discussed separately. (See "Twin-twin transfusion syndrome: Management and outcome".) Screening, diagnosis, and management of TAPS and sFGR are also reviewed separately. (See "Twin anemia-polycythemia sequence (TAPS)" and "Selective fetal growth restriction in monochorionic twin pregnancies".)
PREVALENCE — Our best estimate of the prevalence of TTTS is 9 to 15 percent of monochorionic (MC) diamniotic (DA) twin pregnancies [2,3] and 6 percent of monoamniotic twin pregnancies . These figures may underestimate the true prevalence because they are largely based on data from live borns and sonograms in the second half of pregnancy, which miss early fetal losses that may have been related to TTTS .
Types of vascular connections — Post-delivery placental injection studies in MC twins have identified four types of vascular connections: arteriovenous (AV), venoarterial (VA), arterioarterial (AA), and venovenous (VV). The nomenclature describes the donor fetal vessel first and then the recipient fetal vessel.
Antepartum TTTS — The three major factors in the pathogenesis of TTTS are unbalanced flow volume, release of vasoactive mediators, and lack of AA anastomoses.
●AV anastomoses occur through the placental cotyledon when chorionic plate surface arterial vessels from one twin and chorionic plate surface venous vessels from the other twin descend into the placental parenchyma and connect in the underlying cotyledon to form a capillary network (ie, the cotyledon is supplied by an artery of one twin and blood is drained through a vein of the co-twin).
If there are more or larger AV anastomoses than VA anastomoses (ie, unbalanced anastomoses), then uncompensated hydrostatic and osmotic forces will lead to net transfer of fluid from one twin (donor) to the other twin (recipient), resulting in the TTTS phenotype. If the number and size of AV anastomoses and thus blood flow going in one direction is the same as the number and size and thus blood flow going in the opposite direction (ie, balanced anastomoses), then TTTS does not develop.
The initial developmental process that leads to formation of the unbalanced vascular system and subsequent TTTS phenotype in some MC twin pregnancies but not in others has not been determined. Dichorionic (DC) twins do not develop TTTS (with rare exceptions ) because they each have their own placenta without any intertwin anastomoses, even when the placenta has a fused appearance.
AA and VV anastomoses are very different from AV and VA anastomoses as they occur exclusively on the placental surface (not deep), are end-to-end (not capillary) anastomoses, and allow bidirectional (not unidirectional) blood flow. Thus, they do not cause the TTTS phenotype.
●Vasoactive mediators are released in response to changes in intravascular volume and affect the cardiovascular and renal function of both twins.
Hypoperfusion of the kidneys of the chronically hypovolemic twin (called the donor twin) results in activation of the renin-angiotensin-aldosterone system (RAAS) and release of angiotensin II, renin, aldosterone, and vasopressin in an ongoing attempt to restore its intravascular volume and maintain its blood pressure [6,7]. This leads to oliguria, with anhydramnios and the "stuck twin" phenotype in severe cases.
Chronic hypervolemia in the recipient twin causes its cardiac atria to stretch and release atrial natriuretic peptide; ventricular stretch results in release of brain natriuretic peptide . These hormones promote vasodilation, natriuresis, and inhibition of the RAAS, leading to polyuria and polyhydramnios. Over time, however, the recipient can develop hypertensive cardiomyopathy as a result of ongoing volume overload, elevated levels of endothelin I, and elevated levels of RAAS mediators that it acquires from the donor through the AV anastomoses, even though its own RAAS system is down-regulated [9-11]. Venous hypertension is a late stage of the process and results in movement of intravascular fluid into the interstitial spaces and functional lymphatic obstruction, leading to hydrops fetalis .
●AA anastomoses are thought to be protective against development of TTTS by correcting intertwin volume imbalance caused by the unbalanced AV anastomoses [13,14]. The observation that AA anastomoses are rare to nonexistent in TTTS supports this theory.
Intrapartum TTTS — In a minority of cases, acute intrapartum TTTS occurs during birth from a rapid and large intertwin blood transfusion from donor to recipient [15,16]. This leads to acute anemia and possibly hypovolemic shock in the donor and acute polycythemia in the recipient twin. The reported incidence is 1.5 to 2.5 percent of all MC twins, irrespective of the mode of birth .
The acute transfusion is thought to occur through both AV and AA anastomoses, but it is not clear why a balanced situation acutely becomes unbalanced . Hypotheses include changes/maturation of the placenta late in gestation, hemodynamic changes that occur after the birth of one twin and before the birth of the second twin, and timing of cord clamping.
OUR APPROACH TO MONITORING — Twin pregnancies are often first diagnosed when a pregnant person undergoes a first-trimester ultrasound examination for pregnancy dating, evaluation of vaginal bleeding, or measurement of nuchal translucency as a component of screening for Down syndrome (trisomy 21). Upon diagnosis of twins, determination of chorioamnionicity is essential to guide follow-up, which is different for monochorionic (MC) versus dichorionic (DC) twins. We suggest referring all MC twin pregnancies to a maternal-fetal medicine specialist for consultation and/or comanagement. (See "Twin pregnancy: Overview", section on 'Assessment of chorionicity and amnionicity' and "Twin pregnancy: Routine prenatal care", section on 'Pregnancy monitoring based on chorionicity and amnionicity'.)
In MC twin pregnancies, serial fetal ultrasound examinations are necessary to monitor for development of TTTS, as well as TAPS and selective fetal growth restriction (sFGR) because these disorders collectively affect 15 to 20 percent of MC gestations, have high morbidity and mortality, and are amenable to interventions that can reduce morbidity and mortality. Their clinical findings overlap, so identifying the differences among them will help in differential diagnosis (table 1).
We have developed an ultrasound screening protocol for MC twins, as depicted in the table (table 2), to detect TTTS, TAPS, and sFGR. This protocol is based on data from case series and our clinical experience and modified from guidelines published by the Society for Maternal-Fetal Medicine and the International Society for Ultrasound in Obstetrics and Gynecology [19-21].
In the first trimester, we determine chorionicity and measure nuchal translucency and crown-rump length in both twins as part of routine obstetric ultrasound assessment. In meta-analyses, nuchal translucency discrepancy >20 percent, nuchal translucency >95th percentile in one or both fetuses, crown-rump length discrepancy ≥10 percent, and abnormal ductus venosus (DV) flow at the first-trimester ultrasound scan were each associated with development of TTTS, but with low sensitivity [22,23]. Nuchal translucency discrepancy and abnormal DV flow had the highest sensitivities at 53 and 50 percent, respectively . However, we do not perform DV Doppler in the first trimester for predicting TTTS because Doppler in early pregnancy exposes the twins to the highest ultrasound power without clear benefit in predicting or reducing complications from TTTS.
We typically begin monitoring for TTTS in the second trimester, at 16 weeks of gestation, and continue through 36 weeks (table 2). The onset of TTTS is usually gradual and during the second trimester at or after 16 weeks, but can occur suddenly and later in gestation [19,24]. The peak onset of the disorder is around 20 weeks, with decreasing incidence to 26 weeks and only rare cases reported thereafter until 30 weeks. TAPS, as well as sFGR, typically develop in the late second or the third trimester .
PRENATAL (FETAL) DIAGNOSIS — TTTS is typically diagnosed on an ultrasound examination performed in the early-to-mid second trimester.
Diagnostic criteria — The prenatal diagnosis of TTTS is based upon ultrasonographic evidence of a single MC placenta with twin oligohydramnios/polyhydramnios sequence, after exclusion of other disorders of discordant amniotic fluid volume (see 'Differential diagnosis' below). The maximum vertical amniotic fluid pockets for oligohydramnios and polyhydramnios are usually defined as <2 cm and >8 cm, respectively. Alternatively, some providers use gestational age-based criteria for defining polyhydramnios (≥6 cm at 15 to 17 weeks, ≥8 cm at 18 to 20 weeks, and >10 cm at ≥20 weeks) .
When severe, oligohydramnios in the donor's sac leads to a "stuck twin" appearance: The fetus appears stuck to the uterine wall because there is no or minimal fluid in its sac and its amniotic membrane lies against its body (image 1A-B). By contrast, the recipient twin is freely mobile within a large volume of amniotic fluid (image 2A-E), which also compresses the donor twin's sac.
These criteria reflect the characteristics of the disorder in its classic, pure form. However, diagnosis can be challenging because TAPS, TTTS, and selective fetal growth restriction (sFGR) are not necessarily mutually exclusive of each other and can present together in any combination.
Postdiagnostic fetal evaluation and potential findings — After a presumptive diagnosis of TTTS is made based on identification of amniotic fluid discordancy, we perform the following assessments of both twins to exclude other disorders in the differential diagnosis (see 'Differential diagnosis' below); look for other findings potentially associated with TTTS; and assign the stage (see 'Classic staging' below), on which twin follow-up and pregnancy management are based (see "Twin-twin transfusion syndrome: Management and outcome"). TTTS is not associated with an increased risk for chromosomal abnormalities or genetic syndromes, so fetal genetic studies are not offered unless there is another reason for these studies.
At 16 to 18 weeks:
●Doppler studies of the umbilical artery (UA), umbilical vein (UV), and ductus venosus (DV) are needed for classification of disease severity (see 'Classic staging' below), and middle cerebral artery-peak systolic flow velocity (MCA-PSV) is needed to evaluate for TAPS (defined by MCA-PSV greater than 1.5 multiples of median [MoM] in one twin and less than 0.8 MoM in the other twin), which sometimes coexists with TTTS. (See "Twin anemia-polycythemia sequence (TAPS)", section on 'Diagnostic criteria'.)
●Comprehensive anatomic survey – Twins are at increased risk for congenital anomalies, and MC twins are at increased risk compared with DC twins. Anomalies that could lead to growth disturbance or oligohydramnios are of particular importance since they may affect the differential diagnosis of TTTS versus sFGR versus upper or lower urinary tract anomalies resulting in amniotic fluid discordance. (See 'Differential diagnosis' below.)
●Assessment for hydrops fetalis – One or both fetuses may show signs of hydrops (combination of ascites, pleural or pericardial effusions, and skin edema). If one twin is hydropic, it is usually the recipient twin. Hydrops is a factor in classification of disease severity. (See 'Classic staging' below and "Nonimmune hydrops fetalis", section on 'Diagnosis'.)
●Assessment of bladder size – The donor's bladder size may be normal or decreased. The recipient's bladder size may be normal or increased. Bladder size is a factor in classification of disease severity. (See 'Classic staging' below.)
•Recipient twin – Right ventricular outflow tract abnormalities, including functional or anatomic pulmonary atresia/stenosis, have been observed in approximately 10 percent of recipient twins [27-30]. Hypertrophy can develop in one or both fetal cardiac ventricles. (Hypertrophy is measured with ultrasound and defined as ventricular wall or intraventricular septal thickness greater than two standard deviations [SD] for gestational age).
Right-sided myocardial dysfunction is two- to threefold more common than left-sided dysfunction, although echocardiographic studies have revealed that, in the early stages of TTTS, left ventricular filling pressures can rise and systolic function can decrease before right ventricular function becomes abnormal . Right-side dysfunction is not surprising since the right ventricle is the dominant ventricle in the fetal heart. Depressed myocardial contractility and severe tricuspid regurgitation can be identified in addition to a reversed a-wave on Doppler interrogation of the DV. Functional obstruction of the pulmonary artery is signified by reverse filling of the ductus arteriosus from the aortic arch .
•Donor twin – The donor twin generally has a normal echocardiogram. In advanced stages, the donor may have low output cardiac failure.
●A pre-TTTS state should be considered when findings do not meet diagnostic criteria. Second-trimester MC pregnancies with polyhydramnios of one sac and normal amniotic fluid volume in the other sac or amniotic fluid volume discordance not fulfilling the diagnostic criteria for TTTS are at increased risk of progressing to TTTS, especially if one twin is growth restricted [32,33]. In contrast to our routine screening protocol (table 2), we perform weekly ultrasound examinations in these cases to determine the maximum vertical amniotic fluid pocket until the presence or absence of TTTS becomes clear. We would also perform a prompt ultrasound examination in patients with polyhydramnios in one sac who become acutely symptomatic. (See 'Maternal clinical manifestations' below.)
●Preterm prelabor rupture of membranes (PPROM) of one sac can cause amniotic fluid discordancy. PPROM is readily diagnosed or excluded by testing for amniotic fluid in the vagina. (See "Preterm prelabor rupture of membranes: Clinical manifestations and diagnosis", section on 'Diagnostic evaluation and diagnosis'.)
●Congenital anomalies can result in amniotic fluid discordance (eg, renal agenesis in the suspected donor twin can cause oligohydramnios, upper gastrointestinal tract obstruction in the suspected recipient can cause polyhydramnios). Renal anomalies causing amniotic fluid discordance can usually be readily diagnosed or excluded by a fetal anatomic survey, but gastrointestinal anomalies, such as esophageal atresia, are more challenging. (See "Prenatal sonographic diagnosis of cystic renal disease" and "Prenatal diagnosis of esophageal, gastrointestinal, and anorectal atresia".)
●Congenital fetal infection may be sufficiently severe to cause growth restriction with or without amniotic fluid abnormalities. We do not test for infection when we suspect TTTS, except when fetal findings associated with infection are present, such as cerebral calcifications, cerebral ventriculomegaly, echogenic fetal bowel, hepatosplenomegaly, and/or hepatic calcifications.
●The term selective fetal growth restriction (sFGR) is used in the scenario where the discordance in estimated fetal weight between twins is >25 percent and the small twin's estimated weight is <10th percentile, with or without reduced amniotic fluid volume. The larger twin has normal amniotic fluid volume. Amniotic fluid discordance (when present) raises the possibility of TTTS. In a series of 324 cases referred to a specialty center because TTTS was suspected, the diagnosis was confirmed in 77 percent (n = 249), and the remaining patients had either discordant amniotic fluid volume that did not meet criteria for TTTS (56 percent) or sFGR (44 percent) .
Distinguishing TTTS complicated by IUGR in the donor twin from sFGR can be difficult since in both situations the FGR fetus may have oligohydramnios (table 1). The key to distinguishing between the two entities is based on the ultrasound findings in the normal sized co-twin: In pregnancies with sFGR, the co-twin will be appropriately grown and have normal amniotic fluid volume (defined as maximum vertical pocket >2 cm and <8 cm), whereas when FGR is part of TTTS, the appropriately grown co-twin usually has polyhydramnios (maximum vertical pocket >8 cm) since it is the recipient.
Determining the true diagnosis, TTTS versus sFGR, is paramount in deciding on therapeutic options. Laser photocoagulation of placental anastomoses is the treatment of choice for TTTS with or without concomitant FGR (see "Twin-twin transfusion syndrome: Management and outcome"). Treatment for isolated sFGR is based on expert opinion, variable (expectant management with fetal monitoring, early delivery), and depends on the gestational age (eg, selective reduction at previable gestational ages). (See "Selective fetal growth restriction in monochorionic twin pregnancies".)
Classification of TTTS — Classification systems have been created to provide a standardized means of describing increasing severity of TTTS. The use of different systems must be taken into consideration when comparing reported pregnancy outcomes.
Classic staging — The five classic stages of disease are based on findings from two-dimensional ultrasound and Doppler velocimetry of the UA, UV, and DV . In the seminal publication, oligohydramnios was defined as a maximum vertical pocket ≤2 cm and polyhydramnios was defined as a maximum vertical pocket ≥8 cm .
•Oligohydramnios and polyhydramnios sequence
•The bladder of the donor twin is visible
•Doppler indices (UA, UV, DV) in both twins are normal
•Oligohydramnios and polyhydramnios sequence
•Bladder of the donor is not visualized
•Doppler indices (UA, UV, DV) in both twins are normal
•Oligohydramnios and polyhydramnios sequence
•Abnormal Doppler indices: At least one of the following is present in either twin: absent or reversed end-diastolic velocity in the UA, reversed flow in a-wave of the DV, or pulsatile flow in the UV
•Oligohydramnios and polyhydramnios sequence
•One or both fetuses show signs of hydrops
•Oligohydramnios and polyhydramnios sequence
•One or both fetuses are dead
Although this classic staging represents one method of standardization, there are several important limitations. Atypical presentations can occur; as an example, the donor twin may have both a persistent bladder and abnormal umbilical Doppler flow. In addition, although higher stages are generally associated with a worsening perinatal prognosis, the clinical presentation of a particular case does not always follow an orderly progression of stages. As an example, a stage I case may progress rapidly in several days to stage III, but regression of disease can occur in as many as 15 percent of stage I cases and 60 percent of stage II disease .
Other classification systems — Given the limitation of classic staging for predicting progression of disease, some experts have proposed using fetal echocardiographic assessment (cardiovascular score), mainly of the recipient twin, to provide the information needed to distinguish between pregnancies that are evolving to severe TTTS versus those that have stable early TTTS that can be managed expectantly. We do not use any of these systems, but they are routinely used in some other centers.
●Cardiovascular Profile Score (CVPS) – This score was originally developed for use in hydropic fetuses to predict congestive heart failure and fetal outcome. It incorporates heart size, cardiac function, and Doppler blood flow studies of the UA, UV, and DV into the scoring profile. For each category, 2 points are assigned for normal findings and either 1 or 0 points for abnormal findings, depending on severity .
In one study of CVPS to assess cardiac status and outcome in 62 recipient twins following intervention, the overall neonatal survival rate was 61 percent (76/124), and recipient survival rates were better with higher CVPS (74 percent [25/34] for CVPS of 10 versus 31 percent [5/16] for CVPS <9) . Classic staging was not predictive of recipient survival. The authors concluded that cardiac assessment by CVPS may improve clinical decision making and timing of fetal interventions. However, the results are difficult to interpret since the initial treatment for TTTS was a therapy that is no longer used (amnioreduction) in 51 percent (32/62) of cases, with over one-third at Quintero stage III.
●CHOP score – The Children's Hospital of Philadelphia (CHOP score) has developed a cardiovascular scoring system based on echocardiographic and peripheral Doppler findings in a study of 150 donor and recipient fetuses . When four grades of progressively worsening cardiovascular abnormalities were compared with classic staging, marked differences were noted. As an example, when fetuses classified as stage II were reclassified by cardiovascular score, the spread of cardiovascular score grades from least to most severe was grade 1 (35 percent), grade 2 (30 percent), grade 3 (25 percent), and grade 4 (10 percent). However, a subsequent prospective evaluation of 158 cases of TTTS prior to laser therapy at another center failed to find an association between an increasing CHOP score and perinatal survival .
●The Cincinnati modification of the classic staging system is another cardiovascular scoring system . This system divides stage III into A, B, and C classifications based on progressively worsening echocardiographic findings of three parameters in the recipient fetus (presence and severity of atrioventricular valvular incompetence, ventricular wall thickening, and ventricular function as assessed by the myocardial performance index [MPI]). Cases are upstaged from the classic stage based on the presence of these fetal echocardiographic findings.
Although assessment of the cardiovascular system has provided further insight into the pathophysiology and severity of TTTS, available profiling schemes do not appear to be predictive of progression of disease or perinatal outcome following laser photocoagulation. Determining the role of fetal echocardiography in the diagnosis and management of TTTS will require coordinated research in a multicentered collaborative setting, which is underway through the Fetal Heart Society. Risk stratification in advanced TTTS is being assessed, specifically focusing on the association of mitral regurgitation with perinatal mortality in stage III to IV TTTS .
Many of the proposed components of fetal echocardiographic assessment are technically difficult to perform (such as the MPI, which is used to assess global ventricular function). This raises concern regarding the feasibility and effectiveness of cardiovascular scoring systems as potential screening tests in widespread clinical populations.
MATERNAL CLINICAL MANIFESTATIONS — TTTS is usually first suspected because of characteristic fetal findings on ultrasound examination, as discussed above . The mother is usually asymptomatic, but symptoms related to excessive uterine distention may occur, including discomfort when lying supine, insomnia, early satiety, lower abdominal pain, orthopnea, and pelvic pressure (in patients with advanced cervical change) . Mirror syndrome (ie, generalized maternal edema usually associated with hypertension) has been reported in cases with a hydropic fetus [44-46]. (See "Nonimmune hydrops fetalis", section on 'Mirror syndrome'.)
Premature cervical shortening (image 3) occurs in some patients, although cervical length in TTTS is normally distributed, with a mean±SD of 38±10 mm at 16 to 24 weeks of gestation . The pathogenesis of cervical shortening is unclear. Although excessive uterine distention is the presumed etiology, we have not found an association between intraamniotic pressure and pretreatment cervical length or gestational age at delivery . Pretreatment cervical length <28 mm in patients with TTTS in this gestational age range has been associated with an increased risk for preterm birth, but the optimum management of these patients is unclear, given the lack of data from randomized trials. We consider use of progesterone 200 mg vaginally daily or a pessary to be a reasonable approach but do not place a cerclage. In the largest cohort study, cervical cerclage did not prolong pregnancy or improve perinatal survival . In addition, there is evidence that cerclage may reduce time to birth in this population . However, practice patterns vary widely both in terms of defining the cervical length warranting treatment (eg, <10, 20, or 28 mm) and the intervention offered (vaginal progesterone, pessary, or cerclage).
FOLLOW-UP AND MANAGEMENT — After the diagnosis of TTTS has been made, follow-up and management depend on the stage and are discussed in detail separately. (See "Twin-twin transfusion syndrome: Management and outcome".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple gestation".)
SUMMARY AND RECOMMENDATIONS
●Pathophysiology – The TTTS phenotype results from unbalanced flow through placental intertwin vascular anastomoses that lead to hypovolemia in one twin (donor twin) and hypervolemia in the other (recipient twin). Hypovolemia in the donor stimulates release of vasoactive mediators, which pass through the placental vascular communications and thus increase vascular resistance in both fetuses. (See 'Pathophysiology' above.)
Laser coagulation of placental intertwin vascular anastomoses leads to resolution of the intertwin volume imbalance and secretion and exchange of vasoactive mediators. (See "Twin-twin transfusion syndrome: Management and outcome".)
●Clinical presentation – TTTS is typically first detected on ultrasound examinations performed in the early-to-mid second trimester. Uncommonly, acute intrapartum TTTS results in acute anemia and possibly hypovolemic shock in the donor twin and acute polycythemia in the recipient twin at delivery. (See 'Our approach to monitoring' above and 'Intrapartum TTTS' above.)
●Monitoring – Monochorionic (MC) twin pregnancies should be monitored with serial ultrasound examinations for development of twin-twin transfusion syndrome (TTTS), twin anemia polycythemia sequence (TAPS), and selective fetal growth restriction (sFGR) (table 2).
●Diagnosis – The diagnostic criteria for the classic, pure form of TTTS, TAPS, and sFGR are shown in the table (table 3). However, diagnosis can be challenging because these disorders have overlapping findings and can present together in any combination (table 1). (See 'Our approach to monitoring' above and 'Diagnostic criteria' above.)
●Classification – The five classic stages of TTTS are based on findings from two-dimensional ultrasound and Doppler velocimetry of the umbilical artery, umbilical vein, and ductus venosus. Higher stages, which are characterized by abnormal Dopplers with or without hydrops, are generally associated with a worsening perinatal prognosis, but the clinical presentation of a particular case does not always follow an orderly progression of stages. (See 'Classic staging' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Kenneth J Moise, Jr, MD, and Dr. Anthony Johnson, DO, who contributed to earlier versions of this topic review.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟