Twin anemia-polycythemia sequence (TAPS)

INTRODUCTION — Twin anemia-polycythemia sequence (TAPS) is a complication of monochorionic (MC) twin pregnancies characterized by a highly discordant intertwin hemoglobin difference and, in contrast to twin-twin transfusion syndrome (TTTS), the amniotic fluid volume of each twin is normal in the classic, pure form [1-4]. It can be considered an atypical chronic form of TTTS caused by unbalanced slow transfusion of red blood cells through a few very small (<1 mm diameter) placental arteriovenous (AV) anastomoses [1], leading to large intertwin hemoglobin differences resulting in anemia of one twin and polycythemia of the cotwin. 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 (table 1).

This topic will focus on diagnosis and management of TAPS. Diagnosis and management of TTTS and sFGR are discussed separately.

●(See "Twin-twin transfusion syndrome: Screening, prevalence, pathophysiology, and diagnosis" and "Twin-twin transfusion syndrome: Management and outcome".)

●(See "Selective fetal growth restriction in monochorionic twin pregnancies".)

TYPES OF TAPS AND THEIR PATHOPHYSIOLOGY

Spontaneous TAPS — Spontaneous TAPS refers to a type of chronic TTTS. It has been reported in 3 to 6 percent of previously uncomplicated third-trimester MC diamniotic twins [5,6]. TAPS has also been reported rarely in monozygotic, dichorionic pregnancies in which hairline anastomoses between placental masses lead to chronic exchange of red blood cells [7,8].

●Pathophysiology – MC placentas normally contain arteriovenous (AV), arterio-arterial (AA), and venovenous (VV) anastomoses. AV anastomoses are unidirectional while both AA and VV anastomoses are bidirectional.

The placentas in cases of spontaneous TAPS have on average three to four very small (<1 mm) AV anastomoses (by comparison eight AV anastomoses are found, on average, in normal MC placentas [9]). These tiny unidirectional unbalanced anastomoses allow slow passage of red cells (5 to 15 mL per 24 hours [3]) from the donor twin to the recipient twin, gradually leading to highly discordant hemoglobin levels [10]. The donor twin becomes anemic (which can lead to hydrops fetalis), while the recipient twin becomes polycythemic (which can lead to fetal and placental thrombosis) [11,12]. The slowness of this process allows for hemodynamic compensation across the placental maternal-fetal interface, which is hypothesized to be the reason for absence of the amniotic fluid volume discordancy seen in classic TTTS [13].

AA anastomoses occur in 10 to 20 percent of TAPS placentas and are smaller in these placentas than in placentas of uncomplicated MC twins and placentas in TTTS, both of which have more of these anastomoses [3]. The small number and size of AA anastomoses also contribute to development of TAPS because the bidirectional blood flow in normal AA anastomoses allows intertwin equilibration of blood.

In addition, in MC twins without TAPS, the smaller twin typically has a smaller portion of the shared placenta compared with the larger twin. In TAPS, however, the donor twin is usually smaller than the recipient twin but often has a larger share of the placenta [3].

Post-laser ablation TAPS — Post-laser ablation TAPS refers to a potential sequelae of use of laser ablation for treatment of TTTS [10,14]. It occurs in 2 to 13 percent of such pregnancies, usually within one month but up to 17 weeks after the procedure [10,15]. The wide range in incidence has been attributed to use of different laser ablation techniques and different definitions and criteria for TAPS. Risk factors include TTTS with few anastomoses and no artery-to-artery anastomoses before laser ablation [16].

●Pathophysiology – Based on placental injection studies from TTTS pregnancies treated with laser ablation, post-laser TAPS appears to be caused by incomplete laser surgery that results in a few very small (<1 mm) residual anastomoses, typically AV anastomoses without accompanying AA anastomoses. Use of Solomon technique by ablating between the anastomoses to the edges of the placenta helps in reducing the risk of post-laser TAPS [17]. (See "Twin-twin transfusion syndrome: Management and outcome", section on 'Procedure'.)

As with spontaneous TAPS, these small unbalanced residual AV anastomoses allow slow passage of red cells, usually from the former recipient twin to the former donor twin, gradually leading to highly discordant hemoglobin levels [10]. The former recipient twin becomes anemic, while the former donor twin becomes polycythemic, a reversal of the previous net blood flow during TTTS [11,12]. In the authors' experience, the residual anastomoses can also be in opposite directions, leading the former recipient to become polycythemic and the former donor to become anemic.

SCREENING — In the authors' practice, we monitor MC twins for development of TTTS, TAPS, and sFGR (table 2). To screen for TAPS, we perform serial middle cerebral artery (MCA) peak systolic velocity (PSV) measurements starting at 16 weeks and assess for placental discordance in echogenicity and cardiomegaly.

There is lack of consensus among different societies regarding screening MC twins for TAPS. The Society for Maternal-Fetal Medicine (SMFM) recommends against routine screening for TAPS due to a poor understanding of the natural history and management of the disease, but does recommend screening for TTTS [18]. In stark opposition, the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) guidelines recommend screening for TAPS (in addition to TTTS) every two weeks beginning at 16 weeks [19].

DIAGNOSTIC CRITERIA

Postnatal — At birth, the obstetric provider should suspect TAPS when a striking color difference on the maternal side of the placenta is observed: one side (donor) is pale and the other side (recipient) is dark (picture 1) [20].

In the nursery, TAPS should be suspected if one twin is anemic (hematocrit <45 percent) and the other is polycythemic (hematocrit >65 percent). Postnatal diagnosis of TAPS is based on an intertwin hemoglobin difference ≥8.0 g/dL in conjunction with an intertwin reticulocyte ratio >1.7 (reticulocyte count of the donor twin divided by the reticulocyte count of the recipient twin).

In addition, placental injection examination will show few very small (1 mm) AV anastomoses with flow in a single direction, but is not required for diagnosis [6].

Prenatal — The following criteria reflect the characteristics of TAPS in its classic, pure form. However, prenatal diagnosis can be challenging because TAPS, TTTS, and sFGR are not necessarily mutually exclusive of each other and can present together in any combination.

The accuracy of prenatal diagnosis of TAPS is not verified because of the risks of the confirmatory test, ie, umbilical vein (UV) sampling to determine fetal hemoglobin/hematocrit.

●MCA-PSV – The prenatal diagnosis of TAPS is based on the sonographic evidence of anemia in one twin with concurrent evidence of polycythemia in the cotwin.

•Traditional criteria – TAPS has traditionally been diagnosed when the middle cerebral artery-peak systolic velocity (MCA-PSV) is >1.5 multiples of median (MoM) in one twin (suggestive of anemia) and <0.8 MoM in the other twin (suggestive of polycythemia) [10,12,21,22]. Criteria are not uniform across studies (some authors use MCA-PSV <1.0 MoM to diagnoses polycythemia [6]), creating variation in clinical practices [23]. At our center, we generally use the traditional criteria for screening followed by detailed evaluation to determine management options.

•Emerging criteria – The prenatal diagnosis of TAPS is shifting from reliance upon the strict MCA-PSV cutoffs described above to a system based on absolute intertwin MCA-PSV discordance (delta MCA-PSV) because it appears to have a stronger correlation with the postnatal diagnosis of TAPS [24,25]. A Delphi process resulted in the proposal for delta MCA-PSV ≥1 MoMs to diagnose TAPS [19], with some authorities proposing a delta MCA-PSV >0.5 [24] or >0.37 MoMs for diagnosis [26].

The use of delta MCA-PSV rather than strict MCA-PSV cutoffs is supported by prospective data from children postnatally diagnosed with TAPS [25]. Although MCA-PSV was significantly higher in anemic fetuses than in normal fetuses (1.15 MoM versus 1.02 MoM), MCA-PSV was similar for polycythemic and normal fetuses (0.95 MoM versus 1.02 MoM) and among the 25 children with polycythemia, nine (36 percent) had an MCA PSV >1. Thus, many cases did not meet the traditional criteria for TAPS. On the other hand, the delta MCA-PSV was positively correlated with the intertwin differences in hematocrit required for postnatal diagnosis of TAPS.

Although delta MCA-PSV appears to have better diagnostic accuracy than using the MCA-PSVs of each twin, the optimum cut-off needs to be determined. In a retrospective cohort of 35 twin pregnancies with a postnatal diagnosis of TAPS, a delta MCA-PSV >0.5 was 85 percent sensitive, 100 percent specific, and had a negative likelihood ratio of 0.17 for the diagnosis of TAPS [24]. In addition, validation studies are needed.

●Supportive findings

•Discordant placental echogenicity is a common but nonspecific finding that supports the diagnosis: The anemic donor's region of the placenta is thickened and hyperechoic, while the plethoric recipient twin's region of the placenta has a normal appearance, with clear demarcation between the donor and recipient territories (image 1) [27].

•The donor twin may have cardiomegaly with tricuspid regurgitation and ascites [28].

•The recipient twin may have a starry sky liver (ie, bright echogenic dots throughout a background of diminished echogenicity of the liver parenchyma) [28]. The bright dots are due to increased brightness of the portal venule walls.

POSTDIAGNOSTIC PREGNANCY EVALUATION — After a diagnosis of TAPS is established by MCA-PSV, Doppler flow studies of the umbilical artery (UA), umbilical vein (UV), and ductus venosus (DV) should be performed to classify disease severity, which is the basis for further follow-up and management. The natural history of fetuses without findings of severe disease (cardiac compromise, hydrops) remains unknown.

TAPS is not associated with an increased risk for chromosomal or structural abnormalities or genetic syndromes, so fetal genetic studies are not offered unless there is another reason for these studies.

CLASSIFICATION OF DISEASE SEVERITY

●Disease severity based on traditional criteria:

•Stage 1 – MCA-PSV >1.5 multiples of median (MoM) in the donor and <1.0 MoM in the recipient, without other signs of fetal compromise

•Stage 2 – MCA-PSV >1.7 MoM in the donor and <0.8 MoM in the recipient, without other signs of fetal compromise

•Stage 3 – Stage 1 or 2 plus cardiac compromise of donor by any of the following:

UA:

-Absent or reversed end-diastolic velocity

-Pulsatile flow

DV:

-Increased pulsatility index

-Reversed flow

•Stage 4 – Stage 1 or 2 plus hydrops of donor

•Stage 5 – Demise of one or both fetuses preceded by TAPS

●Disease severity based on emerging criteria:

•Stage 1 – Delta MCA-PSV >0.5 MoM; without signs of fetal compromise

•Stage 2 – Delta MCA-PSV >0.7 MoM; without signs of fetal compromise

•Stage 3 – Stage 1 or 2 delta MCA-PSV findings plus cardiac compromise of the donor or recipient fetus based on abnormal Doppler flow studies in the UA or DV or hydrops (predominantly in the donor fetus)

•Stage 4 – Intrauterine demise of one or both fetuses preceded by TAPS

●Disease severity based postnatal hemoglobin difference (g/dL) between twins:

•Stage 1 – >8

•Stage 2 – >11

•Stage 3 – >14

•Stage 4 – >17

•Stage 5 – >20

DIFFERENTIAL DIAGNOSIS — Although there is some overlap between the findings for TAPS and TTTS (table 1), there are several characteristics that favor each diagnosis:

●MCA-PSV discordance is diagnostic of TAPS and not present in pure TTTS.

●Amniotic fluid discordance (oligohydramnios and polyhydramnios sequence) is essential in pure TTTS and not present in pure TAPS.

●Spontaneous TAPS has been diagnosed between 14 and 35 of weeks gestation, in contrast to TTTS, which is typically diagnosed in the early-to-mid second trimester [29,30].

●Postnatally, an intertwin reticulocyte ratio of >1.7 is required for diagnosis of TAPS because a large intertwin hemoglobin difference alone at delivery may represent acute peripartum TTTS rather than TAPS. Accurate diagnosis is important because the anemia secondary to TAPS is typically euvolemic, whereas anemia in peripartum TTTS requires rapid correction of hypovolemia [20].

Intrauterine infection with parvovirus B19 can cause fetal anemia; however, both fetuses tend to be anemic [31]. (See "Parvovirus B19 infection during pregnancy" and "Parvovirus B19 infection during pregnancy", section on 'Maternal-fetal effects'.)

PROGNOSIS — Spontaneous resolution of TAPS has been observed in 16 percent of cases [32]. In the remaining cases, TAPS may result in delivery of two healthy neonates with isolated intertwin hemoglobin differences that may require neonatal blood transfusion or partial exchange transfusion. However, cerebral injury (leading to neurodevelopmental impairment [eg, cognitive impairment, hearing loss]) or death of one or both twins are other possible outcomes. Postnatal neurodevelopmental impairment may be suspected antenatally because of brain lesions such as intracerebral hemorrhage or ischemic lesions on fetal sonogram and/or magnetic resonance imaging (MRI) [33].

Short-term:

●A meta-analysis of 506 pregnancies in 38 studies reported the following pregnancy outcomes in spontaneous and post-laser TAPS, respectively [34]:

•Intrauterine death: 5.2 versus 10.2 percent

•Neonatal death: 4.0 versus 9.2 percent

•Severe neonatal morbidity: 29.3 versus 33.3 percent

•Severe neurological morbidity: 4.0 versus 11.1 percent

•Preterm birth (spontaneous and iatrogenic): 86.3 versus 100 percent

Limitations of the observational data preclude clear conclusions regarding the better prognosis of spontaneous TAPS and the superiority of any management approach (expectant, laser, intrauterine transfusion, selective reduction). Also, the case reports and retrospective nature of original studies in the systematic review limit the ability to assess exact risk.

Long-term:

●In a study of long-term outcomes (median 48 months of age) of 49 twin pregnancies complicated by spontaneous TAPS [35]:

•Neurodevelopmental impairment occurred in 30 percent (22 out of 74) of survivors, and was more frequent in anemic fetuses (44 versus 18 percent, OR 4.1, 95% CI 1.8-9.1).

•Severe neurodevelopmental impairment was detected in 9 percent of survivors and was also more frequent in anemic fetuses than plethoric fetuses (18 versus 3 percent), although the difference did not reach statistical significance.

On multivariate analysis, independent risk factors for neurodevelopmental impairment were gestational age at delivery and severe anemia.

●In a study of long-term neurodevelopmental outcomes (at 24 to 96 months of age) of 33 twin pregnancies with TAPS after fetoscopic laser ablation for TTTS [36]:

•Mild to moderate cognitive delay (score <85) occurred in 8 of 47 children (17 percent) and severe cognitive delay (score <70) occurred in 2 of 47 children (4 percent) assessed.

•Overall, severe neurodevelopmental impairment occurred in 4 of 47 children (9 percent): cerebral palsy (1), severe motor delay (1), severe cognitive delay (2); these four children were delivered at 28, 29, 29, and 32 weeks of age, which may account for at least some of these impairments.

The small sample size and variety of tests used for neurodevelopmental evaluation limit interpretation of these findings.

PREGNANCY MANAGEMENT

Our approach — Management is similar for both spontaneous and post laser ablation TAPS [32].

●Stage 1 TAPS (MCA-PSV >1.5 multiples of median [MoM] in the donor and <1.0 MoM in the recipient or delta MCA-PSV >0.5 MoM without signs of fetal compromise)

•We manage these pregnancies expectantly with weekly Doppler assessment to assess for progression in stage.

•In the absence of progression, the patient is delivered between 34+0 and 37+0 weeks of gestation [37]. More complicated cases are delivered earlier within this range and less complicated cases are delivered later within the range.

•Progression is managed according to stage and gestational age.

●Stage 2 TAPS (MCA-PSV >1.7 MoM in the donor and <0.8 MoM in the recipient or delta MCA-PSV >0.7 MoM without signs of fetal compromise)

•A course of antenatal corticosteroids is administered to patients between 24+0 and 32+0 weeks of gestation to reduce the neonatal risks in the event of preterm birth. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)

•We manage these pregnancies <32+0 weeks expectantly with twice weekly Doppler assessment to assess for persistence or progression (characterized by development of fetal heart failure, as well as secondary signs of TAPS [discordant placental echogenicity, starry liver]).

-Persistent stage 2 TAPS beyond 32 to 34 weeks of gestation is an indication for delivery.

-Persistent stage 2 TAPS (ie, lasting for more than one to two weeks) at <32 weeks or progression is managed as Stage 3 or 4 TAPS (discussed below).

●Stage 3 or 4 TAPS (based on MCA-PSV criteria plus cardiac compromise [absent or reversed end-diastolic velocity in the umbilical artery (UA), pulsatile flow in the umbilical vein (UV), increased pulsatility index, and/or reversed flow in the DV, hydrops] or death of the donor twin) – There is no consensus regarding the optimal treatment; expectant management, laser surgery, in utero transfusion, selective feticide, and early delivery have been utilized [30,32]. We make the decision regarding the best approach on a case-by-case basis based on the gestational age and the acuity of the TAPS:

•In a patient who develops post-laser ablation TAPS within two weeks of the procedure, if termination of pregnancy is an option, it should be considered; otherwise, a repeat laser procedure is offered up to 28+0 weeks of gestation [38,39]. A repeat laser procedure can often be difficult due to bloody amniotic fluid as a result of the previous procedure.

•In spontaneous cases of TAPS that develop before 28+0 weeks, fetoscopic laser ablation is probably the best option. Because of reduced accessibility and visibility of the placental surface after treatment of TTTS, amnioinfusion and/or amnioreduction may be utilized to improve visualization of fine anastomoses across the intertwin membrane. Alternatively, intrauterine transfusion of red cells (IUT) to the anemic fetus can be undertaken. Both intravenous (IV) and intraperitoneal (IP) transfusion are acceptable methods to correct fetal anemia. We prefer IP transfusion because the slow absorption of red cells typically seen with IP transfusion may more closely mimic fetal physiology. Sometimes a combination approach is used: IV transfusion to correct severe anemia with IP transfusion of a portion of the blood for slower absorption to limit the need for frequent, multiple transfusions.

After treatment, we follow up with ultrasound weekly until resolution. If there is a suspicion for an intracranial lesion, we perform fetal MRI. (See "Intrauterine fetal transfusion of red blood cells".)

•In cases of TAPS that develop between 28+0 and 32+0 weeks of gestation, either of two options is reasonable. Some centers perform an intrauterine transfusion of red cells (IUT) to the anemic fetus, while others perform IUT plus a partial exchange of the polycythemic twin to potentially reduce the complications associated with hyperviscosity. In these cases, 5 mL aliquots of blood are removed and replaced with equal volumes of sterile saline. Repeat transfusion or partial exchanges are based on subsequent MCA-PSVs.

After treatment, we follow up with ultrasound weekly until resolution. If there is a suspicion for an intracranial lesion, we perform fetal MRI.

•Occurrence or persistence of stage 2, 3, or 4 TAPS beyond 32+0 weeks of gestation is an indication for delivery.

Evidence — In a series of 370 MC twin pregnancies diagnosed antenatally with stage 1 to 4 TAPS in 17 fetal therapy centers [32]:

●With all management approaches, perinatal mortality was substantially higher in pregnancies with post-laser TAPS compared with those with spontaneous TAPS.

●Perinatal mortality occurred in 17 percent (39 out of 225) of pregnancies in the expectant-management group, 18 percent (38 out of 215) in the laser group, 18 percent (25 out of 140) of the IUT group, 10 percent (9 out of 86) of the delivery group, and 7 percent (2 out of 30) of the cotwins of the selective-feticide group.

●Severe neonatal morbidity occurred in 49 percent (41 out of 84) of the delivery group, 46 percent (56 out of 122) of the IUT group, 31 percent (60 out of 193) of the expectant-management group, 31 percent (57 out of 182) of the laser-surgery group, and 25 percent (7 out of 28) of the selective-feticide group.

●Median diagnosis to birth interval was longest after selective feticide (10.5 weeks), followed by laser surgery (9.7 weeks), expectant management (7.8 weeks), IUT (4 weeks), and delivery (0.3 weeks).

Stage-based outcomes were not reported. Because of extensive heterogeneity in the management of TAPS, both within and among fetal therapy centers, the optimal management was unclear. Laser surgery treated the cause of TAPS and most prolonged the overall diagnosis to birth interval in the absence of feticide, thus enabling more time for fetal maturation, but it was technically challenging and did not clearly improve or worsen perinatal outcome when compared with expectant management. Because expectant management likely results in continuous exposure to the potential detrimental effects of TAPS and risks for perinatal mortality and morbidity increase with increasing TAPS stage, the authors hypothesized that definitive treatment with laser might be the optimal intervention remote from term to improve perinatal 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

●Etiology/pathophysiology – Twin anemia-polycythemia sequence (TAPS) may occur spontaneously or post-laser ablation for twin-twin transfusion syndrome (TTTS). It is caused by slow unbalanced red cell transfusion across tiny placental anastomoses in monochorionic (MC) placentas that gradually leads to anemia in the donor twin and polycythemia in the recipient twin. Amniotic fluid volumes remain normal. (See 'Types of TAPS and their pathophysiology' above.)

●Screening – We monitor MC twin pregnancies for development of TTTS, TAPS, and selective fetal growth restriction (sFGR) (table 2). To screen for TAPS, we perform serial middle cerebral artery (MCA) peak systolic velocity (PSV) measurements starting at 16 weeks and assess for placental discordance in echogenicity and cardiomegaly. (See 'Screening' above.)

●Diagnosis – TAPS has traditionally been diagnosed prenatally when the middle cerebral artery-peak systolic velocity (MCA-PSV) is >1.5 multiples of median (MoM) in one twin (suggestive of anemia) and <0.8 MoM in the other twin (suggestive of polycythemia. An alternative approach is to use an absolute intertwin MCA-PSV discordance (delta MCA-PSV) ≥1 MoMs. Discordant placental echogenicity, cardiomegaly (donor twin), and starry sky liver (recipient twin) support the diagnosis. (See 'Prenatal' above.)

●Diagnostic evaluation and staging – After making the diagnosis of TAPS, Doppler flow studies of the umbilical artery (UA), umbilical vein (UV), and ductus venosus (DV) should be performed to classify disease severity, which is the basis for further follow-up and management. (See 'Postdiagnostic pregnancy evaluation' above and 'Classification of disease severity' above.)

●Differential diagnosis – Although there is some overlap between the findings for TAPS and TTTS (table 1), key characteristics that help in differential diagnosis are that MCA-PSV discordance is diagnostic of TAPS and not present in pure TTTS and amniotic fluid discordance (oligohydramnios and polyhydramnios sequence) is suggestive of pure TTTS and not present in TAPS. (See 'Differential diagnosis' above.)

●Prognosis – In the absence of fetal treatment, TAPS may result in delivery of two healthy neonates, need for neonatal blood transfusion or partial exchange transfusion, or death of one or both twins. (See 'Prognosis' above.)

●Pregnancy management – The management of TAPS is typically expectant with intervention offered for persistent and worsening stage 2 or higher TAPS. Choice of intervention is based on gestational age, disease stage, and physician expertise. Persistent advanced stage TAPS beyond 32 weeks is managed with delivery. (See 'Pregnancy management' above.)