Twin-Anemia Polycythemia Sequence

Twin Anemia Polycythemia Sequence (TAPS) is a relatively rare but potentially devastating fetal condition that occurs in monochorionic twin pregnancies. Although historical accounts as early as the 17^th century have hinted at the condition, TAPS was first described following laser for twin-twin transfusion syndrome (TTTS) in 2006 by Robyr et al¹. The incidence of TAPS is estimated to be 3-5% in monochorionic twins, and up to 13% after laser therapy for TTTS^2–4.  In contrast to TTTS, which describes the unbalanced sharing of blood volume between the twins, TAPS is characterized by a chronic imbalance in hemoglobin levels between the twins, where one twin becomes anemic (donor) and the other polycythemic (recipient).

            In this chapter, we discuss the pathophysiology, diagnosis, and staging of TAPS. We then review the various management strategies of TAPS, ranging from expectant management to intrauterine interventions. Finally, we discuss the potential post-intervention complications and delivery recommendations.

Maternal care related to disorders of the placenta and placental implantation

O43.021         Fetus-to-fetus placental transfusion syndrome, first trimester

O43.022         Fetus-to-fetus placental transfusion syndrome, second trimester

O43.023         Fetus-to-fetus placental transfusion syndrome, third trimester

O43.029         Fetus-to-fetus placental transfusion syndrome, unspecified trimester

In normal monochorionic pregnancies, there are numerous balanced vascular anastomoses within the shared placenta, which ensure an even blood volume and RBC exchange between the fetuses⁵. These vascular connections can be unidirectional arterio-venous (AV) and bidirectional, arterio-arterial (AA) and veno-venous (VV) vascular anastomosis. The number, caliber and types of vascular anastomoses within the shared placenta will determine the hemodynamic balance between the twins. An imbalance in this exchange, for example, as caused by a disproportionate number of unidirectional small diameter AV anastomoses within an affected monochorionic twin placenta can, over time, present a clinical spectrum manifesting as anemia in one twin and polycythemia in the other. The severity of the clinical presentation will be related to the volume and rapidity of intertwin blood transfusion. In TAPS the limited number of small diameter AV anastomosis which cause a generally slow unidirectional transfusion, leads to significant difference in hemoglobin level over time , but the low velocity and small amount of intertwin transfusion, allow for cardiovascular compensation and accordingly there will be little or no disturbance in amniotic fluid volume⁶. The lack of compensatory, balancing bidirectional AA anastomosis also contributes to the pathophysiology of TAPS.

Prenatal Diagnosis

TAPS arises because of chronic unbalanced blood transfusion between twins via tiny placental anastomoses. Prenatally, the diagnosis is based on Doppler findings, particularly discordant middle cerebral artery peak systolic volume (MCA-PSV) in both twins. Increased donor MCA-PSV suggests fetal anemia, while decreased recipient MCA-PSV indicates fetal polycythemia (Figure 1). The diagnosis will vary based on which criteria is used (set threshold differences in individual MCA-PSV MOM for each twin (traditional criteria) versus absolute intertwin MCA-PSV difference. (delta _MCA-PSV MOM).  Recent studies suggest that the fetal intertwin MCA-PSV MoM difference (delta MCA-PSV) is a promising predictor of neonatal intertwin hemoglobin concentration difference, potentially indicating TAPS⁷.

A five-stage classification system for TAPS has been suggested. This system categorizes the progression of TAPS according to the following criteria: the extent of discordance in middle cerebral artery peak systolic velocity (MCA-PSV), evidence of cardiac compromise, the emergence of hydrops, and, in the latter stages, the occurrence of intrauterine fetal demise.

A summary of the different criteria used for the prenatal and postnatal diagnosis and staging of TAPS can be found in Table 1.

Additional Ultrasound Markers:

Ultrasound findings that support the prenatal diagnosis of TAPS have been described in the literature. Three markers have been identified: placental dichotomy, fetal cardiomegaly, and ‘starry sky’ liver^10–12. Tollenaar et al. recently highlighted the prevalence of ultrasound markers in TAPS patient. The authors reported that at least one of the three ultrasound markers was detected in 86% of the TAPS patients¹².

The three markers have been described as follows:

1. Discordant placental echogenicity and thickness (Figure 2):
   1. The placental territory of the anemic twin appears thick and echogenic in contrast to the thin and hypoechoic portion of the polycythemia recipient twin.
   2. Placental dichotomy was reported to be present in up to 44% of TAPS cases, more commonly found with post-laser TAPS¹².

2. Fetal cardiomegaly in the donor (anemic) twin:
   1. Cardiomegaly can develop in the anemic twin secondary to the abnormally elevated cardiac output, as a compensatory response to the hypoxic environment.
   2. Fetal cardiomegaly was reported to be found in up to 70% of TAPS donor twins¹².

3. ‘Starry Sky’ liver in the recipient (polycythemic) twin (Figure 3):
   1. The name is derived from the characteristic sonographic pattern of the liver, demonstrating clearly identified portal venules against diminished placental echogenicity. This ultrasound finding is the result of hepatic congestion of the liver venules due to polycythemia.
   2. ‘Starry sky’ liver has been described to be found in up to 66% of TAPS recipient twins¹².

Postnatal Diagnosis

Postnatally, TAPS is diagnosed based on the finding of chronic anemia and/or reticulocytosis in the donor, and polycythemia in the recipient.

The following criteria are recommended to establish the postnatal diagnosis of TAPS:

1. Neonatal intertwin hemoglobin difference between the twins of > 8 g/dL
2. At least one of the following:
   1. Reticulocyte count ratio > 1.7
   2. Small vascular anastomoses at placenta surface (< 1mm)

An inter-twin reticulocyte count ratio >1.7 is pathognomonic for TAPS. This ratio is measured by dividing the reticulocyte count of the donor by the reticulocyte count of the recipient. Vascular anastomoses can be detected through color dye injection of the placenta (Figure 4-6).

Although the ISUOG Practice Guidelines on the role of ultrasound in twin pregnancy advises that ultrasound screening for the development of TTTS should commence at 16 weeks of gestation for all monochorionic twin pregnancies, no such recommendation exists for the screening of TAPS¹³.

Due to the chronic etiology of TAPS, the condition requires chronic monitoring. The Delphi study reported an expert consensus regarding the frequency for TAPS monitoring, which should be conducted every two weeks⁸. However, there was no agreement on the optimal gestational age at which to start monitoring for TAPS in monochorionic twin gestations. Once TAPS is diagnosed, ultrasound surveillance should be done weekly^6,8. Additional monitoring will allow for characterization of placental appearance, detection of supportive ultrasound markers, and determination of the optimal management strategy. As a result of the paucity of evidence regarding the improvement of perinatal outcomes with MCA-PSV Doppler monitoring, there is no recommendation for routine monitoring of TAPS patients.

Management for TAPS depends on timing of TAPS diagnosis and staging. Multiple studies found no differences in perinatal mortality and morbidity when comparing the different management options for TAPS^{14, 15}. Thus, choice of strategy should be individualized based on gestational age, severity of TAPS, etiology of TAPS, and feasibility of intervention.

Expectant Management

Expectant management involves ongoing weekly monitoring through obstetric ultrasound, which includes Doppler studies, including MCA-PSV. This approach is advised for stage 1 or 2 TAPS identified in the early second trimester. Other management strategies should be explored in case of advancing TAPS. In a large international cohort study involving 17 fetal therapy centers, Tollenaar and colleagues evaluated the diagnosis, management, and outcome of spontaneous TAPS¹⁶. The authors reported that, despite the severity of TAPS, 16% of pregnancies complicated by spontaneous TAPS managed expectantly experienced spontaneous resolution.

Intrauterine Transfusion (IUT)

One potential approach to patients with TAPS involves intrauterine blood transfusion (IUT) of the anemic donor twin. Alternatively, an exchange transfusion could be performed, which entails the removal of blood from the recipient twin with subsequent transfusion of the donor. IUT should be avoided in fetal patients with TAPS where the disease is advancing rapidly, as it carries the risk of potentially exacerbating the condition^17,18. A risk particularly associated with IUT involves worsening hyperviscosity in the recipient twin secondary to the rapid influx of RBCs¹⁹. IUT can be performed either via an intraperitoneal (IP) route or an intravascular (IV) route. IP-IUT is often preferred as it allows for slower RBC absorption into the donor twin’s circulation, hence preventing the rapid loss of transfused blood into the circulation of the recipient twin and avoiding increasing viscosity. Additionally, a combined procedure of IUT for the donor and partial exchange transfusion for the recipient is could also mitigate the polycythemia hyperviscosity risks^20–22. In cases of rapid recurrence or progression of TAPS after IUT, alternative management strategies should be considered.

Fetoscopic Laser Photocoagulation

The only potentially curative treatment for TAPS involves the fetoscopic laser photocoagulation (FLP) of the residual anastomoses. FLP for TAPS has been described to improve perinatal outcome by prolonging pregnancy and reducing respiratory distress in affected neonates²³. This procedure depends on adequate visualization of the vascular equator along the placenta, which is crucial for reducing the risk of TAPS recurrence. The feasibility and use of FLP for the management of TAPS have been repeatedly validated in previous literature, emphasizing its importance in managing patients with TAPS^23–26. Potential challenges complicating intrauterine access includes the absence of amniotic fluid discordance that is seen in TTTS, and which usually aids fetoscopic visualization.  Moreover, the floating intertwin membrane can obscure the small causative vascular anastomoses and hinder visualization of the equator². It has been noted that the vascular equator often lies closer to the smaller twin's cord insertion, providing potential ease of access for the procedure. Nevertheless, amnioinfusion prior to the operation can also aid in better visualization and access. The use of the Solomon technique (laser coagulation of the complete equator) further enhances the procedure’s efficacy, and is recommended for minimizing the risk of TAPS recurrence, especially in cases of TTTS complicated by TAPS ^27,28. The fetoscopic view of the fetuses and vascular anastomoses is shown in Figure 7 and Video 1. The FLP procedure with Solomonization is shown in Video 2.

Selective Termination

A variety of surgical options exist for selective termination in monochorionic multiple pregnancies, including bipolar cord coagulation, radiofrequency ablation, laser cord coagulation, umbilical cord ligation, interstitial laser, and microwave ablation. The selection among these techniques is determined by the surgeon's preference, the feasibility of intrauterine access and visibility, gestational age, and any additional TAPS findings. Techniques like interstitial laser, radiofrequency, and microwave ablation involve instruments with a smaller diameter, potentially decreasing the risks of complications like membrane rupture or premature birth. Conversely, as pregnancy progresses and both the umbilical cord and blood flow increase, bipolar cord occlusion might be the more appropriate choice due to its efficacy in managing larger blood vessels.

Mode and timing of delivery of pregnancies complicated by TAPS is determined based on obstetric indications for complicated monochorionic twins. In utero treatment of TAPS has been associated with a higher resolution rate of TAPS²⁹ and a longer time between diagnosis and birth³⁰. The mean duration from diagnosis to delivery was reported as the highest (10-11 weeks) among TAPS patients undergoing selective reduction or laser therapy^23,31.

The perinatal outcomes for pregnancies complicated by TAPS varies greatly, ranging from the birth of two healthy neonates in cases of mild TAPS, to the intrauterine demise of both twins in cases of severe TAPS. The main neonatal morbidity lies in the donor twin’s symptomatic anemia, often-requiring transfusion, and the recipient twin’s polycythemia, which can lead to symptoms of cardio-circulatory compromise, potentially requiring a partial exchange transfusion.

Spontaneous vs Post-laser TAPS

Although the overall rate of neonatal mortality in pregnancies complicated by TAPS is similar to that in uncomplicated monochorionic twin pregnancies³, outcomes may differ based on etiology of TAPS. A recent systematic review on perinatal outcomes of pregnancies complicated by TAPS found that fetal patients with spontaneous TAPS have a more favorable prognosis than those with post-laser TAPS¹⁴. In post-laser TAPS patients, prognostic factors associated with spontaneous perinatal morality include antenatal TAPS Stage 4 , donor twin status, and earlier gestational age at birth³². The high rate of perinatal mortality in the donor twin can explain poor perinatal outcomes in post-laser TAPS patients.

Neurodevelopmental Outcomes

Multiple cases of severe brain injury have also been described in TAPS neonates. In a retrospective cohort study, assessing fetal and neonatal brain imaging in 23 monochorionic pregnancies diagnosed with TAPS, brain lesions were detected in 26% of pregnancies and 15.2% of fetal patients, with the majority found in polycythemic twins³³.

Neurodevelopmental impairment (NDI) is another particular concern when considering the postnatal outcomes of patients with TAPS. In a large retrospective study of a cohort of spontaneous TAPS survivors, Tollenaar et al. reported that NDI occurred in 30% of TAPS survivors, and donor twins were four times more likely to experience neurodevelopmental impairments compared to the recipients. Donors also demonstrated lower cognitive scores, a higher incidence of bilateral deafness, and a higher risk of mortality before birth³⁴. Similarly, Slaghekke and colleagues identified NDI and cognitive delay in almost 1 in 5 of children surviving post-laser TAPS³⁵.

Consequently, it is imperative to highlight the importance of postnatal cerebral ultrasound, audiological assessment, and long-term follow up in TAPS patients. Such diagnostic follow-up measures are vital for the early detection and intervention of potential neurodevelopmental complications associated with TAPS.

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