Antenatal management of twin-twin transfusion syndrome and twin anemia-polycythemia sequence

ABSTRACT

Introduction: Twin-twin transfusion syndrome (TTTS) and twin anemia polycythemia sequence (TAPS) are severe complications in monochorionic twin pregnancies associated with high mortality and morbidity risk if left untreated. Both diseases result from imbalanced inter-twin blood transfusion through placental vascular anastomoses.

Areas covered: This review focuses on the differences in antenatal management between TTTS and TAPS.

Expert commentary: The optimal management for TTTS is fetoscopic laser coagulation of the vascular anastomoses, preferably using the Solomon technique in which the whole vascular equator is coagulated. The Solomon technique is associated with a reduction of residual anastomosis and a reduction in post-operative complications. The optimal management for TAPS is not clear and includes expectant management, intra-uterine transfusion with or without partial exchange transfusion and fetoscopic laser surgery.

KEYWORDS:

• Monochorionic twins
• twin-twin transfusion syndrome
• twin anemia-polycythemia sequence
• fetoscopic laser surgery
• intrauterine transfusion
• partial exchange transfusion

1. Introduction

Perinatal mortality and morbidity in twins is significantly increased compared to singletons, partly due to the higher incidence of prematurity and very low birth weight in twins. Risk of adverse outcome is particularly pronounced in monochorionic twins. Twin gestations, which represent 2% of all pregnancies, may either be dizygotic or monozygotic. Dizygotic twins are always dichorionic and have therefore two separate placentas, whereas monozygotic twins most often share their placenta, so-called monochorionic placenta. Dichorionic twins almost never have placental vascular anastomoses whereas virtually all monochorionic twins have vascular anastomoses connecting the two fetal circulations [1]. These vascular anastomoses may lead to severe complications during pregnancy including twin–twin transfusion syndrome (TTTS), twin anemia–polycythemia sequence (TAPS), twin-reversed arterial perfusion, and selective intrauterine growth restriction due to imbalanced inter-twin blood flow. Three types of vascular anastomoses are seen in monochorionic placentas: artery to artery, vein to vein, and artery to vein. Arterio-venous (AV) anastomoses are unidirectional anastomoses in which an artery of one twin is connected with a vein of the co-twin via a shared cotyledon (also called ‘deep-anastomoses’). Blood flow in an AV anastomosis goes in one direction from artery to vein. Arterio-arterial (AA) and veno-venous (VV) anastomoses are ‘superficial’ anastomoses since they lie on the placental surface and are bi-directional. AA anastomoses are considered to have a protective effect against the development of TTTS and TAPS. The consequences of VV anastomoses are not well known [2]. Figure 1 shows an uncomplicated monochorionic placenta after color-dye injection highlighting the different types of vascular anastomoses. Both TTTS and TAPS result from imbalanced blood flow in which one twin (the recipient twin) receives excessive blood from its co-twin (the donor twin) through the AV anastomoses. This review focuses primarily on the differences in antenatal management between TTTS and TAPS.

Figure 1. (Full color available online) Uncomplicated monochorionic twin placenta after color dye injection showing large vascular anastomoses. Arteries are injected with blue and green dye and veins are injected with pink and yellow dye. Arterio-venous anastomoses are indicated with white arrows, an arterio-arterial anastomosis is indicated with a blue arrow and a veno-venous anastomosis is indicated with a green arrow.

2.1 TTTS

TTTS occurs in approximately 10% of all monochorionic twins [3] and is caused by an imbalanced blood flow from donor to recipient resulting in hypovolemia and oligohydramnios in the donor and hypervolemia and polyhydramnios in the recipient twin. The donor may be growth restricted and anemic and the recipient may be polycythemic but these are not diagnostic criteria for TTTS. The diagnosis of TTTS is based on prenatal ultrasound on the presence of oligohydramnios in the donor twin with a maximum deepest vertical pocket (DVP) of 2 cm and polyhydramnios in the recipient with at least a DVP of 8 cm before 20 weeks of gestation and at least 10 cm after 20 weeks of gestation. Quintero et al. [4] introduced a staging system for TTTS. In stage 1 TTTS, bladder filling in the donor is still visible. As the disease progresses, the donor becomes more hypovolemic without bladder filling (stage 2). In stage 3, critical abnormal Doppler measurements (absent/reverse end-diastolic velocity in the umbilical artery, reverse flow in the ductus venosus or pulsatile flow in umbilical vein) are seen. Stage 4 TTTS is characterized by the presence of fetal hydrops, mainly due to progressive cardiac failure. Stage 5 is characterized by intrauterine fetal demise (IUFD) of one or both twins. If left untreated, TTTS can result in an overall mortality rate of 73–100% [5]. Fetal cardiac function evaluation has been proposed to improve stratification of hemodynamic imbalance observed in monochorionic twins with TTTS.

Until a couple of decades ago, the only available antenatal treatment option was (serial) amnioreduction to treat polyhydramnios and reduce the risk of preterm delivery due to increased uterine distention leading to premature contractions and rupture of the membranes. However, amnioreduction is not a causal treatment and only a temporary solution. Nowadays, the preferred antenatal treatment option for TTTS is fetoscopic laser coagulation of the vascular anastomoses at the placental surface. Fetoscopic laser surgery was first introduced by De Lia et al. in 1990 [6]. In 2004, Senat et al. [7] showed in a randomized controlled trial that fetoscopic laser surgery improved survival and neonatal outcome compared to amnioreduction. Survival of at least one twin at 28 days of age was 76% after laser surgery compared to 51% in the amnioreduction group (p = 0.009). A lower incidence of severe cerebral injury was seen in the laser group (14% after amnioreduction compared to 6% after laser surgery, p = 0.02). The increased incidence of cerebral injury after amnioreduction is partly due to the lower gestational age at birth in the amnioreduction group (29.0 weeks after amnioreduction compared to 33.3 weeks after laser, p = 0.004). van Klink et al. [8] showed in a meta-analysis a sevenfold increased risk of severe cerebral injury in live-born children treated with amnioreduction compared to laser (Odds ratio 7.69, 95% confidence interval (CI) 2.78–20.0, p = 0.00). Long-term outcome is also more favorable after laser surgery compared to amnioreduction. The incidence of neurodevelopmental impairment is on average 10% after laser surgery and 20% after amnioreduction [9]. The difference in long-term outcome is probably due to the higher incidence of extreme prematurity and cerebral injury after amnioreduction.

2.2. The Solomon laser technique

Although the majority of studies have shown that laser treatment is effective in most TTTS cases, treatment failure may still occur and can lead to severe complications [10,11]. Up to 33% of placentas treated with laser may still have residual anastomoses [2]. These residual anastomoses can lead to several hematologic complications such as recurrent or reversed TTTS and TAPS. Most residual anastomoses are extremely small (diameter <1 mm) and may thus be missed during fetoscopy. In a recent randomized controlled trial (Solomon trial [12]), a significant reduction in recurrent TTTS and TAPS after fetoscopic laser surgery was reported with the Solomon technique compared to the standard technique. With the Solomon technique, after identifying and coagulating the individual anastomoses, a line is drawn with the laser from one placenta margin to the other (see Figure 2) compared to only coagulating the individual anastomoses with the standard technique. The Solomon trial showed a significant reduction of residual anastomoses (19% in the Solomon group vs. 34% in the standard technique group, p = 0.04) [13]. Increase in complete dichorionization with the Solomon technique leads to a reduction in post-laser TAPS and recurrent TTTS in the standard group versus the Solomon group from 16% to 3% and 7% to 1%, respectively. The Solomon technique did not appear to be associated with an increase in any identifiable adverse outcome or complication and therefore the use of the Solomon technique is recommended for the treatment of TTTS [12]. Importantly, residual anastomoses still occur even after the use of the Solomon technique. Close post-operative monitoring, including Middle Cerebral Artery-Peak Systolic Velocity (MCA-PSV) Doppler measurements, at least biweekly, remains therefore important.

Figure 2. (Full color available online) TTTS placenta treated with the Solomon technique in which a laser coagulation line is clearly visible along the vascular equator.

The reported risk of residual anastomoses varies between the studies and may be related to differences in laser technique and experience of the surgeon. Another important factor is related to technique used to inject the placenta. Reported injection techniques include the use of air, milk, or colored dye. The majority of residual anastomoses are minuscule and can easily be missed if placenta examination is not performed accurately using colored dye injection [2].

2.3 The sequential laser technique

Several studies suggest a possible improvement in outcome with the use of the sequential laser technique. This technique, first described by Quintero et al. [14], is an adaptation of the selective technique where the individual anastomoses are coagulated in a specific order starting with the artery to vein anastomoses from donor to recipient and ending with the artery to vein anastomoses from recipient to donor. The aim of coagulating in this specific order is to reduce the difference in hypovolemia in the donor and hypervolemia in the recipient. In a recent meta-analysis, Akkermans et al. [15] confirmed the beneficial effect of the sequential laser technique, with improvement in double survival rate and reduction of fetal demise. However the studies included in the meta-analysis had a small sample size hampering the interpretation of the results and limiting the conclusions.

2.4 Laser surgery in stage 1 TTTS

Laser surgery is the preferred treatment for TTTS cases with Quintero stage ≥2. Whether laser surgery should also be performed in all cases with TTTS stage 1 is not known. A recent systematic review and meta-analysis [16] on management of TTTS stage 1 showed the best treatment option for TTTS stage 1 is still not clear. Progression of TTTS stage 1 to higher stages is reported to occur in 10–50% of cases in the various studies. The pooled overall survival was 79% after expectant management, 77% after amnioreduction and 68% after laser surgery. Survival of at least one twin was 87% after expectant, 86% after amnioreduction and 81% after laser surgery. The North American Fetal Therapy Network recently published their results in TTTS stage 1 [17]. In this retrospective cohort, 124 cases were divided into 3 groups: expectant management (n = 49, 40%), amnioreduction (n = 30, 24%), and laser surgery (n = 45, 36%). In the expectant management group 60% progressed to a higher stage, 8% stayed stable and 22% regressed. Intervention with amnioreduction or laser surgery was associated with a lower risk of fetal loss. Only laser surgery was associated with a reduction of poor outcome (double fetal demise or delivery <26 weeks) with adjusted odds of 0.26 (95% CI 0.09–0.77) versus expectant management. Currently, a multicenter randomized controlled trial compares expectant management and laser surgery for TTTS stage 1 and should provide answer for the best treatment option for TTTS stage 1 (ClinicalTrials.gov NCT01220011).

2.5 Laser surgery in early or late TTTS

The usual gestational age for laser surgery for TTTS is between 16 and 26 weeks of gestation. However, several authors suggest that these conventional gestational age guidelines of 16–26 weeks should be re-evaluated. Recent studies have shown that laser surgery is feasible and effective in early TTTS cases presenting before 16 weeks of gestation and late TTTS cases presenting after 26 weeks. The outcome in these extreme cases was similar as those observed in cases treated between 16 and 26 weeks [18–20].

3.1 TAPS

TAPS is a chronic form of feto-fetal transfusion in monochorionic twins first described in 2007 and is characterized by large inter-twin hemoglobin differences. The main difference between TAPS and TTTS is based on the absence of oligohydramnios and polyhydramnios in TAPS [21]. Table 1 shows the diagnostic and staging differences between TTTS and TAPS. TAPS may occur spontaneous or after laser treatment for TTTS (post-laser TAPS). The incidence of TAPS varies between 1% and 5% in spontaneous TAPS [2,3] and in up to 16% in post-laser TAPS [11]. Prenatally, TAPS is diagnosed based on Doppler Ultrasound findings with an increased MCA-PSV ≥1.5 MoM (multiples of the median) in the donor, suggestive for fetal anemia, and a decreased MCA-PSV ≤1.0 MoM in the recipient, suggestive for fetal polycythemia. Postnatal criteria are based on the presence of inter-twin hemoglobin difference of ≥8.0 g/dL and at least one of the following: small residual anastomoses at the placental surface (Figure 3) after color dye injection and/or reticulocyte count ratio (reticulocyte donor/reticulocyte recipient) ≥1.7 [22]. The highly increased reticulocyte count in the donor twin reflects the chronic aspect of TAPS. These additional criteria are required to distinguish between TAPS, which is a chronic form of transfusion, and acute peripartum TTTS which is an acute form of transfusion through large anastomoses occurring during delivery. Prenatal and postnatal staging system is based on the severity of TAPS. Prenatal stage 1 is based on the presence of MCA-PSV ≥1.5 MoM in the donor and ≤1.0 MoM in the recipient. In stage 2, MCA-PSV is ≥1.7 MoM in the donor and ≤0.8 MoM in the recipient. Stage 3 shows critical abnormal Doppler findings suggestive of fetal compromise. Stage 4 shows hydrops, mainly in the donor due to severe anemia. Stage 5 is characterized by the presence of IUFD of one or both twins [22].

Table 1. Differences between TTTS and TAPS.

	TTTS	TAPS
Pathogenesis	Transfusion through anastomoses	Transfusion through small anastomoses
Incidence	10%	Spontaneous TAPS: 1–5%
		Post-laser TAPS: up to 16%
Prenatal diagnosis	Oligo-polyhydramnios on prenatal US	Abnormal US Dopplers: MCA-PSV ≥1.5 MoM in donor & ≤1.0 MoM in recipient, without twin oligo-polyhydramnios sequence
Postnatal diagnosis	–	Intertwin Hb difference ≥8 g/dL
		AND at least one of the following:
		Reticulocyte count ratio >1.7
		Small AV-anastomoses (diameter < 1 mm)
Antenatal staging	Stage 1:	Stage 1:
	Donor DVP <2 cm, recipient DVP >8 cm, DVP >10 cm (≥20 weeks)	MCA-PSV ≥1.5 MoM & ≤1.0 MoM
	Stage 2:	Stage 2:
	Donor: no bladderfilling, recipient: full bladder	MCA-PSV ≥1.7 MoM & ≤0.8 MoM
	Stage 3:	Stage 3:
	Doppler abnormalities	Doppler abnormalities
	Stage 4:	Stage 4:
	Hydrops	Hydrops
	Stage 5:	Stage 5:
	IUFD	IUFD

US: Ultrasound; DVP: deepest vertical pocket; MCA-PSV: middle cerebral artery-peak systolic velocity; MoM: multiples of the median; Hb: hemoglobin; IUFD: intrauterine fetal demise; TAPS: twin anemia–polycythemia sequence; TTTS: twin–twin transfusion syndrome.

Figure 3. (Full color available online) TAPS placenta showing a few minuscule arterio-venous anastomoses (white arrows) and a minuscule arterio-arterial anastomosis (blue arrow). All anastomoses have a diameter < 1 mm.

The optimal management for TAPS is not clear. Options for antenatal management include fetoscopic laser surgery, intrauterine blood transfusions (IUT) in the donor, with or without combination of partial exchange transfusion (PET) in the recipient, expectant management, or selective feticide.

3.2 Intrauterine blood transfusion with or without PET

Treatment with IUT in the donor can be performed either through intravascular or intraperitoneal transfusion. Although treatment with IUT has often been reported, it is not a causal treatment and only a temporary solution. Furthermore, a potential negative effect of IUT in the donor is worsening of the polycythemia hyperviscosity syndrome in the recipient. Robyr et al. [11] reported skin necrosis of the leg in the recipient twin of a TAPS case treated with several IUTs. To reduce the risk of increasing polycythemia hyperviscosity, a combination procedure of IUT in the donor and PET in the recipient can be of additional value. The rationale behind this therapy is that PET may help to decrease the viscosity of the blood of the polycythemic recipient. Genova et al. [23] reported on three different TAPS cases treated with IUT with PET. In a computational model where the effect of IUT alone was compared to IUT in combination with PET showed the beneficial effect of PET [24].

3.3 Fetoscopic laser surgery for TAPS

The only causal treatment of TAPS is fetoscopic laser coagulation of the (residual) anastomoses at the vascular equator of the placental surface. Importantly, fetoscopic laser coagulation in TAPS can be more challenging than in TTTS because the absence of polyhydramnios may prevent optimal visualization of the vascular equator due to reduced intrauterine space and motility during fetoscopy [25]. Moreover, placental anastomoses in TAPS are known to be only few and minuscule and may therefore be missed during fetoscopy [25]. Several case reports show the feasibility of fetoscopic laser coagulation in TAPS placentas [26–30]. In a retrospective study where laser treatment for antenatally detected TAPS is compared to IUT or expectant management, laser therapy appeared to improve perinatal outcome by prolonging pregnancy [25]. The median time between diagnosis and birth was 11 weeks in the laser group compared to 5 weeks after intrauterine transfusion and 8 weeks after expectant management. Larger, adequately randomized controlled studies are required to determine the optimal management and to evaluate the possible additional value of fetoscopic laser coagulation for the treatment of TAPS. When performing laser coagulation in TAPS placentas, the Solomon technique should be used because the anastomoses in TAPS are known to be minuscule and may easily be missed [12].

Recently, Tollenaar et al. [31] proposed a treatment strategy for TAPS based on gestational age and antenatal stage. TAPS stage 1 and possibly stage 2 can be observed with close monitoring. In case TAPS progresses quickly to stage 2 or in case of stage ≥3, intervention should be considered. Since laser is the only causal treatment for TAPS, if gestational age is below 28 weeks and laser treatment is feasible, laser treatment should be considered [25]. When laser treatment is not feasible and gestational age is below 32 weeks of pregnancy intrauterine transfusion should be considered. When repeated intrauterine transfusions are expected or in case of severe polycythemia in the recipient, PET of the recipient should be taken into account. However, to determine the optimal management in TAPS adequately powered, randomized controlled studies are needed. Importantly, all invasive procedures (needle procedures and fetoscopic interventions) have an important Achilles’ heels: a hole in the amniotic membranes needs to be made to perform these interventions. This hole is associated with significantly increased risks of preterm prelabor rupture of the membranes, chorioamnionitis, miscarriages, or preterm delivery. Lastly, outcomes of all the interventions that have been described within this manuscript are significantly influenced by the cervical length measured before the procedure. Comparisons between series and different interventions must take all the factors into account.

4. Expert commentary

TTTS and TAPS are severe complications in monochorionic twin pregnancies associated with high mortality and morbidity risk if left untreated. Both diseases result from imbalanced inter-twin blood transfusion through placental vascular anastomoses. The optimal management in TTTS is fetotoscopic laser coagulation of the vascular anastomoses. Recent studies suggest that the Solomon laser technique is associated with a reduction in residual anastomoses and a reduction of post-operative complications. More studies are needed to determine the optimal treatment in TTTS stage 1 and in TTTS cases presenting early in gestation (before 16 weeks) or late (after 26–28 weeks). The optimal management in TAPS is not yet known and includes expectant management, laser surgery, and fetal blood transfusion with or without PET. A randomized controlled trial is urgently needed to determine the optimal treatment in TAPS.

5. Five-year view

In the next few years, a randomized trial for TTTS stage 1 is expected to be completed. Based on these results, the optimal treatment approach in early stage TTTS could be determined and implemented. We are planning to initiate an international multicenter randomized controlled trial to determine the optimal treatment in TAPS. We expect that increased awareness on the potential complications arising in monochorionic twins such as TTTS and TAPS will increase early detection of these complications and improve the management and outcome of these potential devastating diseases. Given the rarity of these disorders, international collaboration and web-based registries are of paramount importance. More studies are needed to improve our understanding of these complex diseases and improve the short and long-term outcome in TTTS and TAPS. Follow-up studies evaluating the long-term neurodevelopment outcome are crucial as the ultimate aim of fetal therapy is to improve disease-free survival, without handicaps.

Key issues

• Virtually all monochorionic twins share a placenta with vascular anastomoses connecting the two fetal circulations.

• Vascular anastomoses can lead to severe complications such as twin-twin transfusion syndrome (TTTS) or twin anemia-polycythemia sequence (TAPS) in 10% and 5% of cases, respectively.

• TTTS is characterized by the presence of oligohydramnios in the donor and polyhydramnios in the recipient.

• TAPS is characterized by chronic anemia in the donor and polycythemia in the recipient without amniotic fluid discordance.

• TAPS may occur spontaneously or after laser surgery for TTTS (post-laser TAPS) due to residual anastomoses.

• The optimal antenatal treatment for TTTS is fetoscopic laser coagulation of the vascular anastomoses.

• The use of the Solomon laser technique in TTTS in which a coagulation laser line is drawn to separate the two placenta shares reduces the risk of residual anastomoses and post-operative complications.

• The optimal antenatal treatment for TAPS is not known and includes expectant management, laser surgery and fetal blood transfusion with or without partial exchange transfusion.

• More studies (preferably randomized trials) are needed to determine the optimal treatment in stage 1 TTTS and in TAPS and should include long-term neurodevelopmental evaluation in survivors.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.