*3.2.2. Management of sFGR*

In order to follow up the sFGR pregnancies, as well as in singleton pregnancies, umbilical artery Doppler waveforms and UA-PI are accessed. In pregnancies complicated with sFGR, there are particularities in the umbilical artery Doppler probably because of the variability in the intertwin vascular anastomoses resistance [93, 94]. Three patterns are observed in the umbilical artery Doppler: positive end-diastolic flow, absent or reversed end-diastolic flow (AREDF), and intermittent absent or reversed end-diastolic flow (iAREDF) [95]. The latter pattern though is to result from the presence of transmitted waveforms from the larger into the smaller twin's cord due to the existence of placental large AA anastomoses (**Figure 6**) [93–95]. Based on these three Doppler types, Gratacós et al. proposed a three-stage classification system of the sFGR fetuses. In stage I, the umbilical artery in the smaller twin has a positive end-diastolic flow; in stage II,

The stage I prognosis is better, with an overall intrauterine mortality rate of 3–4% and a 97% rate of intact survival-free from neurological complications according to two recent meta-analyses. The neonatal morbidity, defined as abnormal brain imaging, respiratory distress syndrome (RDS), admission to the neonatal intensive care unit (NICU), or retinopathy of prematurity (ROP), was reported in about 9% of newborns. The neurologic outcome in this stage seems to be better when compared to the others as well as the gestational age at delivery [84, 93–95, 97]. Stage II sFGR has a poorer prognostic. It is reported that these fetuses tend to have a high risk of hypoxic deterioration and consequently overall, single, and double intrauterine death rates of 16.6%, 8.2%, and 10.4% of cases managed expectantly [97] and a 21% perinatal mortality [84]. The double survival rate in this stage is about 25% [98]. The iAREDF pattern has an intrauterine mortality rate similar to stage II. The overall, single, and double intrauterine death occurred in 13.2%, 7.2%, and 5.5% of cases managed expectantly although this stage is more unpredictable than the others [86, 93, 95, 97, 98]. Some ultrasound markers can be used as adverse predictors such as ductus venosus Z score [98], velamentous cord insertion (**Figure 8**) [99, 100], and weight discordance. A recent meta-analysis found that, in MC twin pregnancies, excluding cases affected by twin to twin transfusion syndrome, twins with birthweight discordance ≥25% were at higher risk of intrauterine death (OR 3.2, 95%CI, 1.5–6.7) and neonatal

**Figure 7.** Classification of selective fetal growth restriction in monochorionic twin pregnancy. In type I, the umbilical artery Doppler waveform has positive end-diastolic flow, while in type II there is absent or reversed end-diastolic flow (AREDF). In type III there is a cyclical/intermittent pattern of AREDF. Extracted from ISUOG. https://www.isuog.org/

uploads/assets/uploaded/b4ce0129-a7e8-40a9-8543c4243fb7638f.pdf [45].

there is an AREDF; and stage III is characterized by iAREDF (**Figure 7**) [95].

136 Multiple Pregnancy - New Challenges

When sFGR presents with an umbilical artery positive end-diastolic flow, the prognosis is good, and therefore it is a consensus that the expectant management based on a weekly fetal growth and UA-PI evaluation should be done to look for progression to more severe stages which can occur in up to 25% of cases. For stages II and III, several studies compared SFLP with cord occlusion or expectant management, but there are not powered studies to support a gold standard treatment. In a retrospective study with 142 stage II sFGR fetuses treated with SFLP, there was survival rate of the smaller, larger, and both twins of 38.7, 67.6, and 34.5%, respectively. The survival rate of at least one twin was 71.8% [103]. When compared to expectant management, SFLP for stage III sFGR showed a higher overall intrauterine death (14.5 vs. 36%, respectively) as well as a higher death rate in the smaller twin which is 19% for the expectant group and 66% for the SFLP group [104]. Other prospective trial with ten pregnant women with sFGR stages II or III and oligohydramnios treated with SFLP showed that only three newborns of the restricted group survived and all of the newborns in the larger twin group were well and alive at 28 days of age [105].

Cord occlusion of the smaller twin is an option for early diagnosed sFGR, when the spontaneous death of the restricted fetus is most likely to happen, but it is the most difficult decision for the parents to make since they give up the life of one child to protect the other. Chalouhi et al. [106] found a 90% survival rate in the larger twin after cord occlusion and a 4.5% neurologic complication rate which is much lower than the 26% rate when a spontaneous intrauterine death occurs [107].

The sFGR treatment is not yet defined. Several factors should be evaluated together with parents such as weight discordance, time of diagnosis (early vs. late), hemodynamic state of the restricted fetus at the time of diagnosis, and the will to protect the larger twin since the adverse outcomes are very low after a cord occlusion [94]. If FLPC or expectant management is elected, parent counseling should be made regarding complications and outcomes to both fetus.

#### **3.3. Twin anemia polycythemia sequence**

The placental angio-architecture is responsible for most of the complications in MC pregnancies. The intertwin vascular anastomoses have a key role in the pathogenesis of TTTS and sFGR. In 2007, a new MC pregnancy complication was described by Lopriore et al. [108] that involves a discordance in postnatal hemoglobin and hematocrit levels, a difference in neonate reticulocyte levels, and small AV anastomoses in the placenta after colored dye injection (**Figure 9**). This condition was named twin anemia polycythemia sequence. TAPS happens when blood from one twin is slowly transfused to the other by small AV anastomoses at a 5–15 ml/ 24 h rate [108]. Unlike TTTS, there is a less acute and well-compensated intertwin transfusion process leading to a discordance in hemoglobin levels without hemodynamic or amniotic fluid alterations [110]. The reticulocyte levels are also increased in the donor newborn and decreased in the recipient, which differ from other acute diseases, such as acute peripartum TTTS [41]. Another characteristic of TAPS is that after colored dye injection in MC placentas after TAPS, AA anastomoses are observed in about 11% and all of them are small (<1 mm). In comparison, the incidence of AA anastomoses in uncomplicated MC pregnancies and TTTS pregnancies is 80 and 25%, respectively [111, 112], which suggests that AA anastomoses protect against TAPS and TTTS. The maternal side of the TAPS placenta also shows an important color difference. The donor side is more white than the recipient side that shows a plethoric aspect like the respective twin (**Figure 10**) [113].

TAPS may occur spontaneously or post-laser surgery. The prevalence of spontaneous TAPS is about 1.6–5% [18, 68, 114], while post-laser TAPS occurs in 3–16% [66], depending on the technique used. The possible pathophysiology for the latter is the inability to identify all AV anastomoses, therefore leaving some small AV anastomoses without coagulation. The Solomon trial showed a significant decrease in post-laser TAPS in the placental dichorionization group,

**Figure 10.** Maternal side of the TAPS placenta showing the difference in color between the plethoric share of the recipient (left side of the placenta) and the anemic share of the donor (right side of the placenta). Adapted from twin research and

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TAPS can be diagnosed either antenatally or postnatally. Antenatal diagnosis (**Table 2**) is based in MCA-PSV measurement in both fetuses showing an increased velocity in the anemic and a decreased velocity in the polycythemic twin. The most used criteria of TAPS diagnosis are an MCA-PSV > 1.5 MoM for the donor twin and <1.0 MoM for the recipient twin [111, 115]. Slaghekke et al. analyzed 43 twin pregnancies complicated by TAPS and found that a MCA-PSV > 1.5 MoM correlated with anemia (hemoglobin levels >5 SD below the mean) with a 94% sensitivity, a 74% specificity, a 76% positive predictive value, and a 94% negative predictive value. In the same study, MCA-PSV ≤ 1.0 MoM correlated with polycythemia (hemoglobin levels >5 SD above the mean) with a 97% sensitivity, a 96% specificity, a 93%

**Table 2.**Antenatal and postnatal diagnostic criteria for TAPS.Adapted from ultrasound Obstet Gynecol. Slaghekke et al. [111].

Placenta with only small (diameter < 1 mm) vascular anastomoses

supporting this hypothesis [66].

human genetics. Tollenaar et al. [113].

*3.3.1. Diagnostic criteria and classification*

**Antenatal criteria Postnatal criteria**

**AND AND 1 of the following** Recipient MCA-PSV ≤ 1.0 MoM Reticulocyte count ratio > 1.7

Donor MCA-PSV ≥ 1.5 MoM Intertwin hemoglobin difference > 8 g/dl

**Figure 9.** TAPS placenta after colored dye injection (blue or green for arteries and pink or yellow for veins). The white arrows indicate the small AV and VA anastomoses. Adapted from placenta. de Villiers et al. [109].

**Figure 10.** Maternal side of the TAPS placenta showing the difference in color between the plethoric share of the recipient (left side of the placenta) and the anemic share of the donor (right side of the placenta). Adapted from twin research and human genetics. Tollenaar et al. [113].

TAPS may occur spontaneously or post-laser surgery. The prevalence of spontaneous TAPS is about 1.6–5% [18, 68, 114], while post-laser TAPS occurs in 3–16% [66], depending on the technique used. The possible pathophysiology for the latter is the inability to identify all AV anastomoses, therefore leaving some small AV anastomoses without coagulation. The Solomon trial showed a significant decrease in post-laser TAPS in the placental dichorionization group, supporting this hypothesis [66].

#### *3.3.1. Diagnostic criteria and classification*

[106] found a 90% survival rate in the larger twin after cord occlusion and a 4.5% neurologic complication rate which is much lower than the 26% rate when a spontaneous intrauterine

The sFGR treatment is not yet defined. Several factors should be evaluated together with parents such as weight discordance, time of diagnosis (early vs. late), hemodynamic state of the restricted fetus at the time of diagnosis, and the will to protect the larger twin since the adverse outcomes are very low after a cord occlusion [94]. If FLPC or expectant management is elected, parent counseling should be made regarding complications and outcomes to both fetus.

The placental angio-architecture is responsible for most of the complications in MC pregnancies. The intertwin vascular anastomoses have a key role in the pathogenesis of TTTS and sFGR. In 2007, a new MC pregnancy complication was described by Lopriore et al. [108] that involves a discordance in postnatal hemoglobin and hematocrit levels, a difference in neonate reticulocyte levels, and small AV anastomoses in the placenta after colored dye injection (**Figure 9**). This condition was named twin anemia polycythemia sequence. TAPS happens when blood from one twin is slowly transfused to the other by small AV anastomoses at a 5–15 ml/ 24 h rate [108]. Unlike TTTS, there is a less acute and well-compensated intertwin transfusion process leading to a discordance in hemoglobin levels without hemodynamic or amniotic fluid alterations [110]. The reticulocyte levels are also increased in the donor newborn and decreased in the recipient, which differ from other acute diseases, such as acute peripartum TTTS [41]. Another characteristic of TAPS is that after colored dye injection in MC placentas after TAPS, AA anastomoses are observed in about 11% and all of them are small (<1 mm). In comparison, the incidence of AA anastomoses in uncomplicated MC pregnancies and TTTS pregnancies is 80 and 25%, respectively [111, 112], which suggests that AA anastomoses protect against TAPS and TTTS. The maternal side of the TAPS placenta also shows an important color difference. The donor side is more white than the

recipient side that shows a plethoric aspect like the respective twin (**Figure 10**) [113].

**Figure 9.** TAPS placenta after colored dye injection (blue or green for arteries and pink or yellow for veins). The white

arrows indicate the small AV and VA anastomoses. Adapted from placenta. de Villiers et al. [109].

death occurs [107].

138 Multiple Pregnancy - New Challenges

**3.3. Twin anemia polycythemia sequence**

TAPS can be diagnosed either antenatally or postnatally. Antenatal diagnosis (**Table 2**) is based in MCA-PSV measurement in both fetuses showing an increased velocity in the anemic and a decreased velocity in the polycythemic twin. The most used criteria of TAPS diagnosis are an MCA-PSV > 1.5 MoM for the donor twin and <1.0 MoM for the recipient twin [111, 115]. Slaghekke et al. analyzed 43 twin pregnancies complicated by TAPS and found that a MCA-PSV > 1.5 MoM correlated with anemia (hemoglobin levels >5 SD below the mean) with a 94% sensitivity, a 74% specificity, a 76% positive predictive value, and a 94% negative predictive value. In the same study, MCA-PSV ≤ 1.0 MoM correlated with polycythemia (hemoglobin levels >5 SD above the mean) with a 97% sensitivity, a 96% specificity, a 93%


**Table 2.**Antenatal and postnatal diagnostic criteria for TAPS.Adapted from ultrasound Obstet Gynecol. Slaghekke et al. [111].

positive predictive value, and a 99% negative predictive value [115]. In some TAPS cases, other ultrasound findings have been reported. The first one is the difference in placental thickness, and echodensity on ultrasound examination was detected [110]. Another ultrasound finding described in TAPS is the so-called starry sky liver [116] which is characterized by clearly identified portal venules and diminished parenchymal echogenicity. More studies are needed to further investigate the validity and significance of these antenatal ultrasound findings for the diagnosis of TAPS.

The only causal treatment for both spontaneous and post-laser TAPS is laser surgery. It is technically more difficult because of the absence of polyhydramnios and a stuck twin, which makes the visualization of the vascular equator more challenging as well as the size of anastomoses, which is difficult to visualize during fetoscopy [111]. The results in small studies are satisfactory, with a survival rate of 94–100% [111, 118, 120, 121] and an apparent improvement in perinatal outcome by prolonging pregnancy and reducing respiratory

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The TAPS management should be made after evaluation of different factors, including TAPS stage, gestational age, and the clinician experience in the different types of treatments. In early stages, TAPS can be managed expectantly. If gestational age is below 26–28 weeks, laser treatment should be considered [113]. When laser treatment is not possible, IUT should be considered. When repeated IUT is expected or in case of severe polycythemia in the recipient,

Twin reversed arterial perfusion sequence resulting in an acardiac twin is a rare condition and occurs in 1:35,000 births or 1% of all monozygotic twins [122]. It consists in one health twin (the "pump" twin) and one acardiac mass which is perfused by the other fetus' heart. This acardiac twin most often has an underdeveloped head and upper body and impressive edema also mostly of the upper body. In some cases, there might be fetal movements. In rare cases, a rudimentary pulsating cardiac structure may be seen. It is though that the VV and AA bidirectional anastomoses are responsible for the perfusion of the acardiac fetus. One study analyzed the TRAPS placenta and found big AA anastomoses as well as veins in direct continuity with each other. They also noted that umbilical cords were attached, with insertion adjacent to each other [123]. The blood from the pump twin flows through the umbilical artery to the umbilical artery of the acardiac twin and then it flows back to the recipient twin through the umbilical vein. The returning blood bypasses the placenta and returns to the pump twin via VV anastomoses, without passing through the placenta. This condition may cause a hyperdynamic circulation and progressive high output cardiac failure in the pump twin causing fetal death in about half of cases if not

The diagnostic is made by turning on the color Doppler and showing the inverse direction of blood flow in the aorta of the acardiac twin [92] (**Figure 11**). TRAPS is usually diagnosed in the 11–13 weeks scan or even in the early endovaginal ultrasound [126–128]. Given the fact that 50% of pump twin dies if expectant management is made and that in 33% of the TRAPS pregnancies diagnosed at the first trimester the healthy twin dies before 18 weeks [123, 129], several intrauterine interventions have been tested in order to improve the perinatal outcomes. The overall survival of the treatment methods is similar among several studies and varies between 71 and 86% [130–134]. The methods used to manage TRAPS are cord ligation; monopolar, bipolar, or laser cord coagulation; and fetoscopic laser coagulation of placental anastomoses. However, intrafetal techniques such as intrafetal laser ablation and intrafetal radiofrequency ablation (RFA) are preferred because, when compared to cord occlusion

distress syndrome [117].

treated [122, 124, 125].

PET of the recipient can be done.

**3.4. Twin reversed arterial perfusion sequence**

The postnatal criteria (**Table 2**) can be used when TAPS is not diagnosed by MCA Doppler. It is based on the finding of discordant hemoglobin levels (Hb difference > 8.0 g/dl) associated with an increased intertwin reticulocyte count ratio > 1.7 that is pathognomonic for TAPS and placental evidence of only small vascular anastomoses [111, 117].

The classification for TAPS was proposed by Slaghekke et al. in 2010 [111] based on the difference in hemoglobin levels postnatally (**Table 3**).
