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Twin–twin transfusion syndrome: Treatment and outcome
Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 227–238
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Twin–twin transfusion syndrome: Treatment and outcome Werner Diehl, MD, Consultant in Fetal and Maternal Medicine *, Anke Diemert, MD, Consultant in Fetal and Maternal Medicine, Kurt Hecher, MD, PhD, Consultant (Professor) of Obstetrics and Fetal Medicine University Medical Centre Hamburg-Eppendorf, Department of Obstetrics and Foetal Medicine, Martinistraße 52, 20246 Hamburg, Germany
Keywords: twin–twin transfusion syndrome monochorionic twins placental vascular anastomoses fetoscopic laser coagulation
Twin–twin transfusion syndrome complicates up to 15% of monochorionic pregnancies in the mid-trimester, and results in high perinatal mortality and morbidity if left untreated. Although some humoral factors play a role in the pathogenesis of the disease, an unequal placental sharing and the presence of placental vascular anastomoses at the chorionic plate, allowing blood volume shifts between the twins, are the anatomic prerequisite for this complication unique to monochorionic twins. Within monochorionic pregnancies, it is possible to identify a subgroup of twin pairs at high risk of developing twin–twin transfusion syndrome or selective intrauterine growth restriction during the course of pregnancy as early as in the first or early second trimester. If progressive amniotic fluid discrepancy advances to moderate twin–twin transfusion syndrome, and finally reaches the stages of severe twin–twin transfusion syndrome, accurate classification of the clinical picture and diagnosis of the individual fetal haemodynamic status are crucial for counselling parents on treatment options and possible outcomes. Clear criteria have been established for fetoscopic laser coagulation of placental vascular anastomoses, which is the treatment of choice for severe twin–twin transfusion syndrome, interrupting blood flow between the twins, and relieving uterine over-distension related to severe polyhydramnios. Ó 2013 Published by Elsevier Ltd.
* Corresponding author. Tel.: þ49 152 2281 5259; Fax: þ49 40 741046767. E-mail address: [email protected] (W. Diehl). 1521-6934/$ – see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.bpobgyn.2013.12.001
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Introduction Monochorionic twinning is related to cleavage of a monozygotic blastomere after the third postconceptional day. An earlier cleavage will result in monozygotic dichorionic twins. After day 9, the monochorionic twin pair will also share a common amniotic cavity (monoamniotic twins) and, after day 12, the cleavage may not be complete, resulting in conjoined twins [1]. Around two-thirds of monozygotic twins are monochorionic, and 12% of these pregnancies will be complicated by twin–twin transfusion syndrome. Another 15% of the monochorionic twins will develop selective intrauterine growth restriction (sIUGR), and 5% will be complicated by TAPS, typically in the early third trimester. On the one hand, these complications are related to the presence of placental vascular anastomoses of monochorionic placentas, which allow shifts of blood from one twin to the other. On the other hand, the placental mass at disposition for each twin will cause growth restriction in one of them (sIUGR), if there is unequal sharing. In some cases, twin–twin transfusion syndrome (TTTS) is combined with severe growth restriction of the donor twin. The presence of vascular anastomoses at the chorionic plate is almost universal to monochorionic placentas, most of them being arteriovenous in nature [2]. As such, arteriovenous anastomoses are uni-directional (allowing blood flow from one twin to the other), with a feeding artery of one twin supplying a placental cotyledon by perforating the chorionic plate to the depth and a draining vein arising from the depth through the chorionic plate to carry oxygenated blood to the co-twin. During fetoscopy in cases of severe TTTS, and in colour dye injection studies of monochorionic placentas, arteriovenous anastomoses in both directions have almost always been observed [3]. Arterio–arterial and veno–venous anastomoses, which run on the surface of the chorionic plate, one vessel directly continuing into the other, allow blood flow in both directions (bi-directional), with a low resistance, and are less common. In arterio–arterial anastomoses, the blood pressure of each twin causes the pulse waves to collide against each other with different beat frequencies, the net flow through these anastomoses thus depending on the haemodynamic state of the respective twin. Because of their low vascular resistance, huge inter-twin shifts of blood volume are possible through arterio–arterial anastomoses, on one hand allowing compensation of volume shifts occurring through arteriovenous anastomoses predominantly in one direction and, on the other hand, permitting an acute and massive blood shift towards an eventually hypotensive co-twin, with the consequence of striking hypovolaemia and the risk for hypoxic-ischaemic encephalopathy in the normotensive twin [4]. Similar volume shifts are believed to occur through veno–venous anastomoses, although in a lower intensity. Such inter-twin vascular accidents, along with chronic transfusion through arteriovenous anastomoses, are believed to be responsible for the increased mortality and morbidity in monochorionic twin pairs [5]. Because of this shared circulation, the development of monochorionic twins is dependent on each other and, in the event of intrauterine death (IUD) of one twin, the surviving twin has up to a 30–35% risk of consecutive IUD or neurologic sequelae [6]. In the event of single fetal demise, the co-twin has a risk of IUD of 15% (3% in dichorionic twins) and a risk of neurologic injury of 26% (2% in dichorionic twins) and, in general, monochorionic twins are 4.81 times more likely to have neurodevelopmental morbidity [7]. Treatment of twin–twin transfusion syndrome Mild-to-moderate cases of TTTS, characterised by discrepant amniotic fluid amounts and moderate differences between the twins in bladder fillings and fetal growth, may progress to any stage of severe TTTS; therefore, fortnightly ultrasound monitoring of these twin pairs and education of the mother of clinical symptoms of TTTS (e.g. rapid uterine growth, increasing discomfort owing to uterine overdistension, and early contractions) are mandatory. Nevertheless, most of these cases remain stable throughout the entire pregnancy, and laser therapy is not needed [5,8]. Fetoscopic laser coagulation of placental vascular anastomoses is the treatment of choice for severe TTTS from 16–26 weeks gestation [9,10], and is indicated for cases fulfilling the diagnostic sonographic criteria exposed earlier in this issue (See Sueters M., Oepkes D., Diagnosis of twin–twin transfusion syndrome, selective fetal growth restriction, twin anaemia polycythaemia sequence and twin reversed arterial perfusion sequence). Pregnancies fulfilling the Doppler criteria for stage III or echocardiographic criteria for stage IV (e.g. hydrops and advanced heart failure) that present in the late second trimester, as
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well as cases presenting with clear disease progression, may also undergo laser therapy after 26 weeks [11]. Thus, with increasing experience, the treatment window for TTTS by fetoscopic laser coagulation has become wider from 15 to 29 weeks, although early procedures carry a higher risk for pregnancy loss. In preparation for fetoscopic laser coagulation, apart from collecting data relevant for diagnosis and staging, a careful ultrasound scan provides the surgeon with a mental spatial map of the possible topography to be found at fetoscopy, by localising the cord insertion sites of the twins, the extent of the placenta, the localisation of the stuck twin, and the probable localisation of the vascular equator. A percutaneous access to the recipient’s amniotic cavity in local anaesthesia under ultrasound guidance, using 2-mm fetoscopes inserted through a previously inserted sheath, has become the standard technique [12]. The insertion site on the maternal abdomen should be chosen opposite to the expected placental vascular equator, so that optimal access to the target vessels can be achieved. In cases with anterior placenta, the entry site has to be chosen through the lateral uterine wall, avoiding the placental edge, maternal uterine vessels, and neighbouring organs, and ideally the collapsed sac of the donor twin. More limited access to the vascular equator, and a tangential angle of view with an unfavourable angle of impact of laser energy on the target vessels, makes these cases more technically challenging. The introduction of 30 fetoscopes for anterior placentas, however, with integrated steering levers for bending the tip of the laser fibre towards the placenta, has shown results, which are comparable to posterior placentas [13]. The insertion line of the inter-twin membrane on the chorionic plate and the cord insertion site of the recipient twin are important intra-amniotic landmarks that provide orientation to the vascular equator. Vessels crossing the line underneath the membrane have to be followed in both directions to check for anastomoses (Figs. 1 and 2). Although the vascular equator will be directly visible from the recipients amniotic cavity (Fig. 3), it may sometimes extend to an area underneath the insertion line of the inter-twin membrane, and some anastomoses may be located in the donor’s amniotic cavity (Fig. 4). In these cases, laser coagulation has to be carried out through the membrane (Fig. 5a and b). Because arteries almost always cross over veins and carryoxygen depleted blood, thus looking darker than light red veins, the direction of blood flow in the
Fig. 1. The insertion line of the inter-twin membrane (yellow arrows) helps for the identification of the vascular equator and anastomoses. The tip of the laser fibre is visible at 12 o’clock. Some veins to the donor are seen crossing underneath the insertion line and forming an arteriovenous anastomosis from recipient to donor, seen at red spot of laser pilot light.
Fig. 2. The insertion line is running vertically in this fetoscopic image. A thin arteriovenous anastomosis is seen under the red pilot light of the laser fibre, which is seen at 5 o’clock.
Fig. 3. Typical arteriovenous anastomoses (AV, yellow circles) along the vascular equator of the chorionic plate. Note the darker colour of arteries and the lighter veins.
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Fig. 4. A thin arteriovenous anastomosis is seen under the inter-twin membrane (yellow circle) in the donor’s amniotic cavity. Sometimes the vascular equator crosses underneath the insertion line of the membrane and laser coagulation is made through the membrane. Unintentional septostomy is possible, although small defects of the membrane will not cause fetal complications.
vessels can be established during fetoscopy. In a few cases with turbid amniotic fluid, an amnioinfusion with saline solution may improve visual conditions. With these factors in mind, the operator can clearly identify the anastomoses. A 400 mm laser fibre is advanced through to operative channel of the fetoscope, and laser energy is fired at a distance of about 1 cm from the vessels. A Neodymium– Yttrium–Aluminium garnet or diode lasers are commonly used, owing to their optimal energy
Fig. 5. (a) A complex arteriovenous anastomosis (yellow circles) from donor to recipient is seen just under the inter-twin membrane insertion line. Darker arteries come from the donor to meet the veins of the recipient twin; (b) laser coagulation was carried out (white area) through the membrane.
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absorbance in the spectrum of haemoglobin. Selective coagulation of the anastomoses at the vascular equator is the most common method, and some centres prefer a sequential coagulation of the arteriovenous anastomoses (from donor to recipient) first and thereafter the vascular anastomoses (from recipient to donor) [14,15]. Recently, additional coagulation of the area between the selectively coagulated anastomoses, known as ‘Solomon technique’ (Fig. 6a and b), has gained interest, and results of survival rates, recurrence of TTTS, and the incidence of TAPS after laser (a complication seen in about 13% of procedures) are promising [16,17]. With this technique, thin anastomoses, which may be difficult to detect in cases of turbid amniotic fluid or at the margin of an anterior placenta, may not be missed (Fig. 7). The Solomon technique and a sequential coagulation, however, may lead to longer operating times, but this issue is currently under investigation. The procedure is always finished with an amnioreduction of the polyhydramnios to a normal amount of amniotic fluid to relieve uterine over-distension. The average operating time is 30 mins, the risk for miscarriage or early delivery caused by preterm premature rupture of membranes (PPROM) is 7%, and delivery takes place at a median gestational age of 34 weeks [12]. A cervical cerclage for a short cervix (<15 mm) directly after the laser procedure can be offered, and may be the only reason for regional anaesthesia [18]. Data are controversial on the benefit of a cerclage after laser therapy; in a recent retrospective study, only a subgroup of patients with a cervix length between 16 and 20 mm showed a significant prolongation of pregnancy [19]. A short cervix (<15 mm) was associated with preterm delivery, regardless of having received a preventive cerclage, thus suggesting an already substantial risk for early delivery. Additionally, pregnancy duration was not affected by the placement of a cerclage in women with a cervix length greater than 20 mm, compared with expectant management, thus suggesting that women whose cervix length is above this cut-off may not be at an increased risk for preterm birth. Therefore, further randomised-controlled studies are warranted to address this issue. In a recent retrospective, multicentre cohort study, Papanna et al. [20] identified risk factors for preterm delivery after fetoscopic laser coagulation. A lower maternal age, history of previous praematurity, shortened cervical length, a larger cannula diameter, amnioinfusion (performed in 41% of cases), and iatrogenic preterm premature rupture of membranes (28%), were significantly associated with a lower gestational age at delivery. As stage I cases do not necessarily progress to more advanced stages, and some of them even regress to almost balanced amniotic fluid amounts, the indication for fetoscopic laser coagulation in this group of women is controversial. Therefore, currently, a randomised-controlled trial comparing expectant management to primary laser is under way (http://clinicaltrials.gov/ct2/show/NCT01220011). Women assigned to the expectant management arm of the study are followed weekly and, if stage progression
Fig. 6. (a) A continuous coagulation line (yellow arrow) is drawn along the showed distance between already coagulated anastomoses (Solomon technique); (b) the coagulation line is almost finished by continuous or spot by spot firing on the chorionic plate.
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Fig. 7. Coagulation line (yellow box) between two anastomoses. A few very thin vessels were coagulated closed using this technique.
or worsening of maternal obstetric parameters owing to massive polyhydramnios occurs, laser therapy is then immediately offered. Apart from exclusion criteria (e.g. short cervix, contractions, maternal discomfort, previous amniocentesis, fetal malformations, and PPROM), only 15% of TTTS cases present with stage I, and many women are referred to laser centres with geographical limitation for weekly follow up. Thus, recruitment seems time consuming. Twin anaemia-polycythaemia sequence has been observed as a consequence of a few missed thin anastomoses after laser in up to 13% of the procedures. The presence of a few small arteriovenous anastomoses, allowing a slow transfusion, gradually leads to highly discordant haemoglobin levels between the twins, and has been related to TAPS [21]. Antenatal diagnosis is made measuring the peak systolic velocities in the middle cerebral artery, when velocities exceed 1.5 multiples of media in the anaemic twin, together with decreased velocities (<1.0 multiples of media) in the polycythaemic cotwin. Postnatally, TAPS is diagnosed by neonatologists in twins, with marked haemoglobin concentration differences (<11 g/dl in the anaemic neonate and >20 g/dl in the polycythaemic neonate) [5]; however, some investigators prefer an inter-twin haemoglobin difference greater than 8 g/dl, and an elevated inter-twin reticulocyte count ratio greater than 1.7 [22]. Around 5% of monochorionic twins present spontaneously with this complication in the early third trimester. The reduced incidence of arterio–arterial anastomoses to compensate for this chronic slow transfusion has also been observed in placental injection studies in placentas from TAPS [23]. Even under optimal conditions of visualisation, small anastomoses may be missed. This is currently the rationale for applying the ‘Solomon technique’, a topic now under investigation [24]. In selected TAPS cases, fetoscopic laser coagulation of the usually thin and marginal anastomoses, may represent a treatment option, as long as safe fetoscopic access is achievable [25,26]. At the gestational age typical for TAPS, however, fetoscopy may be challenging, owing to turbid amniotic fluid and a limited access to the vascular equator because of fetal size and movements. Advanced gestational age at presentation may lead many centres to opt for early delivery. The use of intrauterine blood transfusion to the anaemic twin does not help the polycythaemic co-twin. In a recent systematic review of TTTS cases treated with selective fetoscopic laser coagulation (SFLC), the rates of recurrence of TTTS range from 0% to 16% [27]. Recurrence was defined in most
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studies as the reappearance of polyhydramnios and oligohydramnios, and was related to missed anastomoses. In most cases, a secondary intervention with SFLC was carried out, followed in frequency by amnioreduction and delivery. The lack of comparable data and information on perinatal outcomes precluded a more detailed analysis to guide recommendations for clinical management. In our experience, if recurrence shows a rapid progression, and a new entry port allows a different angle of view on the placenta, a secondary SFLC may be indicated. Otherwise, an amnioreduction may lead to advanced gestational ages. Outcomes after fetoscopic laser coagulation of placental vascular anastomoses Overall survival rates of TTTS after SFLC have been reported in larger studies, ranging from 55– 82.5%, with at least one survivor ranging from 73–90.5% [12,14,26–30]. The reported range of miscarriage after laser in these larger studies, with more than 100 cases, is between 4 and 14% [15], and can be estimated to be around 7%. With increasing experience, the overall survival rates, as well as the rates for two survivors, show improvement. In our centre, in a study of 600 consecutive cases divided into three observation periods (200 cases each, between 1995 and 2007), the percentage of pregnancies with two neonatal survivors increased from 50% in period 1 to 59.5% in period 2, and 69.5% in period 3. The percentage of pregnancies with only one or no survivor decreased from 30.5% and 19.5% to 24% and 16.5%, and to 20% and 10.5%, respectively (P < 0,001; Chi-Square test). Thus, overall survival increased from 65% to 71.5% and 79.5% [31]. This shows that growing experience in intrauterine fetoscopic laser coagulation results in improved neonatal survival rates, owing to a significant increase in pregnancies with two survivors. This is a consequence of the surgical learning curve and to refinements of the surgical technique, which may only be achieved in centres with a critical workload. Staging of severe TTTS is important for counselling parents about survival rates, as they decrease significantly with increasing stage severity. In a previous study at our centre, survival of both fetuses occurred in 75.9% in stage I, 60.5% in stage II, 53.8% in stage III, and 50% in stage IV, and survival of at least one fetus was observed in 93.1% in stage I, 82.7% in stage II, 82.5% in stage III, and 70% in stage IV [32]. In another study, Chmait et al. [33] found that double survival was affected by increasing stage, with fewer donor twins surviving after stage III TTTS and laser therapy. Neurologic damage and long-term follow up In a systematic review by Roberts et al. [34], significantly higher survival rates were found when comparing amniodrainages with selective SFLC in the treatment of TTTS. Although the number of survivors without neurologic abnormalities at 6 months of age was greater after SFLC than after amniodrainages, this difference was no longer significant when comparing survivors with neurological deficit at the same age. The reviews suggested cerebral plasticity as a possible mechanism explaining these results, along with an increased rate of perinatal mortality after amniodrainages. Long-term follow-up studies of survivors after SFLC are scarce, and their evaluation is complex, as no unified neuropaediatric and psychological criteria have been defined for the purpose of evaluating neurodevelopmental impairment in this population. In a group of survivors treated in our centre between 1995 and 1999, follow-up data at the age of 6 years were recently reported [35]. Median gestational age at delivery was 34 þ 4 weeks and, in 8.9% of survivors, severe neurological deficiencies were present. Another 11.6% showed minor neurological abnormalities, and most survivors (79.5%) had normal neurologic examination and tests. These figures did not change significantly compared with former evaluations at the age of 2 years [36,37]. No significant differences were observed in recipient or donor status, or in double compared with single survivor. Nevertheless, the rate of severe neurological deficiencies was significantly increased in the very preterm and extremely preterm infants (<32 weeks). Douglas et al. [38] reported a rate of 10.8% of survivors with documented severe cerebral lesions after SFLC, in whom prematurity less than 28 weeks and less than 32 weeks increased the risk six-fold and four-fold, respectively [38]. In a recent systematic review and meta-analysis [39], cerebral injury and long-term neurodevelopmental impairment after amniodrainages compared with SFLC was addressed. A significantly increased risk of severe cerebral injury in survivors of TTTS treated with amniodrainages was confirmed (OR 7.69, 95% CI 2.78 to 20.0; P ¼ 0.00), with a persistently high risk for survivors of the
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neonatal period. Although not significant, survivors after amniodrainages had an increased risk of periventricular leukomalacia and intraventricular haemorrhage. This incidence decreased with increasing age and, at 6 years, the rate of cerebral palsy was 15% in the survivors after amniodrainages compared with 13% after SFLC. A possible reason for this may be the increased perinatal mortality after amniodrainages, although the risk for severe neurodevelopmental impairment after amniodrainages is high and is closely related to prematurity. A longer exposure to TTTS during intrauterine life may also play an important role. Compared with dichorionic twins at the age of 2 years, neurodevelopmental outcomes of survivors of TTTS after SFLC are similar, compared with higher impairment rates of survivors after amniodrainages [40]. In the follow-up study of the Eurofoetus randomised-controlled trial [9] on long-term neurodevelopment of survivors, the treatment of TTTS (either SFLC or amniodrainages) and the disease stage predicted an adverse neurological outcome [41], thus confirming a higher probability of survival without major neurological impairment in cases treated by SFLC. Further long-term follow-up studies are still needed, and standardised strategies for long-term multidisciplinary follow up are mandatory for counselling parents of affected twins. Cardiovascular outcome In severe TTTS, typical sonographic signs of cardiac compromise are apparent; however, as abnormal flow velocity waveforms in the ductus venosus, myocardial hypertrophy, tricuspid regurgitation, or retrograde perfusion occurs in the truncus pulmonalis in the recipient twins, which improve significantly after successful SFLC during the course of the pregnancy, and a normal cardiac function has been observed after birth [42]. Nevertheless, former recipient twins show an increased prevalence of pulmonary stenosis compared with the general population (7.8 v 0.03%). Most donor twins show a normal cardiac function at diagnosis and, in postnatal follow up, this finding remains unchanged. In a study comparing arterial wall stiffness using the measurement of brachial pulse wave velocities in survivors of TTTS treated either by SFLC or amniodrainages, former donor twins treated with amniodrainages showed an increased stiffness, whereas after SFLC the figures of the donor twins were comparable with dichorionic twins [43]. Such persistent changes are understood as early vascular programming, and seem to be related to cardiovascular disease later in life. Regarding cardiac function, fetoscopic laser coagulation as a causal therapy of TTTS, allows a recovery of haemodynamic parameters to normal values. Whether cardiovascular programming takes place despite this recovery is not yet known, and further long-term follow-up studies until adulthood are warranted. Twin–twin transfusion syndrome in triplets and higher order multiple pregnancies The incidence of dichorionic and monochorionic triplet pregnancies, as well as higher order multiple pregnancies with monochorionic twin pairs or triplets, has increased with the use of assisted reproductive techniques [44,45]. Furthermore, spontaneously conceived high order monochorionic multiples may develop TTTS, as shown by a case of monochorionic quadruplets with double TTTS treated with SFLC in our centre. In a study of 18 triplet pregnancies (15 dichorionic and three monochorionic triplets) treated with SFLC for severe TTTS at a median gestational age of 19.7 weeks in our centre [46], the overall survival rate was 65%. At least one fetus survived in 83% of the cases, and all three fetuses survived in 39%. The median gestational age at delivery was 31.9 weeks. Chorionicity has an important effect on survival rates of high order multiple pregnancies with TTTS and treated with SFLC. In a recent retrospective analysis of a case study, in combination with a meta-analysis of the literature [47], a significantly lower overall survival rate (51% v 76%) and a lower rate of at least one survivor (70% v 91%) in monochorionic compared with dichorionic triplets were observed. Pregnancies with monochorionic triplets are also delivered earlier (28 v 31 weeks). Conclusion Twin–twin transfusion is a severe complication of monochorionic twin pregnancies, with high morbidity and mortality. Placental vascular anastomoses are the anatomic substrate for the development of TTTS, and fetoscopic laser coagulation is the treatment of choice with improved survival rates
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and neurologic outcomes. This has been proven by a randomised-controlled trial. Although early prediction of TTTS is limited, a subgroup of monochorionic twins at high risk for developing TTTS or sIUGR in the further course of the pregnancy can be identified at first-trimester screening and at 16 weeks. A clear definition of severe TTTS has to consider gestational age. The Quintero staging system describes the severity but not necessarily the progress of cases within severe TTTS. Clear criteria for laser therapy have been defined, and the selective coagulation of the placental anastomoses can be completed with a coagulation line placed in between the closed vessels to reduce the rate of missed small anastomoses that may cause recurrence or reversal of TTTS and TAPS during the further course of the pregnancy. Despite the causative surgical treatment of TTTS, with significantly improved survival rates and neurologic outcomes, a risk of about 8% still exists for severe neurologic sequelae of survivors. The degree of cerebral injury and the exact point of occurrence earlier or later during pregnancy, must be established with the full clinical picture of TTTS; if the baby is premature, this must be established in the neonatal period, and should be the aim of further long-term studies.
Practice points Severe TTTS, defined as polyhydramnios (deepest vertical pool >8 cm before 20 weeks and >10 cm thereafter) co-existing with a stuck twin (deepest vertical pool <2 cm) should be treated by fetoscopic laser coagulation of placental anastomoses from 15–28 weeks in specialised fetal medicine centres. Within severe TTTS, staging describes the degree of fetal compromise and is related to survival rates. A preoperative spatial mapping of important landmarks helps in finding the optimal site for percutaneous fetoscopic entry and contributes to orientation along the vascular equator. Selective coagulation of placental anastomoses, with a continuous coagulation line between the anastomoses (Solomon technique) seems to reduce the rate of missed anastomoses, thus reducing the rate of recurrence or reversal of TTTS and the rate of TAPS after the procedure.
Research agenda
Indication of fetoscopic laser coagulation for stage I TTTS. Reduction of PPROM after fetoscopic procedures. Role of laser coagulation in sIUGR and TAPS. Triggers for the development of TTTS. Standardised long-term neurodevelopmental follow-up studies.
Conflict of interests None declared.
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[24] Slaghekke F. Fetoscopic laser coagulation of the entire vascular equator for the treatment of twin-to-twin transfusion syndrome: the ‘Solomon’ study; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC¼1245 [last accessed 02.12.13]. [25] Diehl W, Glosemeyer P, Tavares De Sousa M, et al. Twin anemia-polycythemia sequence in a case of monoamniotic twins. Ultrasound Obstet Gynecol 2013;42:108–11. [26] Yamamoto M, El Murr L, Robyr R, et al. Incidence and impact of perioperative complications in 175 fetoscopy-guided laser coagulation of chorionic plate anastomoses in Feto-Fetal Transfusion Syndrome before 26 weeks of gestation. Am J Obstet Gynecol 2005;193:1110–6. [27] Walsh CA, McAuliffe FM. Recurrent twin-twin transfusion syndrome after selective fetoscopic laser photocoagulation: a systematic review of the literature. Ultrasound Obstet Gynecol 2012;40:506–12. [28] Robyr R, Lewi L, Salomon LJ, et al. Prevalence and management of late fetal complications following successful selective laser coagulation of chorionic plate anastomoses in twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2006;194: 796–803. [29] Middeldorp FM, Sueters M, Lopriore E, et al. Fetoscopic laser surgery in 100 pregnancies with severe twin-to-twin transfusion syndrome in the Netherlands. Fetal Diagn Ther 2007;22:190–4. [30] Morris RK, Selman TJ, Harbidge A, et al. Fetoscopic laser coagulation for severe twin-to-twin transfusion syndrome: factors influencing perinatal outcome, learning curve of the procedure and lessons for new centres. BJOG 2010;117: 1350–7. [31] Diehl W, Diemert A, Glosemeyer P, et al. Development of survival rates after intrauterine therapy for severe mid-trimester twin-twin transfusion syndrome: experience with 600 cases. Ultrasound Obstet Gynecol 2012;36(Suppl. 1):67. [32] Huber A, Diehl W, Bregenzer T, et al. Stage-related outcome in twin-twin transfusion syndrome treated by fetoscopic laser coagulation. Obstet Gynecol 2006;108:333–7. [33] Chmait RH, Kontopoulos EV, Korst LM, et al. Stage-based outcomes of 682 consecutive cases of twin–twin transfusion syndrome treated with laser surgery: the USFetus experience. Am J Obstet Gynecol 2011;204:393.e1–6. *[34] Roberts D, Gates S, Kilby M, et al. Interventions for twin-twin transfusion syndrome: a Cochrane review. Ultrasound Obstet Gynecol 2008;31:701–11. *[35] Graeve P, Banek C, Stegmann-Woessner G, et al. Neurodevelopmental outcome at 6 years of age after intrauterine laser therapy for twin-twin transfusion syndrome. Acta Paediatr 2012;101:1200–5. [36] Banek CS, Hecher K, Hackeloer BJ, et al. Long-term neurodevelopmental outcome after intrauterine laser treatment for severe twin-twin transfusion syndrome. Am J Obstet Gynecol 2003;188:876–80.
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[37] Graef C, Ellenrieder B, Hecher K, et al. Long term neurodevelopmental outcome of 167 children after intrauterine laser treatment for severe twin-twin transfusion syndrome. Am J Obstet Gynecol 2006;194:303–8. [38] Douglas L, Vanderbilt DL, Schrager SM, et al. Prevalence and risk factors of cerebral lesions in neonates after laser surgery for twin-twin transfusion syndrome. Am J Obstet Gynecol 2012;207:320.e1–6. *[39] van Klink JM, Koopman HM, van Zwet EW, et al. Cerebral injury and neurodevelopmental impairment after amnioreduction versus laser surgery in twin-twin transfusion syndrome: a systematic review and meta-analysis. Fetal Diagn Ther 2013;33:81–9. [40] Lenclen R, Ciarlo G, Paupe A, et al. Neurodevelopmental outcome at 2 years in children born preterm treated by amnioreduction or fetoscopic laser surgery for twin-to-twin transfusion syndrome: comparison with dichorionic twins. Am J Obstet Gynecol 2009;201:291.e1–5. *[41] Salomon LJ, Örtqvist L, Aegerter P, et al. Long-term developmental follow-up of infants who participated in a randomized clinical trial of amniocentesis vs laser photocoagulation for the treatment of twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2010;203:444.e1–7. [42] Herberg U, Gross W, Bartmann P, et al. Long term cardiac follow up of severe twin to twin transfusion syndrome after intrauterine laser coagulation. Heart 2006;92:95–100. [43] Gardiner HM, Taylor MJ, Karatza A, et al. Twin-twin transfusion syndrome: the influence of intrauterine laser photocoagulation on arterial distensibility in childhood. Circulation 2003;107:1906–11. [44] Ombelet W, De Sutter P, Van der Elst J, et al. Multiple gestation and infertility treatment: registration, reflection and reaction – the Belgian project. Hum Reprod Update 2005;11:3–14. [45] Imaizumi Y. A comparative study of zygotic twinning and triplet rates in eight countries, 1972–1999. J Biosoc Sci 2003;35: 287–302. [46] Diemert A, Diehl W, Huber A, et al. Laser therapy of twin-to-twin transfusion syndrome in triplet pregnancies. Ultrasound Obstet Gynecol 2010;35:71–4. [47] Peeters SHP, Middeldorp JM, Lopriore E, et al. Monochorionic triplets complicated by fetofetal transfusion syndrome: a case series and review of the literature. Fetal Diagn Ther 2012;32:239–45.
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Best Practice & Research Clinical Obstetrics and Gynaecology journal homepage: www.elsevier.com/locate/bpobgyn
4
Twin–twin transfusion syndrome: Treatment and outcome Werner Diehl, MD, Consultant in Fetal and Maternal Medicine *, Anke Diemert, MD, Consultant in Fetal and Maternal Medicine, Kurt Hecher, MD, PhD, Consultant (Professor) of Obstetrics and Fetal Medicine University Medical Centre Hamburg-Eppendorf, Department of Obstetrics and Foetal Medicine, Martinistraße 52, 20246 Hamburg, Germany
Keywords: twin–twin transfusion syndrome monochorionic twins placental vascular anastomoses fetoscopic laser coagulation
Twin–twin transfusion syndrome complicates up to 15% of monochorionic pregnancies in the mid-trimester, and results in high perinatal mortality and morbidity if left untreated. Although some humoral factors play a role in the pathogenesis of the disease, an unequal placental sharing and the presence of placental vascular anastomoses at the chorionic plate, allowing blood volume shifts between the twins, are the anatomic prerequisite for this complication unique to monochorionic twins. Within monochorionic pregnancies, it is possible to identify a subgroup of twin pairs at high risk of developing twin–twin transfusion syndrome or selective intrauterine growth restriction during the course of pregnancy as early as in the first or early second trimester. If progressive amniotic fluid discrepancy advances to moderate twin–twin transfusion syndrome, and finally reaches the stages of severe twin–twin transfusion syndrome, accurate classification of the clinical picture and diagnosis of the individual fetal haemodynamic status are crucial for counselling parents on treatment options and possible outcomes. Clear criteria have been established for fetoscopic laser coagulation of placental vascular anastomoses, which is the treatment of choice for severe twin–twin transfusion syndrome, interrupting blood flow between the twins, and relieving uterine over-distension related to severe polyhydramnios. Ó 2013 Published by Elsevier Ltd.
* Corresponding author. Tel.: þ49 152 2281 5259; Fax: þ49 40 741046767. E-mail address: [email protected] (W. Diehl). 1521-6934/$ – see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.bpobgyn.2013.12.001
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Introduction Monochorionic twinning is related to cleavage of a monozygotic blastomere after the third postconceptional day. An earlier cleavage will result in monozygotic dichorionic twins. After day 9, the monochorionic twin pair will also share a common amniotic cavity (monoamniotic twins) and, after day 12, the cleavage may not be complete, resulting in conjoined twins [1]. Around two-thirds of monozygotic twins are monochorionic, and 12% of these pregnancies will be complicated by twin–twin transfusion syndrome. Another 15% of the monochorionic twins will develop selective intrauterine growth restriction (sIUGR), and 5% will be complicated by TAPS, typically in the early third trimester. On the one hand, these complications are related to the presence of placental vascular anastomoses of monochorionic placentas, which allow shifts of blood from one twin to the other. On the other hand, the placental mass at disposition for each twin will cause growth restriction in one of them (sIUGR), if there is unequal sharing. In some cases, twin–twin transfusion syndrome (TTTS) is combined with severe growth restriction of the donor twin. The presence of vascular anastomoses at the chorionic plate is almost universal to monochorionic placentas, most of them being arteriovenous in nature [2]. As such, arteriovenous anastomoses are uni-directional (allowing blood flow from one twin to the other), with a feeding artery of one twin supplying a placental cotyledon by perforating the chorionic plate to the depth and a draining vein arising from the depth through the chorionic plate to carry oxygenated blood to the co-twin. During fetoscopy in cases of severe TTTS, and in colour dye injection studies of monochorionic placentas, arteriovenous anastomoses in both directions have almost always been observed [3]. Arterio–arterial and veno–venous anastomoses, which run on the surface of the chorionic plate, one vessel directly continuing into the other, allow blood flow in both directions (bi-directional), with a low resistance, and are less common. In arterio–arterial anastomoses, the blood pressure of each twin causes the pulse waves to collide against each other with different beat frequencies, the net flow through these anastomoses thus depending on the haemodynamic state of the respective twin. Because of their low vascular resistance, huge inter-twin shifts of blood volume are possible through arterio–arterial anastomoses, on one hand allowing compensation of volume shifts occurring through arteriovenous anastomoses predominantly in one direction and, on the other hand, permitting an acute and massive blood shift towards an eventually hypotensive co-twin, with the consequence of striking hypovolaemia and the risk for hypoxic-ischaemic encephalopathy in the normotensive twin [4]. Similar volume shifts are believed to occur through veno–venous anastomoses, although in a lower intensity. Such inter-twin vascular accidents, along with chronic transfusion through arteriovenous anastomoses, are believed to be responsible for the increased mortality and morbidity in monochorionic twin pairs [5]. Because of this shared circulation, the development of monochorionic twins is dependent on each other and, in the event of intrauterine death (IUD) of one twin, the surviving twin has up to a 30–35% risk of consecutive IUD or neurologic sequelae [6]. In the event of single fetal demise, the co-twin has a risk of IUD of 15% (3% in dichorionic twins) and a risk of neurologic injury of 26% (2% in dichorionic twins) and, in general, monochorionic twins are 4.81 times more likely to have neurodevelopmental morbidity [7]. Treatment of twin–twin transfusion syndrome Mild-to-moderate cases of TTTS, characterised by discrepant amniotic fluid amounts and moderate differences between the twins in bladder fillings and fetal growth, may progress to any stage of severe TTTS; therefore, fortnightly ultrasound monitoring of these twin pairs and education of the mother of clinical symptoms of TTTS (e.g. rapid uterine growth, increasing discomfort owing to uterine overdistension, and early contractions) are mandatory. Nevertheless, most of these cases remain stable throughout the entire pregnancy, and laser therapy is not needed [5,8]. Fetoscopic laser coagulation of placental vascular anastomoses is the treatment of choice for severe TTTS from 16–26 weeks gestation [9,10], and is indicated for cases fulfilling the diagnostic sonographic criteria exposed earlier in this issue (See Sueters M., Oepkes D., Diagnosis of twin–twin transfusion syndrome, selective fetal growth restriction, twin anaemia polycythaemia sequence and twin reversed arterial perfusion sequence). Pregnancies fulfilling the Doppler criteria for stage III or echocardiographic criteria for stage IV (e.g. hydrops and advanced heart failure) that present in the late second trimester, as
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well as cases presenting with clear disease progression, may also undergo laser therapy after 26 weeks [11]. Thus, with increasing experience, the treatment window for TTTS by fetoscopic laser coagulation has become wider from 15 to 29 weeks, although early procedures carry a higher risk for pregnancy loss. In preparation for fetoscopic laser coagulation, apart from collecting data relevant for diagnosis and staging, a careful ultrasound scan provides the surgeon with a mental spatial map of the possible topography to be found at fetoscopy, by localising the cord insertion sites of the twins, the extent of the placenta, the localisation of the stuck twin, and the probable localisation of the vascular equator. A percutaneous access to the recipient’s amniotic cavity in local anaesthesia under ultrasound guidance, using 2-mm fetoscopes inserted through a previously inserted sheath, has become the standard technique [12]. The insertion site on the maternal abdomen should be chosen opposite to the expected placental vascular equator, so that optimal access to the target vessels can be achieved. In cases with anterior placenta, the entry site has to be chosen through the lateral uterine wall, avoiding the placental edge, maternal uterine vessels, and neighbouring organs, and ideally the collapsed sac of the donor twin. More limited access to the vascular equator, and a tangential angle of view with an unfavourable angle of impact of laser energy on the target vessels, makes these cases more technically challenging. The introduction of 30 fetoscopes for anterior placentas, however, with integrated steering levers for bending the tip of the laser fibre towards the placenta, has shown results, which are comparable to posterior placentas [13]. The insertion line of the inter-twin membrane on the chorionic plate and the cord insertion site of the recipient twin are important intra-amniotic landmarks that provide orientation to the vascular equator. Vessels crossing the line underneath the membrane have to be followed in both directions to check for anastomoses (Figs. 1 and 2). Although the vascular equator will be directly visible from the recipients amniotic cavity (Fig. 3), it may sometimes extend to an area underneath the insertion line of the inter-twin membrane, and some anastomoses may be located in the donor’s amniotic cavity (Fig. 4). In these cases, laser coagulation has to be carried out through the membrane (Fig. 5a and b). Because arteries almost always cross over veins and carryoxygen depleted blood, thus looking darker than light red veins, the direction of blood flow in the
Fig. 1. The insertion line of the inter-twin membrane (yellow arrows) helps for the identification of the vascular equator and anastomoses. The tip of the laser fibre is visible at 12 o’clock. Some veins to the donor are seen crossing underneath the insertion line and forming an arteriovenous anastomosis from recipient to donor, seen at red spot of laser pilot light.
Fig. 2. The insertion line is running vertically in this fetoscopic image. A thin arteriovenous anastomosis is seen under the red pilot light of the laser fibre, which is seen at 5 o’clock.
Fig. 3. Typical arteriovenous anastomoses (AV, yellow circles) along the vascular equator of the chorionic plate. Note the darker colour of arteries and the lighter veins.
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Fig. 4. A thin arteriovenous anastomosis is seen under the inter-twin membrane (yellow circle) in the donor’s amniotic cavity. Sometimes the vascular equator crosses underneath the insertion line of the membrane and laser coagulation is made through the membrane. Unintentional septostomy is possible, although small defects of the membrane will not cause fetal complications.
vessels can be established during fetoscopy. In a few cases with turbid amniotic fluid, an amnioinfusion with saline solution may improve visual conditions. With these factors in mind, the operator can clearly identify the anastomoses. A 400 mm laser fibre is advanced through to operative channel of the fetoscope, and laser energy is fired at a distance of about 1 cm from the vessels. A Neodymium– Yttrium–Aluminium garnet or diode lasers are commonly used, owing to their optimal energy
Fig. 5. (a) A complex arteriovenous anastomosis (yellow circles) from donor to recipient is seen just under the inter-twin membrane insertion line. Darker arteries come from the donor to meet the veins of the recipient twin; (b) laser coagulation was carried out (white area) through the membrane.
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absorbance in the spectrum of haemoglobin. Selective coagulation of the anastomoses at the vascular equator is the most common method, and some centres prefer a sequential coagulation of the arteriovenous anastomoses (from donor to recipient) first and thereafter the vascular anastomoses (from recipient to donor) [14,15]. Recently, additional coagulation of the area between the selectively coagulated anastomoses, known as ‘Solomon technique’ (Fig. 6a and b), has gained interest, and results of survival rates, recurrence of TTTS, and the incidence of TAPS after laser (a complication seen in about 13% of procedures) are promising [16,17]. With this technique, thin anastomoses, which may be difficult to detect in cases of turbid amniotic fluid or at the margin of an anterior placenta, may not be missed (Fig. 7). The Solomon technique and a sequential coagulation, however, may lead to longer operating times, but this issue is currently under investigation. The procedure is always finished with an amnioreduction of the polyhydramnios to a normal amount of amniotic fluid to relieve uterine over-distension. The average operating time is 30 mins, the risk for miscarriage or early delivery caused by preterm premature rupture of membranes (PPROM) is 7%, and delivery takes place at a median gestational age of 34 weeks [12]. A cervical cerclage for a short cervix (<15 mm) directly after the laser procedure can be offered, and may be the only reason for regional anaesthesia [18]. Data are controversial on the benefit of a cerclage after laser therapy; in a recent retrospective study, only a subgroup of patients with a cervix length between 16 and 20 mm showed a significant prolongation of pregnancy [19]. A short cervix (<15 mm) was associated with preterm delivery, regardless of having received a preventive cerclage, thus suggesting an already substantial risk for early delivery. Additionally, pregnancy duration was not affected by the placement of a cerclage in women with a cervix length greater than 20 mm, compared with expectant management, thus suggesting that women whose cervix length is above this cut-off may not be at an increased risk for preterm birth. Therefore, further randomised-controlled studies are warranted to address this issue. In a recent retrospective, multicentre cohort study, Papanna et al. [20] identified risk factors for preterm delivery after fetoscopic laser coagulation. A lower maternal age, history of previous praematurity, shortened cervical length, a larger cannula diameter, amnioinfusion (performed in 41% of cases), and iatrogenic preterm premature rupture of membranes (28%), were significantly associated with a lower gestational age at delivery. As stage I cases do not necessarily progress to more advanced stages, and some of them even regress to almost balanced amniotic fluid amounts, the indication for fetoscopic laser coagulation in this group of women is controversial. Therefore, currently, a randomised-controlled trial comparing expectant management to primary laser is under way (http://clinicaltrials.gov/ct2/show/NCT01220011). Women assigned to the expectant management arm of the study are followed weekly and, if stage progression
Fig. 6. (a) A continuous coagulation line (yellow arrow) is drawn along the showed distance between already coagulated anastomoses (Solomon technique); (b) the coagulation line is almost finished by continuous or spot by spot firing on the chorionic plate.
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Fig. 7. Coagulation line (yellow box) between two anastomoses. A few very thin vessels were coagulated closed using this technique.
or worsening of maternal obstetric parameters owing to massive polyhydramnios occurs, laser therapy is then immediately offered. Apart from exclusion criteria (e.g. short cervix, contractions, maternal discomfort, previous amniocentesis, fetal malformations, and PPROM), only 15% of TTTS cases present with stage I, and many women are referred to laser centres with geographical limitation for weekly follow up. Thus, recruitment seems time consuming. Twin anaemia-polycythaemia sequence has been observed as a consequence of a few missed thin anastomoses after laser in up to 13% of the procedures. The presence of a few small arteriovenous anastomoses, allowing a slow transfusion, gradually leads to highly discordant haemoglobin levels between the twins, and has been related to TAPS [21]. Antenatal diagnosis is made measuring the peak systolic velocities in the middle cerebral artery, when velocities exceed 1.5 multiples of media in the anaemic twin, together with decreased velocities (<1.0 multiples of media) in the polycythaemic cotwin. Postnatally, TAPS is diagnosed by neonatologists in twins, with marked haemoglobin concentration differences (<11 g/dl in the anaemic neonate and >20 g/dl in the polycythaemic neonate) [5]; however, some investigators prefer an inter-twin haemoglobin difference greater than 8 g/dl, and an elevated inter-twin reticulocyte count ratio greater than 1.7 [22]. Around 5% of monochorionic twins present spontaneously with this complication in the early third trimester. The reduced incidence of arterio–arterial anastomoses to compensate for this chronic slow transfusion has also been observed in placental injection studies in placentas from TAPS [23]. Even under optimal conditions of visualisation, small anastomoses may be missed. This is currently the rationale for applying the ‘Solomon technique’, a topic now under investigation [24]. In selected TAPS cases, fetoscopic laser coagulation of the usually thin and marginal anastomoses, may represent a treatment option, as long as safe fetoscopic access is achievable [25,26]. At the gestational age typical for TAPS, however, fetoscopy may be challenging, owing to turbid amniotic fluid and a limited access to the vascular equator because of fetal size and movements. Advanced gestational age at presentation may lead many centres to opt for early delivery. The use of intrauterine blood transfusion to the anaemic twin does not help the polycythaemic co-twin. In a recent systematic review of TTTS cases treated with selective fetoscopic laser coagulation (SFLC), the rates of recurrence of TTTS range from 0% to 16% [27]. Recurrence was defined in most
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studies as the reappearance of polyhydramnios and oligohydramnios, and was related to missed anastomoses. In most cases, a secondary intervention with SFLC was carried out, followed in frequency by amnioreduction and delivery. The lack of comparable data and information on perinatal outcomes precluded a more detailed analysis to guide recommendations for clinical management. In our experience, if recurrence shows a rapid progression, and a new entry port allows a different angle of view on the placenta, a secondary SFLC may be indicated. Otherwise, an amnioreduction may lead to advanced gestational ages. Outcomes after fetoscopic laser coagulation of placental vascular anastomoses Overall survival rates of TTTS after SFLC have been reported in larger studies, ranging from 55– 82.5%, with at least one survivor ranging from 73–90.5% [12,14,26–30]. The reported range of miscarriage after laser in these larger studies, with more than 100 cases, is between 4 and 14% [15], and can be estimated to be around 7%. With increasing experience, the overall survival rates, as well as the rates for two survivors, show improvement. In our centre, in a study of 600 consecutive cases divided into three observation periods (200 cases each, between 1995 and 2007), the percentage of pregnancies with two neonatal survivors increased from 50% in period 1 to 59.5% in period 2, and 69.5% in period 3. The percentage of pregnancies with only one or no survivor decreased from 30.5% and 19.5% to 24% and 16.5%, and to 20% and 10.5%, respectively (P < 0,001; Chi-Square test). Thus, overall survival increased from 65% to 71.5% and 79.5% [31]. This shows that growing experience in intrauterine fetoscopic laser coagulation results in improved neonatal survival rates, owing to a significant increase in pregnancies with two survivors. This is a consequence of the surgical learning curve and to refinements of the surgical technique, which may only be achieved in centres with a critical workload. Staging of severe TTTS is important for counselling parents about survival rates, as they decrease significantly with increasing stage severity. In a previous study at our centre, survival of both fetuses occurred in 75.9% in stage I, 60.5% in stage II, 53.8% in stage III, and 50% in stage IV, and survival of at least one fetus was observed in 93.1% in stage I, 82.7% in stage II, 82.5% in stage III, and 70% in stage IV [32]. In another study, Chmait et al. [33] found that double survival was affected by increasing stage, with fewer donor twins surviving after stage III TTTS and laser therapy. Neurologic damage and long-term follow up In a systematic review by Roberts et al. [34], significantly higher survival rates were found when comparing amniodrainages with selective SFLC in the treatment of TTTS. Although the number of survivors without neurologic abnormalities at 6 months of age was greater after SFLC than after amniodrainages, this difference was no longer significant when comparing survivors with neurological deficit at the same age. The reviews suggested cerebral plasticity as a possible mechanism explaining these results, along with an increased rate of perinatal mortality after amniodrainages. Long-term follow-up studies of survivors after SFLC are scarce, and their evaluation is complex, as no unified neuropaediatric and psychological criteria have been defined for the purpose of evaluating neurodevelopmental impairment in this population. In a group of survivors treated in our centre between 1995 and 1999, follow-up data at the age of 6 years were recently reported [35]. Median gestational age at delivery was 34 þ 4 weeks and, in 8.9% of survivors, severe neurological deficiencies were present. Another 11.6% showed minor neurological abnormalities, and most survivors (79.5%) had normal neurologic examination and tests. These figures did not change significantly compared with former evaluations at the age of 2 years [36,37]. No significant differences were observed in recipient or donor status, or in double compared with single survivor. Nevertheless, the rate of severe neurological deficiencies was significantly increased in the very preterm and extremely preterm infants (<32 weeks). Douglas et al. [38] reported a rate of 10.8% of survivors with documented severe cerebral lesions after SFLC, in whom prematurity less than 28 weeks and less than 32 weeks increased the risk six-fold and four-fold, respectively [38]. In a recent systematic review and meta-analysis [39], cerebral injury and long-term neurodevelopmental impairment after amniodrainages compared with SFLC was addressed. A significantly increased risk of severe cerebral injury in survivors of TTTS treated with amniodrainages was confirmed (OR 7.69, 95% CI 2.78 to 20.0; P ¼ 0.00), with a persistently high risk for survivors of the
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neonatal period. Although not significant, survivors after amniodrainages had an increased risk of periventricular leukomalacia and intraventricular haemorrhage. This incidence decreased with increasing age and, at 6 years, the rate of cerebral palsy was 15% in the survivors after amniodrainages compared with 13% after SFLC. A possible reason for this may be the increased perinatal mortality after amniodrainages, although the risk for severe neurodevelopmental impairment after amniodrainages is high and is closely related to prematurity. A longer exposure to TTTS during intrauterine life may also play an important role. Compared with dichorionic twins at the age of 2 years, neurodevelopmental outcomes of survivors of TTTS after SFLC are similar, compared with higher impairment rates of survivors after amniodrainages [40]. In the follow-up study of the Eurofoetus randomised-controlled trial [9] on long-term neurodevelopment of survivors, the treatment of TTTS (either SFLC or amniodrainages) and the disease stage predicted an adverse neurological outcome [41], thus confirming a higher probability of survival without major neurological impairment in cases treated by SFLC. Further long-term follow-up studies are still needed, and standardised strategies for long-term multidisciplinary follow up are mandatory for counselling parents of affected twins. Cardiovascular outcome In severe TTTS, typical sonographic signs of cardiac compromise are apparent; however, as abnormal flow velocity waveforms in the ductus venosus, myocardial hypertrophy, tricuspid regurgitation, or retrograde perfusion occurs in the truncus pulmonalis in the recipient twins, which improve significantly after successful SFLC during the course of the pregnancy, and a normal cardiac function has been observed after birth [42]. Nevertheless, former recipient twins show an increased prevalence of pulmonary stenosis compared with the general population (7.8 v 0.03%). Most donor twins show a normal cardiac function at diagnosis and, in postnatal follow up, this finding remains unchanged. In a study comparing arterial wall stiffness using the measurement of brachial pulse wave velocities in survivors of TTTS treated either by SFLC or amniodrainages, former donor twins treated with amniodrainages showed an increased stiffness, whereas after SFLC the figures of the donor twins were comparable with dichorionic twins [43]. Such persistent changes are understood as early vascular programming, and seem to be related to cardiovascular disease later in life. Regarding cardiac function, fetoscopic laser coagulation as a causal therapy of TTTS, allows a recovery of haemodynamic parameters to normal values. Whether cardiovascular programming takes place despite this recovery is not yet known, and further long-term follow-up studies until adulthood are warranted. Twin–twin transfusion syndrome in triplets and higher order multiple pregnancies The incidence of dichorionic and monochorionic triplet pregnancies, as well as higher order multiple pregnancies with monochorionic twin pairs or triplets, has increased with the use of assisted reproductive techniques [44,45]. Furthermore, spontaneously conceived high order monochorionic multiples may develop TTTS, as shown by a case of monochorionic quadruplets with double TTTS treated with SFLC in our centre. In a study of 18 triplet pregnancies (15 dichorionic and three monochorionic triplets) treated with SFLC for severe TTTS at a median gestational age of 19.7 weeks in our centre [46], the overall survival rate was 65%. At least one fetus survived in 83% of the cases, and all three fetuses survived in 39%. The median gestational age at delivery was 31.9 weeks. Chorionicity has an important effect on survival rates of high order multiple pregnancies with TTTS and treated with SFLC. In a recent retrospective analysis of a case study, in combination with a meta-analysis of the literature [47], a significantly lower overall survival rate (51% v 76%) and a lower rate of at least one survivor (70% v 91%) in monochorionic compared with dichorionic triplets were observed. Pregnancies with monochorionic triplets are also delivered earlier (28 v 31 weeks). Conclusion Twin–twin transfusion is a severe complication of monochorionic twin pregnancies, with high morbidity and mortality. Placental vascular anastomoses are the anatomic substrate for the development of TTTS, and fetoscopic laser coagulation is the treatment of choice with improved survival rates
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and neurologic outcomes. This has been proven by a randomised-controlled trial. Although early prediction of TTTS is limited, a subgroup of monochorionic twins at high risk for developing TTTS or sIUGR in the further course of the pregnancy can be identified at first-trimester screening and at 16 weeks. A clear definition of severe TTTS has to consider gestational age. The Quintero staging system describes the severity but not necessarily the progress of cases within severe TTTS. Clear criteria for laser therapy have been defined, and the selective coagulation of the placental anastomoses can be completed with a coagulation line placed in between the closed vessels to reduce the rate of missed small anastomoses that may cause recurrence or reversal of TTTS and TAPS during the further course of the pregnancy. Despite the causative surgical treatment of TTTS, with significantly improved survival rates and neurologic outcomes, a risk of about 8% still exists for severe neurologic sequelae of survivors. The degree of cerebral injury and the exact point of occurrence earlier or later during pregnancy, must be established with the full clinical picture of TTTS; if the baby is premature, this must be established in the neonatal period, and should be the aim of further long-term studies.
Practice points Severe TTTS, defined as polyhydramnios (deepest vertical pool >8 cm before 20 weeks and >10 cm thereafter) co-existing with a stuck twin (deepest vertical pool <2 cm) should be treated by fetoscopic laser coagulation of placental anastomoses from 15–28 weeks in specialised fetal medicine centres. Within severe TTTS, staging describes the degree of fetal compromise and is related to survival rates. A preoperative spatial mapping of important landmarks helps in finding the optimal site for percutaneous fetoscopic entry and contributes to orientation along the vascular equator. Selective coagulation of placental anastomoses, with a continuous coagulation line between the anastomoses (Solomon technique) seems to reduce the rate of missed anastomoses, thus reducing the rate of recurrence or reversal of TTTS and the rate of TAPS after the procedure.
Research agenda
Indication of fetoscopic laser coagulation for stage I TTTS. Reduction of PPROM after fetoscopic procedures. Role of laser coagulation in sIUGR and TAPS. Triggers for the development of TTTS. Standardised long-term neurodevelopmental follow-up studies.
Conflict of interests None declared.
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