Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 215–226
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Diagnosis of twin-to-twin transfusion syndrome, selective fetal growth restriction, twin anaemia-polycythaemia sequence, and twin reversed arterial perfusion sequence Marieke Sueters, MD, PhD, Fellow Maternal Fetal Medicine a, Dick Oepkes, MD, PhD, Consultant, Professor of Obstetrics and Fetal Therapy b, * a
Department of Obstetrics, Leiden University Medical Centre, Leiden, The Netherlands Department of Obstetrics, K-06-35, Leiden University Medical Centre, PO Box 9600, RC Leiden, The Netherlands b
Keywords: twin-to-twin transfusion syndrome selective fetal growth restriction twin anemia polycythemia sequence twin reversed arterial perfusion sequence ultrasound Doppler diagnosis
Monochorionic twin pregnancies are well known to be at risk for a variety of severe complications, a true challenge for the maternal– fetal medicine specialist. With current standards of care, monochorionicity should be established in the first trimester. Subsequently, frequent monitoring using the appropriate diagnostic tools, and in-depth knowledge about the pathophysiology of all possible clinical presentations of monochorionic twin abnormalities, should lead to timely recognition, and appropriate management. Virtually all unique diseases found in monochorionic twins are directly related to placental angio-architecture. This, however, cannot be established reliably before birth. The clinician needs to be aware of the definitions and symptoms of twin-to twin transfusion syndrome, selective fetal growth restriction, twin anaemia– polycythaemia sequence, and twin reversed arterial perfusion sequence, to be able to recognise each disease and take the required action. In this chapter, we address current standards on correct and timely diagnoses of severe complications of monochorionic twin pregnancies. Ó 2014 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: þ31 71 5262896; Fax: þ31 71 5266741. E-mail address: [email protected] (D. Oepkes). 1521-6934/$ – see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpobgyn.2013.12.002
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Introduction Monochorionic twin pregnancies are associated with a variety of serious complications, unique to this group. The underlying pathophysiology of most of these complications seems to be related, directly or indirectly, to the unique angio-architecture of the monochorionic placenta [1]. Imbalanced blood flow, with net transfer of blood and likely of numerous regulating factors, is the accepted cause of twintwin transfusion syndrome (TTTS) and twin anaemia–polycythemia sequence (TAPS). Although the accepted cause of selective fetal growth restriction (sFGR) is an unequally shared placenta, and the reversed blood flow in the cord and the body of the acardiac twin explains its features, the underlying pathophysiology may start with imbalanced blood flow through particular types of vascular anastomoses. With current imaging technology, we cannot reliably visualise these anastomoses. Ultrasound and Doppler examinations enable us to detect early signs and symptoms of the various pathologic conditions in monochorionic twins. As for some, treatment options exist, timely diagnosis and referral is of vital importance. In this chapter, we aim to discuss the clinically relevant diagnostic tools that can and should apply in the management of monochorionic twin pregnancies. Twin-to-twin transfusion syndrome Monochorionic twins share a single placenta with vascular anastomoses that connect the fetal circulations, allowing inter-twin blood transfusion. This is a physiological phenomenon as long as blood flow between the fetuses is balanced. Unbalanced net inter-twin blood transfusion, however, may lead to various forms of serious pathology. The best-known clinical syndrome is TTTS, which is a chronic form of feto–fetal transfusion and affects about 9% of monochorionic twins [2]. In the past, TTTS was diagnosed at the time of birth based on neonatal criteria that included a growth discordance of 15–20% associated with discordant cord or neonatal haemoglobin concentration of 5 g/dl [3]. A subsequent study by Wenstrom et al. [4] showed that any combination of weight and haemoglobin discordance could be seen with equal frequency. The investigators concluded that the historical paediatric parameters should be abandoned for the diagnosis of TTTS. Nowadays, TTTS is diagnosed prenatally by ultrasound examination. It typically presents in the second trimester of pregnancy, and the diagnosis is based on the presence of a twin oligo–polyhydramnios sequence (TOPS). The following ultrasound criteria are required to diagnose TTTS: (1) the twin gestation is diagnosed as monochorionic (ideally with a scan carried out in the first trimester showing a T-sign); and (2) a combination of oligohydramnios exists in one twin’s amniotic cavity, with polyhydramnios in the other twin’s amniotic cavity. Oligohydramnios is defined as a maximum vertical pocket (MVP) of 2 cm. This twin is commonly called the donor twin. Polyhydramnios was originally defined as a MVP of 8 cm [5]. Subsequent studies in Europe have proposed to increase the threshold to 10 cm or more for the MVP after 20 weeks’ gestation [6]. This twin is described as the recipient twin. A twin gestation that meets the above criteria is classified as TTTS. Quintero et al. [5], in 1999, described a classification of TTTS (Table 1), which has been widely adopted and used throughout the world.
Table 1 Staging of twin-to-twin transfusion syndrome. Stage
Oligo/ polyhydramniosa
Absent bladder filling in donor
Critically abnormal Doppler studiesb
Hydrops of either fetus
Intrauterine fetal demise of either fetus
I II III IV V
þ þ þ þ þ
– þ þ þ þ
– – þ þ þ
– – – þ þ
– – – – þ
a Oligohydramnios: maximum vertical pocket of 2 cm or less; polyhydramnios: maximum vertical pocket of 8 cm or over (or 10 cm at >20 weeks’ gestation). b Absent or reversed diastolic velocity in the umbilical artery or ductus venosus or pulsatile umbilical venous velocity.
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Quintero Stage I is defined as an oligo–polyhydramnios sequence with MVP of amniotic fluid of the donor and recipient twin of 2 or less and 8 cm or more (or 10 cm at >20 weeks’ gestation), respectively. Stage II is a more progressive stage, including no visualisation of bladder filling in the donor twin. Some investigators have argued that the presence of a small bladder that fails to fill during prolonged ultrasound examination should also qualify as stage II disease [7]. Stage III disease is diagnosed when the Doppler results are critically abnormal, including absent (Fig. 1) or reversed (Fig. 2) diastolic velocity in the umbilical artery or in the ductus venosus (Fig. 3), or pulsatile umbilical venous velocity (Fig. 4) in either the donor, recipient twin, or both. Therefore, many combinations of Doppler abnormalities are possible. Typically, umbilical artery flow abnormalities are seen in donor twins, whereas recipients more often show abnormal ductus venous or pulsatile umbilical venous Doppler studies, indicative of imminent cardiac failure. Subdividing stage III into stage III-D, III-R, or III-DR, to indicate which twin experiences Doppler abnormalities, is advocated by several centres. Stage IV disease is present when fetal hydrops (e.g. ascites, pericardial effusion, or both, pleural effusions, or scalp oedema) is diagnosed in either twin. Typically this is first seen in the recipient twin. Fetal demise of either fetus is named stage V disease. Several studies have shown that disease severity defined by Quintero stage at presentation is one the determinants of fetal outcome [6,8,9]. Progression to a higher stage is associated with a poorer prognosis [10]. Therefore, early diagnosis of TTTS is important. Essential for optimal outcome is timely diagnosis and timely referral. Despite all the publications and even complete textbooks on TTTS, late referrals with women already in labour, or hydropic fetuses, do still occur. Essential, therefore, is to adhere to, at least, fortnightly ultrasound examination, and in particular combined with patient instruction to report onset of symptoms [11]. It is advised that these fortnightly scans are carried out during the whole pregnancy, starting from 14 weeks gestation. As TTTS usually occurs between 16 and 24 weeks [12], it is of great importance that the fortnightly scans that are carried out at this time period should specifically focus on (early) signs to detect TTTS, as stated in the National Institute of Health and Clinical Excellence guidelines [13]. Although less common, TTTS can occur up to 30 weeks or beyond, and some centres have shown feasibility of fetoscopic laser surgery beyond the common 26-week limit [14,15]. Continuation of the fortnightly scans throughout the pregnancy, therefore, seems to be logical advice. Fetal biometry should not be used to diagnose TTTS. Although estimated fetal weight differences have long been abandoned in diagnosing TTTS, a general belief still exists that donor twins should be smaller than recipients. Typically, a growth discordance of 20% or more or 25% has been used as a diagnostic criterion for selective growth restriction in one of the twin fetuses. Such a birth weight difference, however, is as frequently seen in monochorionic as in dichorionic twins [16]. In a study of
Fig. 1. Absent end-diastolic flow in the umbilical artery.
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Fig. 2. Reversed end-diastolic flow in the umbilical artery.
270 patients with TTTS, only 20% met the criteria for selective growth restriction in the donor twin [17]. Consequently, a difference in estimated fetal weight is not considered a mandatory feature of TTTS. It may, however, be a challenge to distinguish monochorionic twins with single growth restriction from TTTS. The growth-restricted twin may mimic the donor twin presenting with oligohydramnios, a small bladder, and abnormal flow in the umbilical artery. The lack of polyhydramnios in the other amniotic cavity, however, rules out the diagnosis of TTTS. The finding of polyhydramnios without visualisation of an inter-twin membrane may lead to the false diagnosis of a monoamniotic twin pregnancy. Although TTTS may occur in monoamniotic pregnancies, it is more likely that the donor twin has anhydramnios, with its amniotic membrane tightly wrapped around its body. This is called the ‘stuck’ twin phenomenon (Fig. 5). In most cases, the donor twin is fixed to the uterine wall. A variant of this classic stuck twin occurs when dividing membranes envelops the donor twin with severe oligohydramnios and connected to the uterine wall by a laminar stalk of these membranes, the so-called ‘cocoon-sign’ [18] or intrauterine sling [19]. It may seem ‘unstuck’ and free floating in the recipient’s amniotic cavity with polyhydramnios, and can therefore be
Fig. 3. Negative a-wave in ductus venosus.
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Fig. 4. Pulsations in the umbilical vein.
misdiagnosed as being surrounded by a normal amount of amniotic fluid. Other causes of stuck twins, not associated with TTTS that have been identified are viral infections, renal disease, and agenesis of the ductus venosus [20]. In conclusion, the diagnosis and evaluation of stage and severity requires careful history taking, complete detailed evaluation of both twins, their anatomy and functional assessment, placenta and amniotic fluid, with an open mind to rare but important alternative diagnoses. Once the diagnosis is confirmed or at least extremely likely, determining the optimal time and method for intervention becomes the next challenge, which will be discussed elsewhere in this issue of Best Practice and Research Clinical Obstetrics and Gynaecology. Selective fetal growth restriction Abnormal fetal growth by definition means that at least two biometric measurements have been carried out, with an interval of at least 1 and preferably 2 weeks, showing a deviation from the normal
Fig. 5. ‘Stuck’ twin.
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growth rate. A single measurement can only depict fetal size at the moment of assessment. Still, most investigators of fetal growth restriction define their group of interest as a single estimation of, most commonly, estimated fetal weight or sometimes of fetal abdominal circumference alone, falling below a certain cut-off level in a growth chart or reference range. Others argue that any significant discordance in growth or size in monochorionic twins, which genetically have the same growth potential, should be regarded as pathologic [2]. Thus, a significant discordance, even if the smaller twin is above the 10th centile, should alert the clinician. An increasing body of literature is showing an association between a significant difference in twin birth weight and perinatal mortality or neonatal outcome [12,21]. A recent retrospective cohort study [12] showed that both birth weight and estimated fetal weight discordance were associated with adverse outcome, unrelated to the individual fetal size percentile [12]. The cut-off that best separated poor from good outcome was 25% discordance. A prospective evaluation of a large Irish cohort of twin pregnancies (both monochorionic and dichorionic twins) revealed that a discordant abdominal circumference of more than 10%, detected between 14 and 22 weeks, best predicted adverse outcome [22]. A still unresolved issue, however, is how to translate this important knowledge into guidelines for management during pregnancy. Birth weight obviously can be measured with accuracy within grams. Ultrasound estimation of fetal weight is well known to be quite unreliable, with deviations often into the 10–15% range, particularly in earlier gestation [23]. Therefore, to use a certain percentage discordance in estimated fetal weight may lead to incorrect diagnoses, with both a risk for over- and underestimating pathology. Obviously, such a cut-off determined by receiver operator characteristic curve analysis does not mean that an EFW discordance less than 25% can be ignored. A recent attempt to reach consensus among world experts for a universal definition of sFGR in monochorionic twins lead to heated debates, underlining the fact that we currently lack well-designed, adequately powered prospective studies providing evidence for the use of one particular definition over another one. We agree with the authors of a recent review on twin growth that ‘although there are multiple publications on the increased morbidity and mortality rates with discordant growth, there is a paucity of reports on how to manage them optimally and deliver them in a timely manner’ [24]. For current clinical practice, we suggest that detection of discordant growth in monochorionic twins should lead to more close evaluation of the condition of the smaller twin, including Doppler studies. Any concern on the condition of the smaller twin (decreased amniotic fluid, abnormal Doppler results) should alert the clinician to consider further management in a centre specialised in monochorionic twin pathology. Serial and frequent evaluations will lead to individualised management plans, in which gestational age plays a major role. Currently, the place of several management options, including inhospital surveillance, planned preterm delivery, fetoscopic laser surgery, or selective feticide, is still unclear, warranting further prospective studies. To optimise generalisability of such studies, it would be of great value to have a uniform, generally accepted definition and classification system. Until such time, we suggest that a discordantly growing set of monochorionic twins, with one having an estimated fetal weight less than the 10th centile, or discordant abdominal circumference greater than10%, or an estimated fetal weight greater than 20–25%, represents a high-risk situation, and should be diagnosed as sFGR, warranting specialist care. This particular group invariably has a unique placental angio-architecture, and poses special dilemmas for the clinician owing to the so-called feto–fetal conflict; for one fetus, frequent monitoring and iatrogenic preterm birth is warranted, whereas the other may not benefit from early birth, often on the contrary. Discussions on which growth charts to use have been ongoing for decades. It is still widely accepted that growth charts for singletons should be used when evaluating the growth of twins. Many ultrasound machines and electronic databases have specific growth charts programmed into them. Every couple of years, new and often-improved reference ranges for the general or a specific population are published, of which the authors often state that their use will improve care. Given the variation in measurement and the biological variation between pregnancies and fetuses, the use of one chart or another is unlikely to have a major effect in managing sFGR. Using the same equipment, algorithm and chart throughout pregnancy makes sense but should not be vitally important. A recent large cohort study on twins from Ireland (ESPRiT study) [25] showed that the Hadlock formula and curves [25], at least up to 30–32 weeks, can be used to evaluate twin growth. After this
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gestational age, twin growth deviates from this curve, and progressively slows down (Professor S. Daly, personal communication). As this is most likely caused by reduced placental function, with a genetic growth potential of each twin being not dissimilar to singletons, the use of a specific twin chart would only lead to a risk of missing signs of growth restriction, and is therefore not recommended. The next two steps in the diagnostic pathway are to identify the most likely cause for the sFGR, and to evaluate fetal condition. Obviously, as in any pathologic pregnancy, a full, detailed anatomy scan, including evaluation of cardiac structure and function, is essential. Viral infections may, quite surprisingly, cause discordant pathology in monochorionic twins, and should be excluded in any case of growth restriction. Discordancy for genetic syndromes and chromosomal aberrations does occur, and may need amniocentesis to rule out. Most often, however, the picture can be fully explained by the presence of an unequally shared placenta. An additional role is likely for the type and size of the vascular anastomoses, and their influence on the amount of nutrients and oxygen transferred to each fetus [26]. The placental and vascular anatomy may not become clear until after birth. Looking for the cord insertion site may give a clue, with the smaller twin often having a marginal insertion [27]. On the other hand, many monochorionic twins have a different insertion of the cord, with one being more marginal than the other, without showing signs of sFGR. Although it is customary, and recommended, to look for the insertion sites, perhaps even in the first trimester [2], the clinical value of such a screening is yet unknown. More useful is assessment of blood flow waveforms in the umbilical arteries. Growth-restricted fetuses are known to often show abnormal Doppler waveforms in the umbilical artery. In singletons, this attributed to an increased placental resistance. The most common parameters used to evaluate these waveforms are the Pulsatility Index, and presence, absence or reversed end-diastolic flow [28]. Clinical severity of fetal growth restriction is correlated to the Pulsatility Index and to the end-diastolic flow velocity. Reversed end-diastolic flow is thought to occur mainly when, in addition to an increased downstream resistance, the fetal heart starts to decompensate with a decreased ability to generate adequate systolic output. In singletons, this is regarded as a sign of impending demise. In monochorionic twins with sFGR, however, the blood flow in the umbilical arteries of the smaller twin is influenced by the types and diameters of the vascular anastomoses. They almost always present arterio-arterial anastomoses, and certainly influence Doppler waveforms in the umbilical arteries. A unique pattern for this type of twin is the so-called intermittent absent end-diastolic flow, most likely caused by changes in synchronicity of the two fetal heart rates. This pattern is often associated with a larger size arterio-arterial anastomoses [28]. Just as in singletons, absent end diastolic flow seems to carry a worse prognosis compared with fetuses with positive end-diastolic flow in the umbilical artery [29]. A now universally adopted staging, based on umbilical artery Doppler waveforms in the cord of the small twin, was proposed by Gratacos et al. [30] They divided sIUGR twins in Stage I, with constantly present end-diastolic flow, stage II with continuous absent end diastolic flow, and stage III with intermittent absent end diastolic flow. Most of the recent publications on sIUGR report these stages, and often confirm that a higher stage signifies a worse prognosis. Stage III in particular, with the likely presence of a large arterio-arterial anastomoses, seems to have a high risk for sudden fetal demise or brain damage in survivors. Outcomes, however, vary widely, and the predictive value of the Doppler measurements and Gratacos classification urgently requires more appropriate, detailed studies. For optimal interpretation of the umbilical artery Doppler waveforms, strict adherence to careful measurement protocols is important. In Table 2, we outline the preferred method for this measurement. In addition to assessing the umbilical artery Doppler waveforms, other functional parameters need to be evaluated to obtain a complete picture of the fetal condition. These, however, are similar to parameters used in singletons with growth restriction, and include middle cerebral artery Pulsatility index, peak systolic velocity, ductus venosus waveforms, and pulsatility in the intrahepatic umbilical vein using Doppler, amniotic fluid volume, fetal movements, and fetal heart rate tracing. Once the diagnosis of sFGR is clear, and its severity established, then the highly individualised, strongly gestational age-dependent options for further management need to be considered. In general, the options consist of expectant management, fetoscopic laser coagulation, selective feticide, and delivery or termination of the whole pregnancy. Interventions in monochorionic twins will be discussed in another chapter in this issue.
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Table 2 Guideline for measuring umbilical artery Doppler waveforms in monochorionic twins. Use colour Doppler to visualise the umbilical arteries. Put the Doppler cursor in a free loop of the umbilical artery, close to the insertion into the placenta. Ensure an angle of insonation of as near as zero as possible. Only measure the waveforms in the absence of fetal and maternal breathing movements. Assess a minimum of 12 waveforms in each umbilical artery. In case of persistent positive end diastolic flow, measure the Pulsatility Index. In case of absent end diastolic flow or reversed end-diastolic flow, determine whether this alternates with several waveforms with positive end diastolic flow to define intermittent absent end diastolic flow.
Twin anaemia-polycythaemia sequence In 2007, a separate form of chronic feto–fetal transfusion was first named twin-anaemia–polycythaemia-sequence (TAPS) [31]. It is characterised by the presence of large inter-twin haemoglobin differences without amniotic fluid discordances that are needed to diagnose TTTS. It may occur spontaneously or iatrogenically after laser surgery for TTTS. The spontaneous form occurs in 3–5% of monochorionic twin pregnancies, whereas the post-laser form complicates about 2–13% of TTTS cases [2,32,33]. The typical angioarchitecture in TAPS placentas are the minuscule size (14.0 >17.0 >20.0
1 2 3 4 5
Obviously, the best possible outcome in such a twin pregnancy is one healthy child. Apart from establishing the diagnosis, and explaining to parents what this entails, our diagnostic tests are directed at assessing the risk of cardiac decompensation and demise of the so-called ‘pump twin’. This information can then be used to consider an intervention, directed at stopping the blood flow to the acardiac twin. An as yet unresolved issue is whether intervention should be offered to all patients with TRAP, as early as possible. Lewi et al. [40] reported that, in a third of TRAP pregnancies, pump twin demise occurred before 18 weeks’ gestation, without reliable predictors of which pump twin would die and when this would happen. Pagani et al. [41] also concluded that early intervention (in their view best by infra-fetal laser coagulation) would result in the highest intact survival rate. Thus, serial monitoring would no longer be needed. For those that consider the evidence for early intervention in all cases still insufficient, however, careful and frequent assessment of the parameters considered related to the risk of pump twin death. The first part of the diagnostic process, after establishing the diagnosis of TRAP, is evaluating the condition of the pump twin. A full and detailed anatomy scan is indicated, as structural anomalies seem to be present more often than in other monochorionic twins. Secondly, evaluation of cardiac function is a logical step, as cardiac failure caused by the need to provide the growing acardiac co-twin with blood. Measuring cardio-thoracic circumference ratio and ventricular wall thickness plus ductus venosus waveforms can be carried out by any obstetric sonographers. Whether more sophisticated echocardiography aids in management decisions is unclear, and likely depends on local possibilities. Thirdly, the amount of blood flow in the acardiac twin, and its overall size and growth rate, could be related to the risk of pump twin death. In addition, polyhydramnios may occur and add to the risk of adverse outcome. The general idea behind serial monitoring is that the disease process is chronic and progressive, with early signs of deterioration providing time to plan an intervention. In TRAP sequence, however, acute pump twin demise without any pathologic sign does occur, limiting the value of serial monitoring. Although prospective, controlled studies comparing expectant management with early intervention are lacking, available data in our view support the view that the best possible outcome, both in terms of survival as well as gestational age at birth, follows early intervention aimed at stopping the blood flow to the acardiac twin. Conclusion Monochorionic twin pregnancies require frequent, detailed ultrasound and Doppler evaluation by specialists with knowledge and experience in managing the various unique complications of such twins. Early referral in case of suspicion of abnormal or discordant amniotic fluid, growth, or blood flow profiles is strongly advised. Most antenatal treatment modalities are still suboptimal, and require further research. However, successful treatment relies on accurate and tinely diagnosis, of which the details are described in this chapter.
Conflict of interest None declared.
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Practice points Every monochorionic twin should be evaluated at least once every 2 weeks for amniotic fluid volume and bladder filling of each twin for tomel detection of TTTS. Women pregnant with monochorionic twin should be specifically instructed to seek medical attention when they experience a rapid increase in uterine size or other signs possibly related to TTTS. Selective growth restriction, defined as one fetus in an monochorionic twin with an estimated fetal weight below the 10th centile, ands appropriately measured umbilical artery blood flow patterns, help to evaluate severity and likelihood of complications. We recommend routine measurement of middle cerebral artery peak systolic velocities at least every 2 weeks in all monochorionic twins, to enable diagnosis of TAPS. Suspected diagnosis of TTTS, sFGR, TAPS, and TRAP warrants urgent contact with a specialised fetal medicine centre to guide specific management.
Research agenda Evaluate the use of echocardiography in staging, and timing of intervention in TTTS. Improve prediction of occurrence and time of intrauterine fetal demise and antenatal neurologic damage in monochorionic twins with selective fetal growth restriction. Evaluate natural history and possible benefit of interventions of the polycythemic twin in TAPS. Establish better predictors of poor outcome in TRAP sequence, to guide decisions on intervention. Effect of interventions in complicated monochorionic twins on long-term health outcomes of surviving children.
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[25] Hadlock FP, Harrist RB, Martinez-Poyer J. In utero analysis of fetal growth: a sonographic weight standard. Radiology 1991;181:129–33. [26] Fick AL, Feldstein VA, Norton ME, et al. Unequal placental sharing and birth weight discordance in monochorionic diamniotic twins. Am J Obstet Gynecol 2006;195:178–83. [27] Kent EM, Breathnach FM, Gillan JE, et al. Placental cord insertion and birthweight discordance in twin pregnancies: result of the national prospective ESPRiT Study. Am J Obstet Gynecol 2001;205:376.e1–7. *[28] Gratacos E, Lewi L, Carreras E, et al. Incidence and characteristics of umbilical artery intermittent absent and/or reversed end-diastolic flow in complicated and uncomplicated monochorionic twin pregnancies. Ultrasound Obstet Gynecol 2004; 23:456–60. [29] Gratacos E, Carreras E, Becker J, et al. Prevalence of neurological damage in monochorionic twins with selective intrauterine growth restriction and intermittent absent or reversed end-diastolic umbilical artery flow. Ultrasound Obstet Gynecol 2004;24:159–63. *[30] Gratacos E, Lewi L, Munoz B, et al. A classification system for selective intrauterine growth restriction in monochorionic pregnancies according to umbilical artery Doppler flow in the smaller twin. Ultrasound Obstet Gynecol 2007;30:28–34. [31] Lopriore E, Middeldorp JM, Oepkes D, et al. Twin anemia-polycythemia sequence in two monochorionic twin pairs without oligo-polyhydramnios sequence. Placenta 2007;28:47–51. *[32] 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. [33] de Villiers SF, Slaghekke F, Middeldorp JM, et al. Placental characteristics in monochorionic twins with spontaneous versus post-laser twin anemia–polycythemia sequence. Placenta 2013;34:456–9. [34] Zhao DP, de Villiers SF, Slaghekke F, et al. Prevalence, size, number and localization of vascular anastomoses in monochorionic placentas. Placenta 2013;34:589–93. [35] Lopriore E, Deprest J, Slaghekke F, et al. Placental characteristics in monochorionic twins with and without twin anemiapolycythemia sequence. Obstet Gynecol 2008;112:753–8. *[36] Slaghekke F, Kist WJ, Oepkes D, et al. Twin anemia-polycythemia sequence: diagnostic criteria, classification, perinatal management and outcome. Fetal Diagn Ther 2010;27:181–90. *[37] Lopriore E, Slaghekke F, Oepkes D, et al. Clinical outcome in neonates with twin anemia-polycythemia sequence. Am J Obstet Gynecol 2010;203:54.e1–5. [38] Lopriore E, Sueters M, Middeldorp JM, et al. Haemoglobin differences at birth in monochorionic twins without chronic twin-to-twin transfusion syndrome. Prenat Diagn 2005;25:844–50. [39] Lopriore E, Slaghekke F, Oepkes D, et al. Hematological characteristics in neonates with twin anemia-polycythemia sequence (TAPS). Prenat Diagn 2010;30:251–5. *[40] Lewi L, Valencia C, Gonzalez E, et al. The outcome of twin reversed arterial perfusion sequence diagnosed in the first trimester. Am J Obstet Gynecol 2010;203:213.e1–4. *[41] Pagani G, D’Antonio F, Khalil A, et al. Intrafetal laser treatment for twin reversed arterial perfusion sequence: cohort study and meta-analysis. Ultrasound Obstet Gynecol 2013;42:6–14.
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3
Diagnosis of twin-to-twin transfusion syndrome, selective fetal growth restriction, twin anaemia-polycythaemia sequence, and twin reversed arterial perfusion sequence Marieke Sueters, MD, PhD, Fellow Maternal Fetal Medicine a, Dick Oepkes, MD, PhD, Consultant, Professor of Obstetrics and Fetal Therapy b, * a
Department of Obstetrics, Leiden University Medical Centre, Leiden, The Netherlands Department of Obstetrics, K-06-35, Leiden University Medical Centre, PO Box 9600, RC Leiden, The Netherlands b
Keywords: twin-to-twin transfusion syndrome selective fetal growth restriction twin anemia polycythemia sequence twin reversed arterial perfusion sequence ultrasound Doppler diagnosis
Monochorionic twin pregnancies are well known to be at risk for a variety of severe complications, a true challenge for the maternal– fetal medicine specialist. With current standards of care, monochorionicity should be established in the first trimester. Subsequently, frequent monitoring using the appropriate diagnostic tools, and in-depth knowledge about the pathophysiology of all possible clinical presentations of monochorionic twin abnormalities, should lead to timely recognition, and appropriate management. Virtually all unique diseases found in monochorionic twins are directly related to placental angio-architecture. This, however, cannot be established reliably before birth. The clinician needs to be aware of the definitions and symptoms of twin-to twin transfusion syndrome, selective fetal growth restriction, twin anaemia– polycythaemia sequence, and twin reversed arterial perfusion sequence, to be able to recognise each disease and take the required action. In this chapter, we address current standards on correct and timely diagnoses of severe complications of monochorionic twin pregnancies. Ó 2014 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: þ31 71 5262896; Fax: þ31 71 5266741. E-mail address: [email protected] (D. Oepkes). 1521-6934/$ – see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpobgyn.2013.12.002
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Introduction Monochorionic twin pregnancies are associated with a variety of serious complications, unique to this group. The underlying pathophysiology of most of these complications seems to be related, directly or indirectly, to the unique angio-architecture of the monochorionic placenta [1]. Imbalanced blood flow, with net transfer of blood and likely of numerous regulating factors, is the accepted cause of twintwin transfusion syndrome (TTTS) and twin anaemia–polycythemia sequence (TAPS). Although the accepted cause of selective fetal growth restriction (sFGR) is an unequally shared placenta, and the reversed blood flow in the cord and the body of the acardiac twin explains its features, the underlying pathophysiology may start with imbalanced blood flow through particular types of vascular anastomoses. With current imaging technology, we cannot reliably visualise these anastomoses. Ultrasound and Doppler examinations enable us to detect early signs and symptoms of the various pathologic conditions in monochorionic twins. As for some, treatment options exist, timely diagnosis and referral is of vital importance. In this chapter, we aim to discuss the clinically relevant diagnostic tools that can and should apply in the management of monochorionic twin pregnancies. Twin-to-twin transfusion syndrome Monochorionic twins share a single placenta with vascular anastomoses that connect the fetal circulations, allowing inter-twin blood transfusion. This is a physiological phenomenon as long as blood flow between the fetuses is balanced. Unbalanced net inter-twin blood transfusion, however, may lead to various forms of serious pathology. The best-known clinical syndrome is TTTS, which is a chronic form of feto–fetal transfusion and affects about 9% of monochorionic twins [2]. In the past, TTTS was diagnosed at the time of birth based on neonatal criteria that included a growth discordance of 15–20% associated with discordant cord or neonatal haemoglobin concentration of 5 g/dl [3]. A subsequent study by Wenstrom et al. [4] showed that any combination of weight and haemoglobin discordance could be seen with equal frequency. The investigators concluded that the historical paediatric parameters should be abandoned for the diagnosis of TTTS. Nowadays, TTTS is diagnosed prenatally by ultrasound examination. It typically presents in the second trimester of pregnancy, and the diagnosis is based on the presence of a twin oligo–polyhydramnios sequence (TOPS). The following ultrasound criteria are required to diagnose TTTS: (1) the twin gestation is diagnosed as monochorionic (ideally with a scan carried out in the first trimester showing a T-sign); and (2) a combination of oligohydramnios exists in one twin’s amniotic cavity, with polyhydramnios in the other twin’s amniotic cavity. Oligohydramnios is defined as a maximum vertical pocket (MVP) of 2 cm. This twin is commonly called the donor twin. Polyhydramnios was originally defined as a MVP of 8 cm [5]. Subsequent studies in Europe have proposed to increase the threshold to 10 cm or more for the MVP after 20 weeks’ gestation [6]. This twin is described as the recipient twin. A twin gestation that meets the above criteria is classified as TTTS. Quintero et al. [5], in 1999, described a classification of TTTS (Table 1), which has been widely adopted and used throughout the world.
Table 1 Staging of twin-to-twin transfusion syndrome. Stage
Oligo/ polyhydramniosa
Absent bladder filling in donor
Critically abnormal Doppler studiesb
Hydrops of either fetus
Intrauterine fetal demise of either fetus
I II III IV V
þ þ þ þ þ
– þ þ þ þ
– – þ þ þ
– – – þ þ
– – – – þ
a Oligohydramnios: maximum vertical pocket of 2 cm or less; polyhydramnios: maximum vertical pocket of 8 cm or over (or 10 cm at >20 weeks’ gestation). b Absent or reversed diastolic velocity in the umbilical artery or ductus venosus or pulsatile umbilical venous velocity.
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Quintero Stage I is defined as an oligo–polyhydramnios sequence with MVP of amniotic fluid of the donor and recipient twin of 2 or less and 8 cm or more (or 10 cm at >20 weeks’ gestation), respectively. Stage II is a more progressive stage, including no visualisation of bladder filling in the donor twin. Some investigators have argued that the presence of a small bladder that fails to fill during prolonged ultrasound examination should also qualify as stage II disease [7]. Stage III disease is diagnosed when the Doppler results are critically abnormal, including absent (Fig. 1) or reversed (Fig. 2) diastolic velocity in the umbilical artery or in the ductus venosus (Fig. 3), or pulsatile umbilical venous velocity (Fig. 4) in either the donor, recipient twin, or both. Therefore, many combinations of Doppler abnormalities are possible. Typically, umbilical artery flow abnormalities are seen in donor twins, whereas recipients more often show abnormal ductus venous or pulsatile umbilical venous Doppler studies, indicative of imminent cardiac failure. Subdividing stage III into stage III-D, III-R, or III-DR, to indicate which twin experiences Doppler abnormalities, is advocated by several centres. Stage IV disease is present when fetal hydrops (e.g. ascites, pericardial effusion, or both, pleural effusions, or scalp oedema) is diagnosed in either twin. Typically this is first seen in the recipient twin. Fetal demise of either fetus is named stage V disease. Several studies have shown that disease severity defined by Quintero stage at presentation is one the determinants of fetal outcome [6,8,9]. Progression to a higher stage is associated with a poorer prognosis [10]. Therefore, early diagnosis of TTTS is important. Essential for optimal outcome is timely diagnosis and timely referral. Despite all the publications and even complete textbooks on TTTS, late referrals with women already in labour, or hydropic fetuses, do still occur. Essential, therefore, is to adhere to, at least, fortnightly ultrasound examination, and in particular combined with patient instruction to report onset of symptoms [11]. It is advised that these fortnightly scans are carried out during the whole pregnancy, starting from 14 weeks gestation. As TTTS usually occurs between 16 and 24 weeks [12], it is of great importance that the fortnightly scans that are carried out at this time period should specifically focus on (early) signs to detect TTTS, as stated in the National Institute of Health and Clinical Excellence guidelines [13]. Although less common, TTTS can occur up to 30 weeks or beyond, and some centres have shown feasibility of fetoscopic laser surgery beyond the common 26-week limit [14,15]. Continuation of the fortnightly scans throughout the pregnancy, therefore, seems to be logical advice. Fetal biometry should not be used to diagnose TTTS. Although estimated fetal weight differences have long been abandoned in diagnosing TTTS, a general belief still exists that donor twins should be smaller than recipients. Typically, a growth discordance of 20% or more or 25% has been used as a diagnostic criterion for selective growth restriction in one of the twin fetuses. Such a birth weight difference, however, is as frequently seen in monochorionic as in dichorionic twins [16]. In a study of
Fig. 1. Absent end-diastolic flow in the umbilical artery.
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Fig. 2. Reversed end-diastolic flow in the umbilical artery.
270 patients with TTTS, only 20% met the criteria for selective growth restriction in the donor twin [17]. Consequently, a difference in estimated fetal weight is not considered a mandatory feature of TTTS. It may, however, be a challenge to distinguish monochorionic twins with single growth restriction from TTTS. The growth-restricted twin may mimic the donor twin presenting with oligohydramnios, a small bladder, and abnormal flow in the umbilical artery. The lack of polyhydramnios in the other amniotic cavity, however, rules out the diagnosis of TTTS. The finding of polyhydramnios without visualisation of an inter-twin membrane may lead to the false diagnosis of a monoamniotic twin pregnancy. Although TTTS may occur in monoamniotic pregnancies, it is more likely that the donor twin has anhydramnios, with its amniotic membrane tightly wrapped around its body. This is called the ‘stuck’ twin phenomenon (Fig. 5). In most cases, the donor twin is fixed to the uterine wall. A variant of this classic stuck twin occurs when dividing membranes envelops the donor twin with severe oligohydramnios and connected to the uterine wall by a laminar stalk of these membranes, the so-called ‘cocoon-sign’ [18] or intrauterine sling [19]. It may seem ‘unstuck’ and free floating in the recipient’s amniotic cavity with polyhydramnios, and can therefore be
Fig. 3. Negative a-wave in ductus venosus.
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Fig. 4. Pulsations in the umbilical vein.
misdiagnosed as being surrounded by a normal amount of amniotic fluid. Other causes of stuck twins, not associated with TTTS that have been identified are viral infections, renal disease, and agenesis of the ductus venosus [20]. In conclusion, the diagnosis and evaluation of stage and severity requires careful history taking, complete detailed evaluation of both twins, their anatomy and functional assessment, placenta and amniotic fluid, with an open mind to rare but important alternative diagnoses. Once the diagnosis is confirmed or at least extremely likely, determining the optimal time and method for intervention becomes the next challenge, which will be discussed elsewhere in this issue of Best Practice and Research Clinical Obstetrics and Gynaecology. Selective fetal growth restriction Abnormal fetal growth by definition means that at least two biometric measurements have been carried out, with an interval of at least 1 and preferably 2 weeks, showing a deviation from the normal
Fig. 5. ‘Stuck’ twin.
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growth rate. A single measurement can only depict fetal size at the moment of assessment. Still, most investigators of fetal growth restriction define their group of interest as a single estimation of, most commonly, estimated fetal weight or sometimes of fetal abdominal circumference alone, falling below a certain cut-off level in a growth chart or reference range. Others argue that any significant discordance in growth or size in monochorionic twins, which genetically have the same growth potential, should be regarded as pathologic [2]. Thus, a significant discordance, even if the smaller twin is above the 10th centile, should alert the clinician. An increasing body of literature is showing an association between a significant difference in twin birth weight and perinatal mortality or neonatal outcome [12,21]. A recent retrospective cohort study [12] showed that both birth weight and estimated fetal weight discordance were associated with adverse outcome, unrelated to the individual fetal size percentile [12]. The cut-off that best separated poor from good outcome was 25% discordance. A prospective evaluation of a large Irish cohort of twin pregnancies (both monochorionic and dichorionic twins) revealed that a discordant abdominal circumference of more than 10%, detected between 14 and 22 weeks, best predicted adverse outcome [22]. A still unresolved issue, however, is how to translate this important knowledge into guidelines for management during pregnancy. Birth weight obviously can be measured with accuracy within grams. Ultrasound estimation of fetal weight is well known to be quite unreliable, with deviations often into the 10–15% range, particularly in earlier gestation [23]. Therefore, to use a certain percentage discordance in estimated fetal weight may lead to incorrect diagnoses, with both a risk for over- and underestimating pathology. Obviously, such a cut-off determined by receiver operator characteristic curve analysis does not mean that an EFW discordance less than 25% can be ignored. A recent attempt to reach consensus among world experts for a universal definition of sFGR in monochorionic twins lead to heated debates, underlining the fact that we currently lack well-designed, adequately powered prospective studies providing evidence for the use of one particular definition over another one. We agree with the authors of a recent review on twin growth that ‘although there are multiple publications on the increased morbidity and mortality rates with discordant growth, there is a paucity of reports on how to manage them optimally and deliver them in a timely manner’ [24]. For current clinical practice, we suggest that detection of discordant growth in monochorionic twins should lead to more close evaluation of the condition of the smaller twin, including Doppler studies. Any concern on the condition of the smaller twin (decreased amniotic fluid, abnormal Doppler results) should alert the clinician to consider further management in a centre specialised in monochorionic twin pathology. Serial and frequent evaluations will lead to individualised management plans, in which gestational age plays a major role. Currently, the place of several management options, including inhospital surveillance, planned preterm delivery, fetoscopic laser surgery, or selective feticide, is still unclear, warranting further prospective studies. To optimise generalisability of such studies, it would be of great value to have a uniform, generally accepted definition and classification system. Until such time, we suggest that a discordantly growing set of monochorionic twins, with one having an estimated fetal weight less than the 10th centile, or discordant abdominal circumference greater than10%, or an estimated fetal weight greater than 20–25%, represents a high-risk situation, and should be diagnosed as sFGR, warranting specialist care. This particular group invariably has a unique placental angio-architecture, and poses special dilemmas for the clinician owing to the so-called feto–fetal conflict; for one fetus, frequent monitoring and iatrogenic preterm birth is warranted, whereas the other may not benefit from early birth, often on the contrary. Discussions on which growth charts to use have been ongoing for decades. It is still widely accepted that growth charts for singletons should be used when evaluating the growth of twins. Many ultrasound machines and electronic databases have specific growth charts programmed into them. Every couple of years, new and often-improved reference ranges for the general or a specific population are published, of which the authors often state that their use will improve care. Given the variation in measurement and the biological variation between pregnancies and fetuses, the use of one chart or another is unlikely to have a major effect in managing sFGR. Using the same equipment, algorithm and chart throughout pregnancy makes sense but should not be vitally important. A recent large cohort study on twins from Ireland (ESPRiT study) [25] showed that the Hadlock formula and curves [25], at least up to 30–32 weeks, can be used to evaluate twin growth. After this
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gestational age, twin growth deviates from this curve, and progressively slows down (Professor S. Daly, personal communication). As this is most likely caused by reduced placental function, with a genetic growth potential of each twin being not dissimilar to singletons, the use of a specific twin chart would only lead to a risk of missing signs of growth restriction, and is therefore not recommended. The next two steps in the diagnostic pathway are to identify the most likely cause for the sFGR, and to evaluate fetal condition. Obviously, as in any pathologic pregnancy, a full, detailed anatomy scan, including evaluation of cardiac structure and function, is essential. Viral infections may, quite surprisingly, cause discordant pathology in monochorionic twins, and should be excluded in any case of growth restriction. Discordancy for genetic syndromes and chromosomal aberrations does occur, and may need amniocentesis to rule out. Most often, however, the picture can be fully explained by the presence of an unequally shared placenta. An additional role is likely for the type and size of the vascular anastomoses, and their influence on the amount of nutrients and oxygen transferred to each fetus [26]. The placental and vascular anatomy may not become clear until after birth. Looking for the cord insertion site may give a clue, with the smaller twin often having a marginal insertion [27]. On the other hand, many monochorionic twins have a different insertion of the cord, with one being more marginal than the other, without showing signs of sFGR. Although it is customary, and recommended, to look for the insertion sites, perhaps even in the first trimester [2], the clinical value of such a screening is yet unknown. More useful is assessment of blood flow waveforms in the umbilical arteries. Growth-restricted fetuses are known to often show abnormal Doppler waveforms in the umbilical artery. In singletons, this attributed to an increased placental resistance. The most common parameters used to evaluate these waveforms are the Pulsatility Index, and presence, absence or reversed end-diastolic flow [28]. Clinical severity of fetal growth restriction is correlated to the Pulsatility Index and to the end-diastolic flow velocity. Reversed end-diastolic flow is thought to occur mainly when, in addition to an increased downstream resistance, the fetal heart starts to decompensate with a decreased ability to generate adequate systolic output. In singletons, this is regarded as a sign of impending demise. In monochorionic twins with sFGR, however, the blood flow in the umbilical arteries of the smaller twin is influenced by the types and diameters of the vascular anastomoses. They almost always present arterio-arterial anastomoses, and certainly influence Doppler waveforms in the umbilical arteries. A unique pattern for this type of twin is the so-called intermittent absent end-diastolic flow, most likely caused by changes in synchronicity of the two fetal heart rates. This pattern is often associated with a larger size arterio-arterial anastomoses [28]. Just as in singletons, absent end diastolic flow seems to carry a worse prognosis compared with fetuses with positive end-diastolic flow in the umbilical artery [29]. A now universally adopted staging, based on umbilical artery Doppler waveforms in the cord of the small twin, was proposed by Gratacos et al. [30] They divided sIUGR twins in Stage I, with constantly present end-diastolic flow, stage II with continuous absent end diastolic flow, and stage III with intermittent absent end diastolic flow. Most of the recent publications on sIUGR report these stages, and often confirm that a higher stage signifies a worse prognosis. Stage III in particular, with the likely presence of a large arterio-arterial anastomoses, seems to have a high risk for sudden fetal demise or brain damage in survivors. Outcomes, however, vary widely, and the predictive value of the Doppler measurements and Gratacos classification urgently requires more appropriate, detailed studies. For optimal interpretation of the umbilical artery Doppler waveforms, strict adherence to careful measurement protocols is important. In Table 2, we outline the preferred method for this measurement. In addition to assessing the umbilical artery Doppler waveforms, other functional parameters need to be evaluated to obtain a complete picture of the fetal condition. These, however, are similar to parameters used in singletons with growth restriction, and include middle cerebral artery Pulsatility index, peak systolic velocity, ductus venosus waveforms, and pulsatility in the intrahepatic umbilical vein using Doppler, amniotic fluid volume, fetal movements, and fetal heart rate tracing. Once the diagnosis of sFGR is clear, and its severity established, then the highly individualised, strongly gestational age-dependent options for further management need to be considered. In general, the options consist of expectant management, fetoscopic laser coagulation, selective feticide, and delivery or termination of the whole pregnancy. Interventions in monochorionic twins will be discussed in another chapter in this issue.
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Table 2 Guideline for measuring umbilical artery Doppler waveforms in monochorionic twins. Use colour Doppler to visualise the umbilical arteries. Put the Doppler cursor in a free loop of the umbilical artery, close to the insertion into the placenta. Ensure an angle of insonation of as near as zero as possible. Only measure the waveforms in the absence of fetal and maternal breathing movements. Assess a minimum of 12 waveforms in each umbilical artery. In case of persistent positive end diastolic flow, measure the Pulsatility Index. In case of absent end diastolic flow or reversed end-diastolic flow, determine whether this alternates with several waveforms with positive end diastolic flow to define intermittent absent end diastolic flow.
Twin anaemia-polycythaemia sequence In 2007, a separate form of chronic feto–fetal transfusion was first named twin-anaemia–polycythaemia-sequence (TAPS) [31]. It is characterised by the presence of large inter-twin haemoglobin differences without amniotic fluid discordances that are needed to diagnose TTTS. It may occur spontaneously or iatrogenically after laser surgery for TTTS. The spontaneous form occurs in 3–5% of monochorionic twin pregnancies, whereas the post-laser form complicates about 2–13% of TTTS cases [2,32,33]. The typical angioarchitecture in TAPS placentas are the minuscule size (14.0 >17.0 >20.0
1 2 3 4 5
Obviously, the best possible outcome in such a twin pregnancy is one healthy child. Apart from establishing the diagnosis, and explaining to parents what this entails, our diagnostic tests are directed at assessing the risk of cardiac decompensation and demise of the so-called ‘pump twin’. This information can then be used to consider an intervention, directed at stopping the blood flow to the acardiac twin. An as yet unresolved issue is whether intervention should be offered to all patients with TRAP, as early as possible. Lewi et al. [40] reported that, in a third of TRAP pregnancies, pump twin demise occurred before 18 weeks’ gestation, without reliable predictors of which pump twin would die and when this would happen. Pagani et al. [41] also concluded that early intervention (in their view best by infra-fetal laser coagulation) would result in the highest intact survival rate. Thus, serial monitoring would no longer be needed. For those that consider the evidence for early intervention in all cases still insufficient, however, careful and frequent assessment of the parameters considered related to the risk of pump twin death. The first part of the diagnostic process, after establishing the diagnosis of TRAP, is evaluating the condition of the pump twin. A full and detailed anatomy scan is indicated, as structural anomalies seem to be present more often than in other monochorionic twins. Secondly, evaluation of cardiac function is a logical step, as cardiac failure caused by the need to provide the growing acardiac co-twin with blood. Measuring cardio-thoracic circumference ratio and ventricular wall thickness plus ductus venosus waveforms can be carried out by any obstetric sonographers. Whether more sophisticated echocardiography aids in management decisions is unclear, and likely depends on local possibilities. Thirdly, the amount of blood flow in the acardiac twin, and its overall size and growth rate, could be related to the risk of pump twin death. In addition, polyhydramnios may occur and add to the risk of adverse outcome. The general idea behind serial monitoring is that the disease process is chronic and progressive, with early signs of deterioration providing time to plan an intervention. In TRAP sequence, however, acute pump twin demise without any pathologic sign does occur, limiting the value of serial monitoring. Although prospective, controlled studies comparing expectant management with early intervention are lacking, available data in our view support the view that the best possible outcome, both in terms of survival as well as gestational age at birth, follows early intervention aimed at stopping the blood flow to the acardiac twin. Conclusion Monochorionic twin pregnancies require frequent, detailed ultrasound and Doppler evaluation by specialists with knowledge and experience in managing the various unique complications of such twins. Early referral in case of suspicion of abnormal or discordant amniotic fluid, growth, or blood flow profiles is strongly advised. Most antenatal treatment modalities are still suboptimal, and require further research. However, successful treatment relies on accurate and tinely diagnosis, of which the details are described in this chapter.
Conflict of interest None declared.
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Practice points Every monochorionic twin should be evaluated at least once every 2 weeks for amniotic fluid volume and bladder filling of each twin for tomel detection of TTTS. Women pregnant with monochorionic twin should be specifically instructed to seek medical attention when they experience a rapid increase in uterine size or other signs possibly related to TTTS. Selective growth restriction, defined as one fetus in an monochorionic twin with an estimated fetal weight below the 10th centile, ands appropriately measured umbilical artery blood flow patterns, help to evaluate severity and likelihood of complications. We recommend routine measurement of middle cerebral artery peak systolic velocities at least every 2 weeks in all monochorionic twins, to enable diagnosis of TAPS. Suspected diagnosis of TTTS, sFGR, TAPS, and TRAP warrants urgent contact with a specialised fetal medicine centre to guide specific management.
Research agenda Evaluate the use of echocardiography in staging, and timing of intervention in TTTS. Improve prediction of occurrence and time of intrauterine fetal demise and antenatal neurologic damage in monochorionic twins with selective fetal growth restriction. Evaluate natural history and possible benefit of interventions of the polycythemic twin in TAPS. Establish better predictors of poor outcome in TRAP sequence, to guide decisions on intervention. Effect of interventions in complicated monochorionic twins on long-term health outcomes of surviving children.
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