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Neonatal morbidity in twin–twin transfusion syndrome
Early Human Development 87 (2011) 595–599
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Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Best practice guidelines
Neonatal morbidity in twin–twin transfusion syndrome Enrico Lopriore a,⁎, Dick Oepkes b, 1, Frans J. Walther a, 2 a b
Division of Neonatology, Department of Pediatrics, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, The Netherlands Division of Fetal Medicine, Department of Obstetrics, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, The Netherlands
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Keywords: Twin–twin transfusion syndrome Monochorionic twins Laser surgery Amnioreduction Neonatal morbidity
a b s t r a c t Twin–twin transfusion syndrome (TTTS) is a severe complication of monochorionic twin pregnancies associated with high perinatal mortality and morbidity rates. Management in TTTS is a major challenge for obstetricians and neonatologists. Twins which are often born prematurely and may suffer from typical conditions associated with prematurity. In addition, surviving twins with TTTS are at increased risk for other complications including neurological, cardiovascular, renal and hematologic morbidity. Rare complications such as hypoxic–ischemic lesions to limbs or intestines and amniotic band syndrome have also been reported in TTTS survivors. This review focuses on the neonatal and pediatric mortality and morbidity in TTTS survivors, with special emphasis on the long-term neurodevelopmental outcome. © 2011 Elsevier Ireland Ltd. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . 2. Neonatal mortality . . . . . . . . . . . . . . . . . . . . 3. Cerebral injury and neurologic morbidity . . . . . . . . . 4. Cardiovascular morbidity and right ventricular outflow tract 5. Renal morbidity . . . . . . . . . . . . . . . . . . . . . 6. Hematologic morbidity . . . . . . . . . . . . . . . . . . 7. Hepatic infarction and intestinal injury . . . . . . . . . . 8. In utero acquired limb ischemia . . . . . . . . . . . . . 9. Amniotic band syndrome (ABS) . . . . . . . . . . . . . 10. Congenital skin loss or Aplasia cutis congenital (ACC) . . . 11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . 12. Key guidelines . . . . . . . . . . . . . . . . . . . . . 13. Research directions . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . obstruction (RVOTO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Twin-to-twin transfusion syndrome (TTTS) is a severe complication of monochorionic twin pregnancies which results from unbalanced intertwin blood transfusion through placental vascular anastomoses. TTTS is characterized by the presence of oligohydramnion in the donor twin and polyhydramnion in the recipient twin. If left
⁎ Corresponding author. Tel.: +31 71 5262909; fax: +31 71 5248198. E-mail addresses: [email protected] (E. Lopriore), [email protected] (D. Oepkes), [email protected] (F.J. Walther). 1 Tel.: +31 71 5269111; fax: +31 71 5248198. 2 Tel.: +31 71 5262909; fax: +31 71 5248198. 0378-3782/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2011.07.006
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untreated, TTTS is associated with very high perinatal mortality and morbidity rates. Recent developments in prenatal care strategies and management options for patients with TTTS have led to a significant decrease in perinatal mortality rates. Nevertheless, TTTS remains one of the most lethal conditions in perinatal medicine and the optimal management is still a major challenge for both obstetricians and neonatologists. As perinatal survival in TTTS improves, attention is shifting toward short- and long-term outcome in surviving children. Since monochorionic twins are often delivered prematurely, twins are at risk for morbidity associated with prematurity such as respiratory distress syndrome, chronic lung disease, necrotizing enterocolitis and cerebral injury including intraventricular hemorrhage and periventricular
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leukomalacia. In addition, TTTS-survivors are at risk for other complications including atypical cerebral lesions (e.g. arterial stroke), cardiac morbidity, renal failure and hematologic disorders. Rare complications such as hypoxic–ischemic lesions to limbs or intestines, amniotic band syndrome and congenital skin loss have also been reported in TTTS survivors. An increasing number of studies in TTTSsurvivors are gradually shedding more light on the wide range of morbidity associated with TTTS. This review will focus on the neonatal outcome (mortality and morbidity) and neonatal management in TTTS survivors. 2. Neonatal mortality Several studies have shown that TTTS is associated with a high rate of neonatal mortality, ranging from 5 up to 29% [1,2]. Unfortunately, detailed information on the exact rates (and causes) is hard to discern since most outcome studies only mention the overall perinatal mortality rate (combined intrauterine and neonatal death), and fail to specify separately the neonatal mortality rate. Neonatal mortality rates appear to be higher in TTTS treated with amnioreduction compared to TTTS treated with laser surgery. The rate of neonatal mortality ranges from 14% to 29% in TTTS cases series treated with serial amnioreduction compared to 5 to 8% in TTTS cases series treated with laser [1,2]. In the Eurofetus trial, neonatal death was significantly higher in the amnioreduction group than in the laser group, 29% (41/140) versus 8% (12/144) (p b 0.01), respectively [1]. High mortality rates in TTTS are largely due to the high proportion of infants with extreme prematurity and very low birth weight [1–3]. Neonatal mortality in TTTS is also reported to be due to withdrawal of intensive care in cases with severe cerebral injury [1]. 3. Cerebral injury and neurologic morbidity Several studies report an increased risk of cerebral injury and neurologic morbidity in TTTS. Severe cerebral lesions detected in TTTS include cystic periventricular leukomalacia (PVL), cerebral whitematter cysts, severe intraventricular hemorrhage (IVH), ventricular dilatation and cerebral atrophy [3]. Arterial ischemic stroke has been diagnosed in neonatal survivors of TTTS [4]. In addition, sporadic reports of TTTS-cases associated with vein of Galen malformation or polymicrogyria have been published [5,6]. Minor lesions such as subependymal pseudocysts and lenticostriate vasculopathy have been described in monochorionic twins with TTTS [4]. The exact pathogenesis of cerebral injury in TTTS is not fully understood and can result from either antenatal or postnatal injury. Cerebral lesions detected antenatally are thought to be related to cerebral hemodynamic disturbances in utero [7]. Early neonatal brain scans show that antenatally acquired cerebral lesions occur in 10 to 35% of TTTS survivors compared to 3% in dichorionic twins and 2% in uncomplicated monochorionic twins [4]. Cerebral lesions may also be secondary to postnatal injury associated with extreme prematurity, which predisposes to cystic PVL and IVH. Donors and recipients appear to be equally at risk for cerebral injury [4]. Hypoxic–ischemic damage caused by cerebral hypoperfusion is probably the main cause for cerebral injury in donor twins, whereas hyperviscosity and polycythemia causing vascular sludging may be an important cause for cerebral injury in recipient twins. Sludging of polycythemic blood is also thought to be one of the causes of arterial stroke in recipient twins [4]. The incidence of cerebral lesions in TTTS varies greatly between the studies and ranges from 3 to 41% [1,4,8]. Several methodological differences may explain this discrepancy, such as the regimen of ultrasound scans, the definition of abnormality on cranial ultrasound, and the number of patients included in each study. The detection of cystic PVL is known to be less reliable when only a few scans are performed during the neonatal period, because up to one third of
severe cerebral lesions may then be missed. A restricted ultrasound regimen may lead to an underestimation of adverse outcome in TTTS survivors. In a large prospective study performed at our center, using an intensive ultrasound regimen that consisted of almost weekly ultrasound scans until term age, we found a 14% incidence of severe cerebral lesions in TTTS survivors after laser surgery [4]. Cerebral injury is reported to occur less frequently in TTTS survivors treated with laser surgery than with serial amnioreduction [1]. In the randomized trial by Senat et al., infants in the laser group had a lower incidence of cystic PVL than in the amnioreduction group (6% vs. 14%, p = 0.02) [1]. Of note, the definition of cystic PVL was restricted to the most severe cases of leukomalacia with very large cysts (≥grade 3), suggesting that the true incidence of cystic PVL (including grade 2) in this study was even higher in both groups. Given the increased risk of cerebral injury, cranial ultrasound scans should be performed routinely in all TTTS survivors at birth. Nevertheless, although cranial ultrasound scanning is useful in the detection of cerebral injury, its sensitivity for subsequent neurologic deficit is not high. Accurate neurologic and developmental outcome in TTTS can only be assessed with complete and structured long-term follow-up examination (see next review on long-term outcome in TTTS by van Klink et al.).
4. Cardiovascular morbidity and right ventricular outflow tract obstruction (RVOTO) Cardiovascular complications occur more frequently in monochorionic twins than in singletons, 3.8% versus 0.6% respectively, and are mostly due to cardiac dysfunction occurring in twins with TTTS [9,10]. Congenital heart disease occurs 12 times more frequently in TTTS than in the general population and is found mainly in recipient twins. Reported cardiovascular morbidity can be transient, progressive and sometimes persist beyond the neonatal period and includes fetal and neonatal hypertension, persistent pulmonary hypertension of the neonate (PPHN), tricuspid regurgitation, left chamber myocardial infarction, pulmonary artery calcification and RVOTO [9,10]. Two theories have been postulated to explain the pathogenesis of cardiovascular morbidity in recipients with TTTS. The first theory suggests that cardiovascular complications are a consequence of increased preload due to chronic hypervolemia causing cardiac hypertrophy [9,10]. The second theory states that cardiovascular morbidity is due to an increased afterload induced by elevated levels of vasoconstrictive substances such as endothelin-1 found in recipients [9,10]. Higher rates of hypertension reported in recipients may support this second theory [3,11]. Whether cardiomyopathy in the recipient is primarily due to increased afterload or increased preload, is still open for debate. Biventricular hypertrophy with prevalent left ventricular hypertrophic cardiomyopathy may be present in 40 to 100% of the recipient twins depending on the criteria [9]. Fetal hypertrophic cardiomyopathy may lead to fetal hydrops in 10 to 15% of recipient twins. Nevertheless, hypertrophic cardiomyopathy appears to be reversible in most cases after delivery. Cardiac hypertrophy may also lead to a functional obstruction of the outflow tract of the right ventricle, due to valvular or subvalvular pulmonary stenosis. RVOTO occurs in 4 to 11% of recipients and is associated with high mortality rates [10]. RVOTO may be progressive and require urgent treatment with pulmonary balloon valvuloplasty or surgery after birth [10]. Neonatologists must be aware of the risk of RVOTO in recipient twins because prompt diagnosis and treatment are of paramount importance. Improvement of cardiac function after delivery is also often reported in recipient twins, suggesting that removal of the causal factors helps the heart function to recover. Whether the risk of RVOTO is lower in TTTS cases treated with laser compared to TTTS cases treated with amnioreduction is not well known.
E. Lopriore et al. / Early Human Development 87 (2011) 595–599 Table 1 Postnatal TAPS classification. Stage Stage Stage Stage Stage Stage
Intertwin hemoglobin difference 1 2 3 4 5
N 8.0 g/dL N11.0 g/dL N14.0 g/dL N17.0 g/dL N20.0 g/dL
5. Renal morbidity Various renal complications have been reported in TTTS, mostly in donor twins, and include renal cortical necrosis and fibrosis, transient renal insufficiency and hematuria, acute renal failure requiring longterm peritoneal dialysis, or permanent tubular dysfunction with polyuria due to renal tubular dysgenesis [12]. Autopsy studies in TTTS report that renal tubular dysgenesis, characterized by loss of proximal convoluted tubules, is found in almost 50% of donor twins [12]. The pathogenesis of glomerular and tubular injury is probably secondary to hypoxic–ischemic injury due to chronic prenatal renal hypoperfusion. Even though oliguric renal failure occurs frequently in donor twins, complete recovery of adequate renal function is usually reported [13]. Renal injury may also lead, sporadically, to the development of chronic renal insufficiency requiring dialysis and kidney transplantation [3]. The exact incidence of renal failure in TTTS is not well known and only few small studies have reported on the subject. In a small study in 33 TTTS twin pairs treated conservatively with amnioreduction, we found 2 donors with major renal morbidity. One of the donors died from terminal renal failure, the other child requires hemodialysis [3]. In a prospective study of 40 TTTS twin pairs treated with laser, we found no major renal morbidity and only one donor had symptoms of transient mild renal failure [2]. Recently, Beck et al. evaluated the longterm outcome of kidney function in a small study of 18 pairs of TTTS survivors after laser treatment and found no long-term impairment of renal function [14]. Despite severe alteration of renal function before antenatal treatment, laser surgery seems to protect TTTS survivors against permanent renal injury. Lenclen et al. recently published a study on the neonatal outcome in TTTS preterm neonates (24–34 weeks' gestation) who were treated with either amnioreduction or laser surgery and compared with dichorionic twins [15]. The reported incidence of renal failure in the amnioreduction group, laser group and dichorionic twins group was 20% (6/30), 7% (7/98) and 1% (3/239), respectively. These (limited) data show that TTTS may sporadically lead to (permanent) renal injury, particularly in TTTS treated with amnioreduction. Renal function should thus be monitored carefully at birth in donor twins with TTTS by measuring urine output and serial serum creatinine levels to rule out renal insufficiency. 6. Hematologic morbidity In the past, the definition of TTTS was based on an intertwin hemoglobin difference N 5 g/dL (in addition to a birth weight dis-
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cordance N 20%) [9]. These traditional postnatal criteria were inadequate and have been long been replaced by more accurate prenatal ultrasound criteria [9]. Moreover, studies with fetal blood sampling in TTTS pregnancies have shown that the hemoglobin levels in donors are not always lower than in recipients [9]. Nevertheless, large intertwin hemoglobin differences at birth may still be detected in TTTS and donors often require blood transfusions while recipient require treatment with partial exchange transfusion [2]. In TTTS treated with laser, large inter-twin hemoglobin differences at birth are often related to the presence of residual vascular anastomoses. We recently reported a new form of chronic feto-fetal transfusion, termed “twin anemia polycythemia sequence” (TAPS) [16]. TAPS may occur in 2– 13% of TTTS twins after laser and is characterized by chronic anemia (with reticulocytosis) in donors and polycythemia in recipients [16]. At birth, donors are often pale while recipients are often plethoric. The pathogenesis of TAPS is due to small residual arterio-venous (AV) anastomoses in the absence of twin oligo-polyhydramnios sequence (TOPS). Various criteria have been proposed for the postnatal diagnosis of TAPS using different nomograms to define anemia and polycythemia. We recently proposed the use of simplified diagnostic criteria and a classification system in order to stimulate uniformity and avoid discrepancies between centers in reporting TAPS rates (Tables 1–2) [16]. The proposed definition for postnatal TAPS includes an inter-twin Hb difference greater than 8.0 g/dL, and at least one of the following criteria: a reticulocyte count ratio N 1.7 and/or placenta injection with colored dye showing with only small (diameter b 1 mm) AV anastomoses (Fig. 1) [16]. Postnatal management of TAPS is based on blood transfusion in the anemic donor and partial exchange transfusion for the polycythemic recipient. In a recent case–control study, we found that thrombocytopenia (platelet count b 150 × 10 9/L) occurred more often in the TAPS group than in the control group of uncomplicated monochorionic twins matched for gestational age, 45% (17/38) versus 11% (11/38), respectively (p b 0.01) [16]. In the TAPS group, mean platelet count was significantly lower in recipients than in donors, 133 × 10 9/L versus 218 × 10 9/L, respectively (p b 0.01), probably due to polycythemia in recipients [16]. In another recently published case–control study, we found that the incidence of short-term neonatal morbidity in TAPS is similar to gestation age matched monochorionic twin controls [16].
7. Hepatic infarction and intestinal injury Injuries to abdominal organs have been reported in TTTS [9,17–21]. Two cases of perinatal hepatic infarction and thrombo-embolic liver calcifications after TTTS have been described [9,18]. In addition, several cases of ileal and jejunal atresia in TTTS have been published [17–21]. Several mechanisms have been postulated to explain the possible association between intestinal atresia and TTTS, including mesenteric ischemia due to hypoperfusion (in donors) and hyperviscosity (in recipients), hemodynamic alterations and embolic phenomenon after laser. Most cases (75%, 6/8) occurred in recipient twins after fetoscopic laser surgery (75%, 6/8) (see Table 2). However, a cause and effect relationship with several risk factors (such as recipient-status and
Table 2 Intestinal atresia and perforation reported in TTTS infants. Authors (year) ref
TTTS-treatment
Affected twin
Intestinal injury
Outcome
Arul et al. (2001) [17] Arul et al. (2001) [17] Philip et al. (2002) [21] Philip et al. (2002) [21] Schnater et al. (2005) [18] Morikawa et al. (2008) [20] Saura et al. (2010) [19] Saura et al. (2010) [19]
Laser surgery Laser surgery None Amnioreduction Laser surgery Laser surgery Laser surgery Laser surgery
Recipient Recipient Donor Recipient Recipient Recipient Recipient Donor
Ileal atresia Ileal atresia Intestinal perforation Ileal perforation Ileal atresia Ileal atresia Ileal atresia Jejunal atresia
Uncomplicated recovery Uncomplicated recovery Neonatal death Uncomplicated recovery Uncomplicated recovery Neonatal death Uncomplicated recovery Uncomplicated recovery
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utero acquired defects of extremities are an extremely rare phenomenon, with a reported prevalence of lower leg deficiencies of 0.02%, suggesting a 10-fold higher prevalence in monochorionic twins [23]. Our study also shows that in utero acquired limb ischemia may occur in all monochorionic twins, with and without TTTS. Most pathophysiologic mechanisms proposed to explain these injuries are based on hemodynamic disturbances. Necrotic tissue injury and gangrene can result from vascular sludging and peripheral ischemia due to the polycythemia-hyperviscosity syndrome since most of these injuries occur in recipient twins [23]. Several other mechanisms have also been proposed including idiopathic thrombosis, thrombotic injury induced by laser-surgery, anomalous vasculature and umbilical artery steal phenomenon [23].
9. Amniotic band syndrome (ABS) Fig. 1. Characteristic TAPS placenta after color dye injection showing only one small arteriovenous anastomosis crossing the vascular equator. Note the color difference between the pale placenta share of the donor twin (left side of the picture) and the plethoric placental share of the recipient twin (right side of the picture).
laser surgery) is difficult to establish due to the small number of patients. Detlefsen reported 4 TTTS infants with necrotizing enterocolitis (NEC) and perforation of the distal ileum [22]. The authors suggest that NEC may occur more often in TTTS, particularly in donor twins, due to hypoperfusion of the gastrointestinal tract with consecutive hypoxemic damage [22]. In both cases, the two sets of twins were born extremely prematurely (at respectively 25 and 27 weeks' gestation). Whether NEC resulted primarily from TTTS or from extreme prematurity is impossible to discern. 8. In utero acquired limb ischemia Antenatal hypoxic–ischemic injury leading to lower limb necrosis has been described in several TTTS-cases, mainly in recipient twins. In a large study of 775 monochorionic twin pregnancies with and without TTTS assessed at our center and the University Hospital in Leuven (Belgium), we found a 0.26% (4/1550) prevalence of in utero acquired limb ischemia (per fetus) [23]. An ischemic defect of the right upper limb was detected in two recipient twins in the TTTS group (Fig. 2), whereas an ischemic defect of the right lower limb was found in two infants in the group without TTTS. In the general population, in
Fig. 2. In utero acquired ischemic defect of the right hand in a TTTS-survivor.
Several cases of ABS have recently been reported in TTTS [24–26]. ABS is a serious but rare iatrogenic complication which may occur after an invasive procedure for TTTS, due to disruption of the amniotic membrane (amniocentesis, amnioreduction or septostomy). Rujiwetpongstorn et al. reported a case of severe ABS in TTTS treated with septostomy and amnioreduction, leading to cord amputation of the donor twin [24]. The deceased donor had pieces of membrane tightening both legs. The right thigh became entangled in the bands connecting to the umbilical cord of the live fetus. In two recent retrospective cohort-studies of TTTS treated with laser surgery, Winer et al. and Habli et al. reported an incidence of ABS of 1.8% (8/438) and 3.3% (5/152), respectively [25,26]. All the affected cases in the series from Winer et al. were recipient twin [25]. However, in a recent case of ABS detected at our center, the affected twin was the donor twin. Amniotic bands were wrapped around the toes of both feet of the donor and leading to the amputation of a number of those (Fig. 3). Whether ABS occurs more often in TTTS treated with amnioreduction, septostomy or laser surgery is not known.
10. Congenital skin loss or Aplasia cutis congenital (ACC) Congenital skin loss of the lower extremity was reported in monochorionic twins treated with laser surgery for TTTS, [27]. Whether skin loss was caused by endoscopic laser surgery is not clear. Two other cases of ACC have recently been reported in monochorionic twins treated with interstitial laser therapy for fetal reduction [28]. However, in both cases fetal reduction was not performed for TTTS. ACC is known to occur more frequently in monochorionic twins, independently of the presence of TTTS and treatment with endoscopic laser surgery [28]. The pathophysiologic mechanisms leading to ACC in monochorionic twins are not well known.
Fig. 3. Amniotic bands wrapped around several toes of the left foot of a TTTS-survivor.
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11. Conclusions TTTS is associated with an increased risk of neonatal mortality and morbidity. Considering the high incidence of cerebral injury, serial neonatal cranial scans and careful neurodevelopmental follow-up are strongly advised in all surviving twins to rule out severe neurological disabilities. Pediatricians should also be aware of other complications in TTTS survivors, such as PPHN, RVOTO, renal failure, intestinal ischemic diseases, in utero acquired limb ischemia and ABS. Increased awareness may improve neonatal care for these children. Lastly, continuing close collaboration between obstetricians and neonatologists is crucial in order to improve care of infants with TTTS. 12. Key guidelines • TTTS survivors are at increased risk for cerebral injury (mostly cystic PVL) and require accurate follow-up investigations after birth. • TTTS survivors are at increased risk for rare morbidity including PPHN, RVOTO, renal failure, intestinal ischemic diseases, in utero acquired limb ischemia and amniotic band syndrome. 13. Research directions • Detailed and sequential imaging studies (including fetal MRI studies) may shed more light on the timing, incidence and risk factors of cerebral injury in TTTS treated with and without laser surgery • More and larger long-term follow-up studies (until school age) are needed to determine the incidence and risk factors in TTTS, treated with and without laser surgery. References [1] Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004;351:136–44. [2] Lopriore E, Sueters M, Middeldorp JM, Oepkes D, Vandenbussche FP, Walther FJ. Neonatal outcome in twin-to-twin transfusion syndrome treated with fetoscopic laser occlusion of vascular anastomoses. J Pediatr 2005;147:597–602. [3] Lopriore E, Nagel HT, Vandenbussche FP, Walther FJ. Long-term neurodevelopmental outcome in twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2003;189:1314–9. [4] Lopriore E, Wezel-Meijler G, Middeldorp JM, Sueters M, Vandenbussche FP, Walther FJ. Incidence, origin, and character of cerebral injury in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery. Am J Obstet Gynecol 2006;194:1215–20. [5] Steggerda S, Lopriore E, Sueters M, Bartelings M, Vandenbussche F, Walther F. Twin-to-twin transfusion syndrome, vein of galen malformation, and transposition of the great arteries in a pair of monochorionic twins: coincidence or related association? Pediatr Dev Pathol 2006;9:52–5. [6] Sugama S, Kusano K. Monozygous twin with polymicrogyria and normal co-twin. Pediatr Neurol 1994;11:62–3. [7] Banek CS, Hecher K, Hackeloer BJ, Bartmann P. 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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[8] Cincotta RB, Gray PH, Gardener G, Soong B, Chan FY. Selective fetoscopic laser ablation in 100 consecutive pregnancies with severe twin–twin transfusion syndrome. Aust N Z J Obstet Gynaecol 2009;49:22–7. [9] Lopriore E, Middeldorp JM, Sueters M, Vandenbussche FP, Walther FJ. Twin-totwin transfusion syndrome: from placental anastomoses to long-term neurodevelopmental outcome. Curr Pediatr Rev 2005;1:191–203. [10] Lopriore E, Bokenkamp R, Rijlaarsdam M, Sueters M, Vandenbussche FP, Walther FJ. Congenital heart disease in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery. Congenit Heart Dis 2007;2:38–43. [11] Mahieu-Caputo D, Salomon LJ, Le Bidois J, Fermont L, Brunhes A, Jouvet P, et al. Fetal hypertension: an insight into the pathogenesis of the twin–twin transfusion syndrome. Prenat Diagn 2003;23:640–5. [12] De Paepe ME, Stopa E, Huang C, Hansen K, Luks FI. Renal tubular apoptosis in twinto-twin transfusion syndrome. Pediatr Dev Pathol 2003;6:215–25. [13] Cincotta RB, Gray PH, Phythian G, Rogers YM, Chan FY. Long term outcome of twin–twin transfusion syndrome. Arch Dis Child Fetal Neonatal Ed 2000;83: F171–6. [14] Beck M, Graf C, Ellenrieder B, Bokenkamp A, Huber A, Hecher K, et al. Long-term outcome of kidney function after twin–twin transfusion syndrome treated by intrauterine laser coagulation. Pediatr Nephrol 2005;20:1657–9. [15] Lenclen R, Paupe A, Ciarlo G, Couderc S, Castela F, Ortqvist L, et al. Neonatal outcome in preterm monochorionic twins with twin-to-twin transfusion syndrome after intrauterine treatment with amnioreduction or fetoscopic laser surgery: comparison with dichorionic twins. Am J Obstet Gynecol 2007;196:450–7. [16] Slaghekke F, Kist WJ, Oepkes D, Pasman SA, Middeldorp JM, Klumper FJ, et al. Twin anemia–polycythemia sequence: diagnostic criteria, classification, perinatal management and outcome. Fetal Diagn Ther 2010;27:181–90. [17] Arul GS, Carroll S, Kyle PM, Soothill PW, Spicer RD. Intestinal complications associated with twin–twin transfusion syndrome after antenatal laser treatment: Report of two cases. J Pediatr Surg 2001;36:301–2. [18] Schnater JM, Zalen-Sprock RM, Schaap AH, Festen S, Aronson DC. Ileal atresia and thrombo-embolic liver calcifications diagnosed after treatment with intrauterine laser coagulation therapy for twin-to-twin transfusion syndrome: report of 2 cases. J Pediatr Surg 2005;40:875–6. [19] Saura L, Munoz ME, Castanon M, Eixarch E, Corradini M, Aguilar C, et al. Intestinal complications after antenatal fetoscopic laser ablation in twin-to-twin transfusion syndrome. J Pediatr Surg 2010;45:E5–8. [20] Morikawa M, Sago H, Yamada T, Hayashi S, Yamada T, Cho K, et al. Ileal atresia after fetoscopic laser photocoagulation for twin-to-twin transfusion syndrome—a case report. Prenat Diagn 2008;28:1072–4. [21] Philip I, Ford A, Haslam R. Congenital bowel perforation in twin-to-twin transfusion syndrome. Pediatr Surg Int 2002;18:733–4. [22] Detlefsen B, Boemers TM, Schimke C. Necrotizing enterocolitis in premature twins with twin-to-twin transfusion syndrome. Eur J Pediatr Surg 2008;18:50–2. [23] Lopriore E, Lewi L, Oepkes D, Debeer A, Vandenbussche FP, Deprest J, et al. In utero acquired limb ischemia in monochorionic twins with and without twin-to-twin transfusion syndrome. Prenat Diagn 2008;28:800–4. [24] Rujiwetpongstorn J, Tongsong T. Amniotic band syndrome following septostomy in management of twin–twin transfusion syndrome: a case report. J Perinatol 2008;28:377–9. [25] Winer N, Salomon LJ, Essaoui M, Nasr B, Bernard JP, Ville Y. Pseudoamniotic band syndrome: a rare complication of monochorionic twins with fetofetal transfusion syndrome treated by laser coagulation. Am J Obstet Gynecol 2008;198:393–5. [26] Habli M, Bombrys A, Lewis D, Lim FY, Polzin W, Maxwell R, et al. Incidence of complications in twin–twin transfusion syndrome after selective fetoscopic laser photocoagulation: a single-center experience. Am J Obstet Gynecol 2009;201:417. [27] Stone CA, Quinn MW, Saxby PJ. Congenital skin loss following Nd:YAG placental photocoagulation. Burns 1998;24:275–7. [28] O'Donoghue K, Barigye O, Pasquini L, Chappell L, Wimalasundera RC, Fisk NM. Interstitial laser therapy for fetal reduction in monochorionic multiple pregnancy: loss rate and association with aplasia cutis congenita. Prenat Diagn 2008;28: 535–43.
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
Best practice guidelines
Neonatal morbidity in twin–twin transfusion syndrome Enrico Lopriore a,⁎, Dick Oepkes b, 1, Frans J. Walther a, 2 a b
Division of Neonatology, Department of Pediatrics, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, The Netherlands Division of Fetal Medicine, Department of Obstetrics, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, The Netherlands
a r t i c l e
i n f o
Keywords: Twin–twin transfusion syndrome Monochorionic twins Laser surgery Amnioreduction Neonatal morbidity
a b s t r a c t Twin–twin transfusion syndrome (TTTS) is a severe complication of monochorionic twin pregnancies associated with high perinatal mortality and morbidity rates. Management in TTTS is a major challenge for obstetricians and neonatologists. Twins which are often born prematurely and may suffer from typical conditions associated with prematurity. In addition, surviving twins with TTTS are at increased risk for other complications including neurological, cardiovascular, renal and hematologic morbidity. Rare complications such as hypoxic–ischemic lesions to limbs or intestines and amniotic band syndrome have also been reported in TTTS survivors. This review focuses on the neonatal and pediatric mortality and morbidity in TTTS survivors, with special emphasis on the long-term neurodevelopmental outcome. © 2011 Elsevier Ireland Ltd. All rights reserved.
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . 2. Neonatal mortality . . . . . . . . . . . . . . . . . . . . 3. Cerebral injury and neurologic morbidity . . . . . . . . . 4. Cardiovascular morbidity and right ventricular outflow tract 5. Renal morbidity . . . . . . . . . . . . . . . . . . . . . 6. Hematologic morbidity . . . . . . . . . . . . . . . . . . 7. Hepatic infarction and intestinal injury . . . . . . . . . . 8. In utero acquired limb ischemia . . . . . . . . . . . . . 9. Amniotic band syndrome (ABS) . . . . . . . . . . . . . 10. Congenital skin loss or Aplasia cutis congenital (ACC) . . . 11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . 12. Key guidelines . . . . . . . . . . . . . . . . . . . . . 13. Research directions . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . obstruction (RVOTO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Twin-to-twin transfusion syndrome (TTTS) is a severe complication of monochorionic twin pregnancies which results from unbalanced intertwin blood transfusion through placental vascular anastomoses. TTTS is characterized by the presence of oligohydramnion in the donor twin and polyhydramnion in the recipient twin. If left
⁎ Corresponding author. Tel.: +31 71 5262909; fax: +31 71 5248198. E-mail addresses: [email protected] (E. Lopriore), [email protected] (D. Oepkes), [email protected] (F.J. Walther). 1 Tel.: +31 71 5269111; fax: +31 71 5248198. 2 Tel.: +31 71 5262909; fax: +31 71 5248198. 0378-3782/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2011.07.006
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untreated, TTTS is associated with very high perinatal mortality and morbidity rates. Recent developments in prenatal care strategies and management options for patients with TTTS have led to a significant decrease in perinatal mortality rates. Nevertheless, TTTS remains one of the most lethal conditions in perinatal medicine and the optimal management is still a major challenge for both obstetricians and neonatologists. As perinatal survival in TTTS improves, attention is shifting toward short- and long-term outcome in surviving children. Since monochorionic twins are often delivered prematurely, twins are at risk for morbidity associated with prematurity such as respiratory distress syndrome, chronic lung disease, necrotizing enterocolitis and cerebral injury including intraventricular hemorrhage and periventricular
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leukomalacia. In addition, TTTS-survivors are at risk for other complications including atypical cerebral lesions (e.g. arterial stroke), cardiac morbidity, renal failure and hematologic disorders. Rare complications such as hypoxic–ischemic lesions to limbs or intestines, amniotic band syndrome and congenital skin loss have also been reported in TTTS survivors. An increasing number of studies in TTTSsurvivors are gradually shedding more light on the wide range of morbidity associated with TTTS. This review will focus on the neonatal outcome (mortality and morbidity) and neonatal management in TTTS survivors. 2. Neonatal mortality Several studies have shown that TTTS is associated with a high rate of neonatal mortality, ranging from 5 up to 29% [1,2]. Unfortunately, detailed information on the exact rates (and causes) is hard to discern since most outcome studies only mention the overall perinatal mortality rate (combined intrauterine and neonatal death), and fail to specify separately the neonatal mortality rate. Neonatal mortality rates appear to be higher in TTTS treated with amnioreduction compared to TTTS treated with laser surgery. The rate of neonatal mortality ranges from 14% to 29% in TTTS cases series treated with serial amnioreduction compared to 5 to 8% in TTTS cases series treated with laser [1,2]. In the Eurofetus trial, neonatal death was significantly higher in the amnioreduction group than in the laser group, 29% (41/140) versus 8% (12/144) (p b 0.01), respectively [1]. High mortality rates in TTTS are largely due to the high proportion of infants with extreme prematurity and very low birth weight [1–3]. Neonatal mortality in TTTS is also reported to be due to withdrawal of intensive care in cases with severe cerebral injury [1]. 3. Cerebral injury and neurologic morbidity Several studies report an increased risk of cerebral injury and neurologic morbidity in TTTS. Severe cerebral lesions detected in TTTS include cystic periventricular leukomalacia (PVL), cerebral whitematter cysts, severe intraventricular hemorrhage (IVH), ventricular dilatation and cerebral atrophy [3]. Arterial ischemic stroke has been diagnosed in neonatal survivors of TTTS [4]. In addition, sporadic reports of TTTS-cases associated with vein of Galen malformation or polymicrogyria have been published [5,6]. Minor lesions such as subependymal pseudocysts and lenticostriate vasculopathy have been described in monochorionic twins with TTTS [4]. The exact pathogenesis of cerebral injury in TTTS is not fully understood and can result from either antenatal or postnatal injury. Cerebral lesions detected antenatally are thought to be related to cerebral hemodynamic disturbances in utero [7]. Early neonatal brain scans show that antenatally acquired cerebral lesions occur in 10 to 35% of TTTS survivors compared to 3% in dichorionic twins and 2% in uncomplicated monochorionic twins [4]. Cerebral lesions may also be secondary to postnatal injury associated with extreme prematurity, which predisposes to cystic PVL and IVH. Donors and recipients appear to be equally at risk for cerebral injury [4]. Hypoxic–ischemic damage caused by cerebral hypoperfusion is probably the main cause for cerebral injury in donor twins, whereas hyperviscosity and polycythemia causing vascular sludging may be an important cause for cerebral injury in recipient twins. Sludging of polycythemic blood is also thought to be one of the causes of arterial stroke in recipient twins [4]. The incidence of cerebral lesions in TTTS varies greatly between the studies and ranges from 3 to 41% [1,4,8]. Several methodological differences may explain this discrepancy, such as the regimen of ultrasound scans, the definition of abnormality on cranial ultrasound, and the number of patients included in each study. The detection of cystic PVL is known to be less reliable when only a few scans are performed during the neonatal period, because up to one third of
severe cerebral lesions may then be missed. A restricted ultrasound regimen may lead to an underestimation of adverse outcome in TTTS survivors. In a large prospective study performed at our center, using an intensive ultrasound regimen that consisted of almost weekly ultrasound scans until term age, we found a 14% incidence of severe cerebral lesions in TTTS survivors after laser surgery [4]. Cerebral injury is reported to occur less frequently in TTTS survivors treated with laser surgery than with serial amnioreduction [1]. In the randomized trial by Senat et al., infants in the laser group had a lower incidence of cystic PVL than in the amnioreduction group (6% vs. 14%, p = 0.02) [1]. Of note, the definition of cystic PVL was restricted to the most severe cases of leukomalacia with very large cysts (≥grade 3), suggesting that the true incidence of cystic PVL (including grade 2) in this study was even higher in both groups. Given the increased risk of cerebral injury, cranial ultrasound scans should be performed routinely in all TTTS survivors at birth. Nevertheless, although cranial ultrasound scanning is useful in the detection of cerebral injury, its sensitivity for subsequent neurologic deficit is not high. Accurate neurologic and developmental outcome in TTTS can only be assessed with complete and structured long-term follow-up examination (see next review on long-term outcome in TTTS by van Klink et al.).
4. Cardiovascular morbidity and right ventricular outflow tract obstruction (RVOTO) Cardiovascular complications occur more frequently in monochorionic twins than in singletons, 3.8% versus 0.6% respectively, and are mostly due to cardiac dysfunction occurring in twins with TTTS [9,10]. Congenital heart disease occurs 12 times more frequently in TTTS than in the general population and is found mainly in recipient twins. Reported cardiovascular morbidity can be transient, progressive and sometimes persist beyond the neonatal period and includes fetal and neonatal hypertension, persistent pulmonary hypertension of the neonate (PPHN), tricuspid regurgitation, left chamber myocardial infarction, pulmonary artery calcification and RVOTO [9,10]. Two theories have been postulated to explain the pathogenesis of cardiovascular morbidity in recipients with TTTS. The first theory suggests that cardiovascular complications are a consequence of increased preload due to chronic hypervolemia causing cardiac hypertrophy [9,10]. The second theory states that cardiovascular morbidity is due to an increased afterload induced by elevated levels of vasoconstrictive substances such as endothelin-1 found in recipients [9,10]. Higher rates of hypertension reported in recipients may support this second theory [3,11]. Whether cardiomyopathy in the recipient is primarily due to increased afterload or increased preload, is still open for debate. Biventricular hypertrophy with prevalent left ventricular hypertrophic cardiomyopathy may be present in 40 to 100% of the recipient twins depending on the criteria [9]. Fetal hypertrophic cardiomyopathy may lead to fetal hydrops in 10 to 15% of recipient twins. Nevertheless, hypertrophic cardiomyopathy appears to be reversible in most cases after delivery. Cardiac hypertrophy may also lead to a functional obstruction of the outflow tract of the right ventricle, due to valvular or subvalvular pulmonary stenosis. RVOTO occurs in 4 to 11% of recipients and is associated with high mortality rates [10]. RVOTO may be progressive and require urgent treatment with pulmonary balloon valvuloplasty or surgery after birth [10]. Neonatologists must be aware of the risk of RVOTO in recipient twins because prompt diagnosis and treatment are of paramount importance. Improvement of cardiac function after delivery is also often reported in recipient twins, suggesting that removal of the causal factors helps the heart function to recover. Whether the risk of RVOTO is lower in TTTS cases treated with laser compared to TTTS cases treated with amnioreduction is not well known.
E. Lopriore et al. / Early Human Development 87 (2011) 595–599 Table 1 Postnatal TAPS classification. Stage Stage Stage Stage Stage Stage
Intertwin hemoglobin difference 1 2 3 4 5
N 8.0 g/dL N11.0 g/dL N14.0 g/dL N17.0 g/dL N20.0 g/dL
5. Renal morbidity Various renal complications have been reported in TTTS, mostly in donor twins, and include renal cortical necrosis and fibrosis, transient renal insufficiency and hematuria, acute renal failure requiring longterm peritoneal dialysis, or permanent tubular dysfunction with polyuria due to renal tubular dysgenesis [12]. Autopsy studies in TTTS report that renal tubular dysgenesis, characterized by loss of proximal convoluted tubules, is found in almost 50% of donor twins [12]. The pathogenesis of glomerular and tubular injury is probably secondary to hypoxic–ischemic injury due to chronic prenatal renal hypoperfusion. Even though oliguric renal failure occurs frequently in donor twins, complete recovery of adequate renal function is usually reported [13]. Renal injury may also lead, sporadically, to the development of chronic renal insufficiency requiring dialysis and kidney transplantation [3]. The exact incidence of renal failure in TTTS is not well known and only few small studies have reported on the subject. In a small study in 33 TTTS twin pairs treated conservatively with amnioreduction, we found 2 donors with major renal morbidity. One of the donors died from terminal renal failure, the other child requires hemodialysis [3]. In a prospective study of 40 TTTS twin pairs treated with laser, we found no major renal morbidity and only one donor had symptoms of transient mild renal failure [2]. Recently, Beck et al. evaluated the longterm outcome of kidney function in a small study of 18 pairs of TTTS survivors after laser treatment and found no long-term impairment of renal function [14]. Despite severe alteration of renal function before antenatal treatment, laser surgery seems to protect TTTS survivors against permanent renal injury. Lenclen et al. recently published a study on the neonatal outcome in TTTS preterm neonates (24–34 weeks' gestation) who were treated with either amnioreduction or laser surgery and compared with dichorionic twins [15]. The reported incidence of renal failure in the amnioreduction group, laser group and dichorionic twins group was 20% (6/30), 7% (7/98) and 1% (3/239), respectively. These (limited) data show that TTTS may sporadically lead to (permanent) renal injury, particularly in TTTS treated with amnioreduction. Renal function should thus be monitored carefully at birth in donor twins with TTTS by measuring urine output and serial serum creatinine levels to rule out renal insufficiency. 6. Hematologic morbidity In the past, the definition of TTTS was based on an intertwin hemoglobin difference N 5 g/dL (in addition to a birth weight dis-
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cordance N 20%) [9]. These traditional postnatal criteria were inadequate and have been long been replaced by more accurate prenatal ultrasound criteria [9]. Moreover, studies with fetal blood sampling in TTTS pregnancies have shown that the hemoglobin levels in donors are not always lower than in recipients [9]. Nevertheless, large intertwin hemoglobin differences at birth may still be detected in TTTS and donors often require blood transfusions while recipient require treatment with partial exchange transfusion [2]. In TTTS treated with laser, large inter-twin hemoglobin differences at birth are often related to the presence of residual vascular anastomoses. We recently reported a new form of chronic feto-fetal transfusion, termed “twin anemia polycythemia sequence” (TAPS) [16]. TAPS may occur in 2– 13% of TTTS twins after laser and is characterized by chronic anemia (with reticulocytosis) in donors and polycythemia in recipients [16]. At birth, donors are often pale while recipients are often plethoric. The pathogenesis of TAPS is due to small residual arterio-venous (AV) anastomoses in the absence of twin oligo-polyhydramnios sequence (TOPS). Various criteria have been proposed for the postnatal diagnosis of TAPS using different nomograms to define anemia and polycythemia. We recently proposed the use of simplified diagnostic criteria and a classification system in order to stimulate uniformity and avoid discrepancies between centers in reporting TAPS rates (Tables 1–2) [16]. The proposed definition for postnatal TAPS includes an inter-twin Hb difference greater than 8.0 g/dL, and at least one of the following criteria: a reticulocyte count ratio N 1.7 and/or placenta injection with colored dye showing with only small (diameter b 1 mm) AV anastomoses (Fig. 1) [16]. Postnatal management of TAPS is based on blood transfusion in the anemic donor and partial exchange transfusion for the polycythemic recipient. In a recent case–control study, we found that thrombocytopenia (platelet count b 150 × 10 9/L) occurred more often in the TAPS group than in the control group of uncomplicated monochorionic twins matched for gestational age, 45% (17/38) versus 11% (11/38), respectively (p b 0.01) [16]. In the TAPS group, mean platelet count was significantly lower in recipients than in donors, 133 × 10 9/L versus 218 × 10 9/L, respectively (p b 0.01), probably due to polycythemia in recipients [16]. In another recently published case–control study, we found that the incidence of short-term neonatal morbidity in TAPS is similar to gestation age matched monochorionic twin controls [16].
7. Hepatic infarction and intestinal injury Injuries to abdominal organs have been reported in TTTS [9,17–21]. Two cases of perinatal hepatic infarction and thrombo-embolic liver calcifications after TTTS have been described [9,18]. In addition, several cases of ileal and jejunal atresia in TTTS have been published [17–21]. Several mechanisms have been postulated to explain the possible association between intestinal atresia and TTTS, including mesenteric ischemia due to hypoperfusion (in donors) and hyperviscosity (in recipients), hemodynamic alterations and embolic phenomenon after laser. Most cases (75%, 6/8) occurred in recipient twins after fetoscopic laser surgery (75%, 6/8) (see Table 2). However, a cause and effect relationship with several risk factors (such as recipient-status and
Table 2 Intestinal atresia and perforation reported in TTTS infants. Authors (year) ref
TTTS-treatment
Affected twin
Intestinal injury
Outcome
Arul et al. (2001) [17] Arul et al. (2001) [17] Philip et al. (2002) [21] Philip et al. (2002) [21] Schnater et al. (2005) [18] Morikawa et al. (2008) [20] Saura et al. (2010) [19] Saura et al. (2010) [19]
Laser surgery Laser surgery None Amnioreduction Laser surgery Laser surgery Laser surgery Laser surgery
Recipient Recipient Donor Recipient Recipient Recipient Recipient Donor
Ileal atresia Ileal atresia Intestinal perforation Ileal perforation Ileal atresia Ileal atresia Ileal atresia Jejunal atresia
Uncomplicated recovery Uncomplicated recovery Neonatal death Uncomplicated recovery Uncomplicated recovery Neonatal death Uncomplicated recovery Uncomplicated recovery
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utero acquired defects of extremities are an extremely rare phenomenon, with a reported prevalence of lower leg deficiencies of 0.02%, suggesting a 10-fold higher prevalence in monochorionic twins [23]. Our study also shows that in utero acquired limb ischemia may occur in all monochorionic twins, with and without TTTS. Most pathophysiologic mechanisms proposed to explain these injuries are based on hemodynamic disturbances. Necrotic tissue injury and gangrene can result from vascular sludging and peripheral ischemia due to the polycythemia-hyperviscosity syndrome since most of these injuries occur in recipient twins [23]. Several other mechanisms have also been proposed including idiopathic thrombosis, thrombotic injury induced by laser-surgery, anomalous vasculature and umbilical artery steal phenomenon [23].
9. Amniotic band syndrome (ABS) Fig. 1. Characteristic TAPS placenta after color dye injection showing only one small arteriovenous anastomosis crossing the vascular equator. Note the color difference between the pale placenta share of the donor twin (left side of the picture) and the plethoric placental share of the recipient twin (right side of the picture).
laser surgery) is difficult to establish due to the small number of patients. Detlefsen reported 4 TTTS infants with necrotizing enterocolitis (NEC) and perforation of the distal ileum [22]. The authors suggest that NEC may occur more often in TTTS, particularly in donor twins, due to hypoperfusion of the gastrointestinal tract with consecutive hypoxemic damage [22]. In both cases, the two sets of twins were born extremely prematurely (at respectively 25 and 27 weeks' gestation). Whether NEC resulted primarily from TTTS or from extreme prematurity is impossible to discern. 8. In utero acquired limb ischemia Antenatal hypoxic–ischemic injury leading to lower limb necrosis has been described in several TTTS-cases, mainly in recipient twins. In a large study of 775 monochorionic twin pregnancies with and without TTTS assessed at our center and the University Hospital in Leuven (Belgium), we found a 0.26% (4/1550) prevalence of in utero acquired limb ischemia (per fetus) [23]. An ischemic defect of the right upper limb was detected in two recipient twins in the TTTS group (Fig. 2), whereas an ischemic defect of the right lower limb was found in two infants in the group without TTTS. In the general population, in
Fig. 2. In utero acquired ischemic defect of the right hand in a TTTS-survivor.
Several cases of ABS have recently been reported in TTTS [24–26]. ABS is a serious but rare iatrogenic complication which may occur after an invasive procedure for TTTS, due to disruption of the amniotic membrane (amniocentesis, amnioreduction or septostomy). Rujiwetpongstorn et al. reported a case of severe ABS in TTTS treated with septostomy and amnioreduction, leading to cord amputation of the donor twin [24]. The deceased donor had pieces of membrane tightening both legs. The right thigh became entangled in the bands connecting to the umbilical cord of the live fetus. In two recent retrospective cohort-studies of TTTS treated with laser surgery, Winer et al. and Habli et al. reported an incidence of ABS of 1.8% (8/438) and 3.3% (5/152), respectively [25,26]. All the affected cases in the series from Winer et al. were recipient twin [25]. However, in a recent case of ABS detected at our center, the affected twin was the donor twin. Amniotic bands were wrapped around the toes of both feet of the donor and leading to the amputation of a number of those (Fig. 3). Whether ABS occurs more often in TTTS treated with amnioreduction, septostomy or laser surgery is not known.
10. Congenital skin loss or Aplasia cutis congenital (ACC) Congenital skin loss of the lower extremity was reported in monochorionic twins treated with laser surgery for TTTS, [27]. Whether skin loss was caused by endoscopic laser surgery is not clear. Two other cases of ACC have recently been reported in monochorionic twins treated with interstitial laser therapy for fetal reduction [28]. However, in both cases fetal reduction was not performed for TTTS. ACC is known to occur more frequently in monochorionic twins, independently of the presence of TTTS and treatment with endoscopic laser surgery [28]. The pathophysiologic mechanisms leading to ACC in monochorionic twins are not well known.
Fig. 3. Amniotic bands wrapped around several toes of the left foot of a TTTS-survivor.
E. Lopriore et al. / Early Human Development 87 (2011) 595–599
11. Conclusions TTTS is associated with an increased risk of neonatal mortality and morbidity. Considering the high incidence of cerebral injury, serial neonatal cranial scans and careful neurodevelopmental follow-up are strongly advised in all surviving twins to rule out severe neurological disabilities. Pediatricians should also be aware of other complications in TTTS survivors, such as PPHN, RVOTO, renal failure, intestinal ischemic diseases, in utero acquired limb ischemia and ABS. Increased awareness may improve neonatal care for these children. Lastly, continuing close collaboration between obstetricians and neonatologists is crucial in order to improve care of infants with TTTS. 12. Key guidelines • TTTS survivors are at increased risk for cerebral injury (mostly cystic PVL) and require accurate follow-up investigations after birth. • TTTS survivors are at increased risk for rare morbidity including PPHN, RVOTO, renal failure, intestinal ischemic diseases, in utero acquired limb ischemia and amniotic band syndrome. 13. Research directions • Detailed and sequential imaging studies (including fetal MRI studies) may shed more light on the timing, incidence and risk factors of cerebral injury in TTTS treated with and without laser surgery • More and larger long-term follow-up studies (until school age) are needed to determine the incidence and risk factors in TTTS, treated with and without laser surgery. References [1] Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004;351:136–44. [2] Lopriore E, Sueters M, Middeldorp JM, Oepkes D, Vandenbussche FP, Walther FJ. Neonatal outcome in twin-to-twin transfusion syndrome treated with fetoscopic laser occlusion of vascular anastomoses. J Pediatr 2005;147:597–602. [3] Lopriore E, Nagel HT, Vandenbussche FP, Walther FJ. Long-term neurodevelopmental outcome in twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2003;189:1314–9. [4] Lopriore E, Wezel-Meijler G, Middeldorp JM, Sueters M, Vandenbussche FP, Walther FJ. Incidence, origin, and character of cerebral injury in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery. Am J Obstet Gynecol 2006;194:1215–20. [5] Steggerda S, Lopriore E, Sueters M, Bartelings M, Vandenbussche F, Walther F. Twin-to-twin transfusion syndrome, vein of galen malformation, and transposition of the great arteries in a pair of monochorionic twins: coincidence or related association? Pediatr Dev Pathol 2006;9:52–5. [6] Sugama S, Kusano K. Monozygous twin with polymicrogyria and normal co-twin. Pediatr Neurol 1994;11:62–3. [7] Banek CS, Hecher K, Hackeloer BJ, Bartmann P. Long-term neurodevelopmental outcome after intrauterine laser treatment for severe twin–twin transfusion syndrome. Am J Obstet Gynecol 2003;188:876–80.
599
[8] Cincotta RB, Gray PH, Gardener G, Soong B, Chan FY. Selective fetoscopic laser ablation in 100 consecutive pregnancies with severe twin–twin transfusion syndrome. Aust N Z J Obstet Gynaecol 2009;49:22–7. [9] Lopriore E, Middeldorp JM, Sueters M, Vandenbussche FP, Walther FJ. Twin-totwin transfusion syndrome: from placental anastomoses to long-term neurodevelopmental outcome. Curr Pediatr Rev 2005;1:191–203. [10] Lopriore E, Bokenkamp R, Rijlaarsdam M, Sueters M, Vandenbussche FP, Walther FJ. Congenital heart disease in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery. Congenit Heart Dis 2007;2:38–43. [11] Mahieu-Caputo D, Salomon LJ, Le Bidois J, Fermont L, Brunhes A, Jouvet P, et al. Fetal hypertension: an insight into the pathogenesis of the twin–twin transfusion syndrome. Prenat Diagn 2003;23:640–5. [12] De Paepe ME, Stopa E, Huang C, Hansen K, Luks FI. Renal tubular apoptosis in twinto-twin transfusion syndrome. Pediatr Dev Pathol 2003;6:215–25. [13] Cincotta RB, Gray PH, Phythian G, Rogers YM, Chan FY. Long term outcome of twin–twin transfusion syndrome. Arch Dis Child Fetal Neonatal Ed 2000;83: F171–6. [14] Beck M, Graf C, Ellenrieder B, Bokenkamp A, Huber A, Hecher K, et al. Long-term outcome of kidney function after twin–twin transfusion syndrome treated by intrauterine laser coagulation. Pediatr Nephrol 2005;20:1657–9. [15] Lenclen R, Paupe A, Ciarlo G, Couderc S, Castela F, Ortqvist L, et al. Neonatal outcome in preterm monochorionic twins with twin-to-twin transfusion syndrome after intrauterine treatment with amnioreduction or fetoscopic laser surgery: comparison with dichorionic twins. Am J Obstet Gynecol 2007;196:450–7. [16] Slaghekke F, Kist WJ, Oepkes D, Pasman SA, Middeldorp JM, Klumper FJ, et al. Twin anemia–polycythemia sequence: diagnostic criteria, classification, perinatal management and outcome. Fetal Diagn Ther 2010;27:181–90. [17] Arul GS, Carroll S, Kyle PM, Soothill PW, Spicer RD. Intestinal complications associated with twin–twin transfusion syndrome after antenatal laser treatment: Report of two cases. J Pediatr Surg 2001;36:301–2. [18] Schnater JM, Zalen-Sprock RM, Schaap AH, Festen S, Aronson DC. Ileal atresia and thrombo-embolic liver calcifications diagnosed after treatment with intrauterine laser coagulation therapy for twin-to-twin transfusion syndrome: report of 2 cases. J Pediatr Surg 2005;40:875–6. [19] Saura L, Munoz ME, Castanon M, Eixarch E, Corradini M, Aguilar C, et al. Intestinal complications after antenatal fetoscopic laser ablation in twin-to-twin transfusion syndrome. J Pediatr Surg 2010;45:E5–8. [20] Morikawa M, Sago H, Yamada T, Hayashi S, Yamada T, Cho K, et al. Ileal atresia after fetoscopic laser photocoagulation for twin-to-twin transfusion syndrome—a case report. Prenat Diagn 2008;28:1072–4. [21] Philip I, Ford A, Haslam R. Congenital bowel perforation in twin-to-twin transfusion syndrome. Pediatr Surg Int 2002;18:733–4. [22] Detlefsen B, Boemers TM, Schimke C. Necrotizing enterocolitis in premature twins with twin-to-twin transfusion syndrome. Eur J Pediatr Surg 2008;18:50–2. [23] Lopriore E, Lewi L, Oepkes D, Debeer A, Vandenbussche FP, Deprest J, et al. In utero acquired limb ischemia in monochorionic twins with and without twin-to-twin transfusion syndrome. Prenat Diagn 2008;28:800–4. [24] Rujiwetpongstorn J, Tongsong T. Amniotic band syndrome following septostomy in management of twin–twin transfusion syndrome: a case report. J Perinatol 2008;28:377–9. [25] Winer N, Salomon LJ, Essaoui M, Nasr B, Bernard JP, Ville Y. Pseudoamniotic band syndrome: a rare complication of monochorionic twins with fetofetal transfusion syndrome treated by laser coagulation. Am J Obstet Gynecol 2008;198:393–5. [26] Habli M, Bombrys A, Lewis D, Lim FY, Polzin W, Maxwell R, et al. Incidence of complications in twin–twin transfusion syndrome after selective fetoscopic laser photocoagulation: a single-center experience. Am J Obstet Gynecol 2009;201:417. [27] Stone CA, Quinn MW, Saxby PJ. Congenital skin loss following Nd:YAG placental photocoagulation. Burns 1998;24:275–7. [28] O'Donoghue K, Barigye O, Pasquini L, Chappell L, Wimalasundera RC, Fisk NM. Interstitial laser therapy for fetal reduction in monochorionic multiple pregnancy: loss rate and association with aplasia cutis congenita. Prenat Diagn 2008;28: 535–43.