Twin-to-twin transfusion syndrome : from placental anastomoses to long term outcome

Lopriore, E. (2006)

Doctoral Thesis

Twin-to-twin transfusion syndrome (TTTS) is a severe complication of monochorionic twin pregnancies associated with high perinatal mortality and morbidity rates. Placental vascular anastomoses, almost invariably present in monochorionic placentas, are the essential anatomical substrate for the development of TTTS. TTTS is thought to result from unbalanced inter-twin blood flow between the donor twin and the recipient twin through the vascular anastomoses, leading to hypovolemia and oligohydramnios in the donor and hypervolemia and polyhydramnios in the recipient. Despite significant developments in the diagnosis, staging and management of TTTS, the pathogenesis of TTTS is still poorly understood and, most importantly, perinatal mortality and morbidity in TTTS remain strikingly high. In this thesis, several studies on TTTS are presented regarding various aspects of this disease, including studies on monochorionic placentas to investigate the pathogenesis of TTTS, description of a new form of chronic TTTS and the short and long-term outcome in TTTS treated with fetoscopic laser surgery. In Chapter 2, an overview of the literature is presented. This review analyzes the possible pathophysiologic mechanisms involved, discusses the latest findings in diagnosis, therapy and prognosis, and focuses on neonatal and pediatric morbidity associated with TTTS. In Chapter 3 we describe a novel technique to calculate the net feto-fetal blood flow through placental arterio-venous anastomoses in a case of TTTS treated with laser surgery and subsequent intrauterine transfusion. In this study we determined that the net blood flow through the five unidirectional arterio-venous anastomoses was approximately 28 ml/24h, much lower than previously measured with Doppler ultrasound. This finding may also explain the inaccuracy of Doppler flow measurements, as such low flow velocities cannot possibly be detected with current Doppler techniques. Measurements of anastomotic blood flow are of major importance for the validation and development of accurate computer modeling in TTTS. In Chapter 4 we studied the role of velamentous cord insertion and discordant placental sharing in the pathogenesis of TTTS by comparing monochorionic placentas with and without TTTS. Previously, several studies reported an increased incidence of velamentous cord insertions in TTTS placentas and suggested a direct relation between velamentous cord insertion, unequal placental sharing and the development of TTTS. In this study we examined 76 monochorionic placentas with TTTS and 63 monochorionic placentas without TTTS. The incidence of velamentous cord insertion (per fetus) in the TTTS group and the no-TTTS group was 13% and 14% (p = 0.79), respectively. Placental sharing discordance in the TTTS group and the no-TTTS group was 20% in both groups (p = 0.83). In the TTTS group, donor twins had more often a velamentous cord insertion than recipient twins (24% and 3%, respectively, P < 0.001) and smaller placental shares (44% and 56% respectively, p < 0.001)). Our findings suggest that velamentous cord insertion and smaller placental share in donor twins are a consequence of developing TTTS, rather than a cause of TTTS. In Chapter 5 the frequency of residual placental vascular anastomoses after fetoscopic laser surgery for TTTS was studied. Presence of residual anastomoses was investigated in relation to adverse outcome and to intertwin hemoglobin difference at birth. Residual anastomoses were detected in 33% (17/52) of placentas. Adverse outcome (fetal demise, neonatal death or severe cerebral injury) was similar in the groups with and without residual anastomoses, 18% (6/34) and 29% (20/70), respectively (p = 0.23). Large inter-twin hemoglobin differences (> 5 g/dL) were found in 65% (11/17) of cases with residual anastomoses and 20% (7/35) of cases without residual anastomoses (p < 0.01). The first conclusion of this study is that laser treatment needs to be improved as only 2/3 of monochorionic placentas are functionally __dichorionized__. The second conclusion is that residual anastomoses in this study are not associated with adverse outcome. Lack of association between residual anastomoses and adverse outcome may partly be due to the small size of the majority of residual anastomoses (< 1mm diameter in 64% of the cases) and the presence of __protective__ residual superficial anastomoses in 35% of the cases. Finally, we concluded that residual anastomoses are often associated with neonatal hematological complications. In Chapter 6 we describe two pairs of monochorionic twins without TTTS but with marked discordant hemoglobin levels. We named this new form of TTTS, the twin anemia-polycythemia sequence (TAPS). In the two reported TAPS cases, both donor twins were severely anemic requiring blood transfusion and both recipients were polycythemic, one requiring partial volume exchange transfusions. Inter-twin difference in reticulocyte counts was extremely high, suggesting a chronic form of inter-twin blood transfusion. Placental injection studies revealed a preponderance of very small (< 1 mm) arterio-venous anastomoses in one direction. Nowadays, routine prenatal measurements of middle cerebral artery peak systolic velocity using Doppler ultrasound are recommended after laser surgery to rule out fetal anemia or (iatrogenic) TAPS. We suggest that routine Doppler studies also be performed in uncomplicated monochorionic twin pregnancies without TOPS. Signs of fetal anemia in a monochorionic twin should then alert the perinatologist of the possibility of TAPS. TAPS should be diagnosed when a large inter-twin discordance in fetal or neonatal hemoglobin levels and reticulocyte counts is found, in the absence of TOPS. Placental injection studies may then reveal a preponderance of very small arterio-venous anastomoses. Discordant hemoglobin levels occur not only in chronic TTTS and in TAPS, but are also reported to occur in uncomplicated monochorionic pregnancies due to acute peripartum TTTS. In Chapter 7 we studied the inter-twin difference in hemoglobin levels at birth in monochorionic twins without TTTS compared to a control group of dichorionic twins, in relation to birth order and placental vascular anatomy. We found that hemoglobin differences occur more frequently in monochorionic twins without chronic TTTS than in dichorionic twins, but only when measured on the second day of life. Furthermore, hemoglobin differences in monochorionic twins are associated with birth order and with the presence of superficial vascular anastomoses. We found that second-born monochorionic twins have significantly higher hemoglobin values than first-born twins. Our findings support the hypothesis that second-born monochorionic twins are more likely to receive a large placental blood transfusion rather than lose blood into the placenta. We also report that hemoglobin differences in monochorionic twins are greater in the presence of superficial vascular anastomoses. In analogy to acute perimortem TTTS, it is conceivable that superficial vascular anastomoses may also be responsible for rapid placento-fetal blood transfusion during delivery. Chapter 8, 9 and 10 focus on the short-term outcome in TTTS treated with fetoscopic laser surgery. The neonatal outcome in TTTS survivors treated with laser at our center is presented in Chapter 8. We compared the outcome in a TTTS group after laser treament with a control group of monochorionic twins without TTTS delivered at our center. We found that neonatal mortality in the TTTS and no-TTTS group was 8% (6/76) and 3% (3/90) respectively (p = 0.03). Overall, the incidence of adverse neonatal outcome (neonatal mortality, major neonatal morbidity or severe cerebral lesions) in the TTTS and no-TTTS group was 26% (20/76) and 13% (12/90), respectively (RR = 1.97, 95% CI = 1.03 to 3.77). We concluded that the risk for adverse neonatal outcome is two-fold increased in TTTS treated with laser than in monochorionic twins without TTTS. Details on the short-term neurological outcome in TTTS survivors treated with fetoscopic laser surgery are presented in Chapter 9. Again we compared the results with a control group of monochorionic twins without TTTS. Incidence of antenatally acquired severe cerebral lesions in the TTTS group was 10% (8/84) and 2% (2/108) in the no-TTTS group (p = 0.02). Incidence of severe cerebral lesions at discharge was 14% (12/84) in the TTTS group and 6% (6/108) in the no-TTTS group (p = 0.04). Antenatal injury was responsible for severe cerebral lesions in 67% (8/12) of the TTTS group. We conclude that the incidence of severe cerebral lesions in TTTS treated with fetoscopic laser surgery is high and results mainly from antenatal injury. Details on the short-term cardiac outcome in TTTS survivors treated with fetoscopic laser surgery are presented in Chapter 10 and compared to a control group of monochorionic twins without TTTS. Echocardiography was performed within one week after delivery. At birth, blood pressure was measured in all survivors and endothelin-1 was determined in umbilical cord blood. Data on right ventricular outflow tract obstruction in TTTS treated with laser surgery at our center but delivered elsewhere were reviewed retrospectively from medical records. We found that the incidence of right ventricular outflow tract obstruction in recipients was 4% (3/75). We found no difference in afterload parameters between donors and recipients after laser treatment. We concluded that the incidence of congenital heart disease in TTTS survivors treated with fetoscopic laser occlusion of vascular anastomoses is around 5%, which is higher than in the general population (0.5%). In particular, the increased risk of right ventricular outflow tract obstruction in recipient twins warrants close cardiac monitoring during fetal and neonatal life. The long-term neurodevelopmental outcome in TTTS is presented in Chapter 11 and 12. Chapter 11 describes the long-term neurodevelopmental outcome in TTTS treated conservatively. All TTTS-cases admitted at our center between January 1990 and December 1998 were included in the study. Perinatal mortality was 50% (29/58). Neurological and mental development at school age was assessed during a home visit in all TTTS-survivors (n = 29). The incidence of adverse neurodevelopmental outcome in TTTS survivors was 21% (6/29) and was due to cerebral palsy (n = 6) and developmental delay (n = 5). The incidence of adverse neurodevelopmental outcome in the group of survivors who were treated with amnioreduction was 26% (5/19). Two of the four children born after intrauterine fetal demise of their co-twin had cerebral palsy. Chapter 12 describes the long-term neurodevelopmental outcome in TTTS treated with fetoscopic laser surgery. All TTTS-cases treated consecutively at our center between August 2000 and December 2003 were included in the study. Perinatal mortality was 30% (49/164). Neurological, mental and psychomotor development at 2 years of age was assessed in all TTTS-survivors (n = 115). Overall, the incidence of neurodevelopmental impairment was 17% (19/115) and was due to cerebral palsy (n = 8), mental developmental delay (n = 9), psychomotor developmental delay (n = 12) and deafness (n = 1). In both long-term follow-up studies, we concluded that neurodevelopmental delay in TTTS, regardless of type of antenatal treatment, is high and warrants long-term follow-up. In conclusion, although laser surgery appears to be the best available treatment option for TTTS, perinatal mortality and morbidity rates in TTTS treated with laser are still significant. More research and new developments are required to further improve the short and long-term outcome in TTTS.

• Fetoscopic laser surgery
• Morbidity
• Perinatal mortality
• Twin-to-twin transfusion syndrome

• All authors: Lopriore, E.
• Supervisor: Kanhai, H.H.H.; Walther, F.J.
• Co-supervisor: Vandenbussche, F.P.H.A.
• Qualification: Doctor (dr.)
• Awarding Institution: Department of Gynaecology, Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2006-09-13
• ISBN (print): 9090209581
• Court: LEI Universiteit Leiden
• Sponsorship: Karl Storz BV, Stichting FEMAR, Viasys BV, Nycomed BV