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Vascular Distribution Patterns in Monochorionic Twin Placentas
Placenta (2005), 26, 471e475 doi:10.1016/j.placenta.2004.06.014
Vascular Distribution Patterns in Monochorionic Twin Placentas M. E. De Paepe*, P. DeKoninck and R. M. Friedman Department of Pathology, Women and Infants Hospital and Brown Medical School, 101 Dudley Street, Providence, RI 02905, United States Paper accepted 29 June 2004
Several recent publications have focused on the association between the occurrence of twin-to-twin transfusion syndrome (TTTS) in diamniotic-monochorionic twins and the presence of a number of selected anatomic placental characteristics (distribution of vascular territory, cord insertion, type and number of inter-twin anastomoses). In contrast, the potential importance of the vascular distribution patterns of the individual twins remains to be elucidated. Based on its gross architectural distribution pattern, chorionic vasculature is traditionally described as disperse, magistral or mixed. The aim of this study was (1) to determine the relative prevalence of these vascular distribution patterns in monochorionic twin placentas, and (2) to correlate these patterns with the presence of TTTS and known anatomic placental features linked to TTTS. The placentas of 89 consecutive diamnioticmonochorionic twins (15 with TTTS, 74 without TTTS), examined at Women and Infants Hospital, were studied. Disperse vascular patterns were seen in 53% of twins, and magistral or mixed patterns in 47%. The prevalence of magistral/mixed vascular patterns was significantly higher in TTTS gestations than in non-TTTS gestations (60% versus 44%, P ! 0.05) and, in TTTS gestations, much higher in donor twins than in recipient twins (87% versus 33%, P ! 0.005). A strong association was found between the presence of magistral/mixed patterns and marginal/velamentous cord insertion, low number of inter-twin anastomoses, and uneven distribution of the vascular territories. These findings suggest that the magistral/mixed vascular distribution pattern may represent an important placental architectural feature contributing to the complex pathophysiology of TTTS. Placenta (2005), 26, 471e475 Ó 2004 Published by Elsevier Ltd.
INTRODUCTION Approximately 10e20% of monochorionic twin gestations are complicated by severe chronic twin-to-twin transfusion syndrome (TTTS), characterized by a gradual shift of blood volume from the donor twin to the recipient twin through inter-twin vascular anastomoses. The pathogenesis of TTTS remains incompletely understood. However, the risk for development of TTTS in diamniotic-monochorionic twin gestations has been linked to a number of anatomic characteristics of the placenta, specifically, unequal sharing of the single-disc placenta, velamentous or marginal cord insertion, fewer anastomoses overall, and relative paucity of superficial artery-to-artery anastomoses in particular [1e5]. In view of its putative critical role in the pathogenesis of TTTS, the architecture of the inter-twin vascular communications has been the subject of numerous studies [1,5e8]. Placental vascular communications occur in virtually all monochorionic placentas [7e9] and are either superficial (artery-to-artery or vein-to-vein) or deep (artery-to-vein). * Corresponding author. Tel.: C1 401 274 1122x1544; fax: C1 401 453 7681. E-mail address: [email protected] (M.E. De Paepe). 0143e4004/$esee front matter
Whereas superficial artery-to-artery anastomoses are believed to protect against the development of TTTS, deep artery-tovein anastomoses are unidirectional and have been implicated in the unequal distribution of flow between the two twins. In contrast to the inter-twin vascular communications, no attention has been given thus far to the characteristics of the vascular distribution patterns of the individual diamnioticmonochorionic twins. Chorionic vascular patterns are traditionally described as disperse, magistral or mixed [6]. The ‘‘disperse’’ pattern is characterized by a fine network of vessels that branch out from the cord insertion to the various placental cotyledons. The ‘‘magistral’’ pattern has arteries of relatively uniform size that course across the placental surface nearly to the edge without diminishing in diameter. In singleton placentas, the disperse type of vessel distribution is more common (62%), while the magistral type occurs in 38% [6,10]. Placental vascular diameter, vascular resistance and flow patterns are widely believed to be determinants of TTTS in monochorionic placentas. In their mathematical model of monochorionic placental circulation, Umur et al. [11] have shown that vascular diameter and resistance are important determinants of hemodynamic imbalance in diamniotic-monochorionic placentas, especially in blood vessels with a high pressure differential, such as artery-to-vein anastomoses. We Ó 2004 Published by Elsevier Ltd.
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therefore speculated that the particular vascular distribution types, each characterized by specific vascular branching patterns and peripheral vascular diameters, may play an important role in the development of TTTS in monochorionic twins. The aim of this study was (1) to determine the relative prevalence of disperse and magistral vascular distribution patterns in monochorionic twin placentas, and (2) to correlate these patterns with the presence of TTTS and other anatomic placental characteristics linked to TTTS. Increased knowledge of the placental anatomy in diamniotic-monochorionic gestations may lead to a better understanding of the pathophysiology of TTTS, and may even be of prognostic value in this often lethal condition. MATERIALS AND METHODS The vascular distribution patterns were determined in a consecutive series of diamniotic-monochorionic twin placentas submitted to the Department of Pathology at Women and Infants Hospital (2001e2003). The accompanying charts were reviewed to determine whether the pregnancy was complicated by severe chronic TTTS, as defined by ultrasonographic evidence of severe polyhydramnios in one twin and concomitant oligohydramnios in the other, as well as additional signs (absence of bladder in the donor twin, critically abnormal Doppler studies, hydrops and/or demise of one or both twins) [12]. Gross examination of the placenta and injection of the placental vasculature were performed as previously described in detail [7]. The following anatomic variables were recorded for each placenta: the type of cord insertion (paracentral, marginal, velamentous), the relative distribution of the vascular territories, the number and type of inter-twin anastomoses, and the placental vascular distribution patterns of the individual twins. The vascular distribution patterns were categorized as disperse, magistral or mixed. The disperse pattern was defined as a superficial vascular arrangement characterized by regular, near-symmetric dichotomous branching, resulting in a progressive diminution of vascular caliber (Figure 1, top). For the purpose of this study, a pattern was categorized as disperse if R75% of the twin’s vascular territory showed this pattern. A vascular pattern was categorized as magistral if R75% of the vascular territory showed relatively large-sized vessels, extending from the insertion of the cord to the periphery without a significant reduction of diameter (Figure 1, bottom). A variable number of small-sized side branches extended from the main vessels in the magistral pattern. The mixed vascular distribution pattern was defined as the presence of combined disperse- and magistral-type vessels, with each type involving less than 75% of the individual twin’s territory. Determination of vascular pattern was performed by a single perinatal pathologist (MEDP) who had no knowledge of the clinical outcome. Results were expressed as percentages or mean G standard deviation where appropriate. The relative frequency of
Figure 1. Diagram representing disperse (top) and magistral (bottom) distribution patterns of placental chorionic vasculature.
findings in TTTS and non-TTTS groups and in placentas with magistral/mixed versus disperse patterns was compared using Fisher’s exact test. The number of vascular anastomoses in TTTS versus non-TTTS and in magistral/ mixed versus disperse groups was compared using unpaired Student t-test. A P value !0.05 was considered statistically significant. RESULTS Clinical data The vascular distribution patterns were studied in a consecutive series of 89 diamniotic-monochorionic twin placentas. Fifteen cases (17%) showed clinical and ultrasound evidence of severe chronic TTTS. Nine of these 15 twins had undergone fetoscopic laser coagulation of the communicating vessels. Seventy-four twins (83%) showed no evidence of TTTS and are designated as ‘non-TTTS’ cases. The gestational age at delivery ranged from 20 to 37 weeks for
De Paepe et al.: Vasculature in Monochorionic Placentas
TTTS twins (mean: 26 G 6 weeks) and from 24 to 40 weeks for non-TTTS twins (mean: 34 G 3 weeks). Analysis of vascular patterns The vascular distribution patterns were categorized as disperse, magistral, or mixed (combination of disperse and magistral) (Figure 2). In 68 of 89 (76%) placentas, at least one of the twins showed a magistral or mixed vascular pattern. In the remaining 21 placentas (24%), both twins showed disperse vascular patterns. When twins were considered separately, a disperse pattern was seen in 94/178 (53%) fetuses, a magistral pattern in 48/178 (27%), and a mixed pattern in 36/178 (20%). The prevalence of magistral or mixed magistral/disperse vascular patterns was significantly higher in twins with TTTS than in twins not affected by TTTS (60% versus 44%, respectively, P ! 0.05) (Figure 3A). Interestingly, the prevalence of magistral or mixed vascular patterns in TTTS twins was more than two-fold higher in donor twins than in recipient twins (13/15 (87%) versus 5/15 (33%), P ! 0.005) (Figure 3B). Correlation between vascular pattern and distribution of vascular territory Uneven distribution of vascular territory, defined as greater than 25% discordance between the two twin territories, was
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identified in 29/89 (33%) diamniotic-monochorionic placentas and was seen significantly more frequently in TTTS placentas than in non-TTTS placentas (73% versus 24%, P ! 0.005). The prevalence of magistral/mixed vascular patterns was significantly higher in placentas with uneven territorial distribution than in placentas with even distribution (Figure 3C). Indeed, 93% (27/29) of placentas with uneven distribution of vascular territories had magistral or mixed vascular patterns in at least one twin, compared with only 68% (41/60) of placentas with even territorial distribution (P ! 0.02, Fisher’s exact test). Correlation between vascular pattern and number of inter-twin vascular anastomoses The total number of inter-twin vascular anastomoses (arteryto-artery, vein-to-vein and artery-to-vein) was determined following color-coded dye injection of the placental vessels, as described [7]. Laser-coagulated TTTS placentas were excluded, as the number of grossly identifiable anastomoses has been shown to be significantly reduced after laser ablation [13]. Placentas in which both twins showed disperse vascular patterns had an average of 9.6 G 1.2 inter-twin anastomoses (range: 5e22). However, when at least one twin showed a magistral or mixed vascular pattern, the average number of anastomoses was only 6.1 G 0.4 (range: 1e17) (P ! 0.001, unpaired Student t-test).
Figure 2. Vascular distribution patterns in diamniotic-monochorionic twin placentas. (A) Placenta (non-TTTS) with bilateral disperse vascular patterns. The vasculature was injected with color-coded dye according to the following scheme. Left twin: yellow: artery, green: vein; right twin: yellow: artery (filled during injection of left twin through artery-to-artery anastomosis), red: vein. (B) Close-up of lower part of vascular equator, showing numerous bidirectional deep arteryto-vein anastomoses, as well as a single superficial artery-to-artery anastomosis (arrow). (C) Placenta (oligohydramnios/polyhydramnios) with magistral vascular pattern in one twin (left) and disperse pattern in the other (right). The following color code was applied for injection. Left twin: yellow: artery, blue: vein; right twin: red: artery, green: vein. Part of the arterial network of the right twin is filled with yellow dye, due to the presence of a small artery-to-artery anastomosis (arrow). (D) Close-up of the lower part of the vascular equator, showing relative paucity of inter-twin communications.
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Figure 3. Relative frequency of vascular distribution patterns in diamniotic-monochorionic twin placentas. (A) Relative frequency (in %) of the various vascular distribution patterns in twins with or without twin-to-twin transfusion syndrome (TTTS). The frequency of magistral/mixed vascularity was significantly higher in TTTS than in non-TTTS twins (P ! 0.05). (B) Relative frequency (in %) of the various vascular distribution patterns in donor and recipient twins with TTTS. *P ! 0.005 versus recipient. (C) Relative frequency (in %) of the various vascular distribution patterns in diamniotic-monochorionic twin placentas with even or uneven (O25% discordance) distribution of vascular territories. *P ! 0.02 versus even.
It has been suggested that the presence of artery-to-artery anastomoses has a protective effect on the development or severity of TTTS. We therefore determined the relationship between the presence or absence of AA anastomoses, the presence and severity of TTTS, and the various placental vascular types. Artery-to-artery anastomoses were present in 10/15 (67%) of TTTS placentas and in 65/74 (88%) of nonTTTS placentas (P ! 0.05). However, the presence or absence of artery-to-artery anastomoses did not correlate with a particular vascular distribution pattern, and the prevalence of magistral/mixed vascular patterns was virtually identical in placentas with or without artery-to-artery anastomoses (76% versus 78%, respectively). Correlation between vascular pattern and cord insertion The types of umbilical cord insertion were classified as either paracentral or marginal, the latter category including both marginal and velamentous (membranous) types of insertion. Of the 178 individual fetuses (89 sets of twins), 64 (36%) had marginal cord insertions, while 114 (64%) had paracentral cord insertions. In placentas with marginal cord insertion, the prevalence of magistral or mixed vascular patterns was more than two-fold higher than in placentas with paracentral cord insertion (75% versus 31%, P ! 0.0001, Fisher’s exact test). The prevalence of marginal cord insertion in our study was found to be equally high in TTTS and non-TTTS twins (37% versus 36%, respectively), suggesting that cord insertion may not be a critical determinant for the development of TTTS. Nevertheless, both TTTS and non-TTTS twins showed a strong correlation between type of cord insertion and vascular distribution pattern. Eleven of 30 (37%) twins with TTTS had a marginal cord insertion; nine of these 11 twins (82%) had magistral or mixed vasculature. Fifty-three of 148 (36%) twins without TTTS had a marginal cord insertion; 39 of these 53 twins (74%) had magistral or mixed vasculature.
DISCUSSION This study describes the relative frequency of disperse, magistral, or mixed vascular distribution patterns in diamniotic-monochorionic twin placentas. We found that the prevalence of magistral or mixed vascular types in monochorionic twin placentas was higher than that previously reported for singletons (47% versus 38%) [10]. In addition, we determined that the prevalence of magistral/mixed vascular types was significantly higher in placentas of twins with TTTS compared with those without TTTS (60% versus 44%). Furthermore, in twin pairs with TTTS, donor twins were significantly more likely to have magistral/mixed vascular patterns than recipients (87% versus 33%). These observations suggest that the presence of a magistral/mixed vascular distribution pattern in one or both diamniotic-monochorionic twins may be implicated in the development of TTTS. We determined that the presence of magistral/mixed vascular patterns was strongly linked to the presence of some, but not all, of the placental anatomic variables implicated in TTTS [1e5]. Specifically, a significant correlation was found between magistral/mixed vascularity and uneven distribution of vascular territory. In addition, the overall number of anastomoses (superficial and deep) was significantly lower in placentas with magistral/mixed vascular patterns in at least one twin. Finally, in concordance with similar findings in singleton placentas [10,14,15], we found that the magistral/ mixed vascular patterns were more frequently seen in association with marginal/velamentous cord insertion. The mechanisms underlying the preferential magistral patterning of chorionic vessels in diamniotic-monochorionic placentas with TTTS remain undetermined. While the regulation of uteroplacental (decidual and villous capillary) vasculogenesis and angiogenesis is increasingly being unraveled [16,17], our understanding of the regulation of fetoplacental (umbilical and chorionic) angiogenesis remains limited. Several lines of evidence suggest that placental angiogenesis,
De Paepe et al.: Vasculature in Monochorionic Placentas
analogous to angiogenesis in most organs and tissues, is regulated by the coordinated interaction of angiogenic (vascular endothelial growth factors (VEGFs) and their receptors, angiopoietin) and anti-angiogenic factors, in concert with local paracrine mediators, such as nitric oxide [16e18]. The higher prevalence of magistral patterns in TTTS donor twins is intriguing and suggests that additional physical factors, such as vascular pressure and flow and/or oxygen tension, may influence early vascular patterning. By analogy, oxygen gradients across the placental lobule have been shown to have differential effects on uteroplacental angiogenesis [18]. The hemodynamic implications of magistral versus disperse vascular patterns in the context of diamniotic-monochorionic twin gestation remain unclear. Most older studies [19,20] have suggested that, in singleton placentas, the nature of the chorionic vasculature has no effect on fetal or perinatal outcome. Recent pulsed Doppler ultrasound studies, however, have demonstrated that magistral or mixed chorionic vessel
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patterns in singleton placentas are correlated with enddiastolic zero flow in the umbilical artery [21]. The lower enddiastolic blood flow velocities in the magistral type have been attributed to the smaller peripheral vascular tree, resulting in higher resistance against the blood flow in the umbilical artery. It is tempting to speculate that lower flow velocities in magistral vessels may, especially when associated with other detrimental placental factors, be instrumental in ‘tipping’ the hemodynamic balance towards chronic TTTS. In summary, this study demonstrates that the prevalence of magistral/mixed vascular patterns is relatively high in diamniotic-monochorionic twin placentas, especially in those complicated by TTTS. We speculate that the presence of a magistral/mixed vascular distribution pattern in the donor part of the placenta, in concert with uneven territorial distribution and paucity of artery-to-artery anastomoses, may contribute to the development of TTTS in diamnioticmonochorionic twins.
ACKNOWLEDGEMENTS The authors wish to thank Francois I. Luks, M.D., Ph.D., for the artwork.
REFERENCES [1] Bajoria R. Vascular anatomy of monochorionic placenta in relation to discordant growth and amniotic fluid volume. Hum Reprod 1998;13: 2933e40. [2] Denbow ML, Cox P, Talbert D, Fisk NM. Colour Doppler energy insonation of placental vasculature in monochorionic twins: absent arterio-arterial anastomoses in association with twin-to-twin transfusion syndrome. Br J Obstet Gynaecol 1998;105:760e5. [3] Fries MH, Goldstein RB, Kilpatrick SJ, Golbus MS, Callen PW, Filly RA. The role of velamentous cord insertion in the etiology of twinetwin transfusion syndrome. Obstet Gynecol 1993;81:569e74. [4] Gaziano EP, De Lia JE, Kuhlmann RS. Diamnionic monochorionic twin gestations: an overview. J Matern Fetal Med 2000;9:89e96. [5] Machin G, Still K, Lalani T. Correlations of placental vascular anatomy and clinical outcomes in 69 monochorionic twin pregnancies. Am J Med Genet 1996;61:229e36. [6] Benirschke K, Kaufmann P. Pathology of the human placenta. New York: Springer-Verlag; 2000. [7] De Paepe ME, Burke S, Luks FI, Pinar H, Singer DB. Demonstration of placental vascular anatomy in monochorionic twin gestations. Pediatr Dev Pathol 2002;5:37e44. [8] Denbow ML, Cox P, Taylor M, Hammal DM, Fisk NM. Placental angioarchitecture in monochorionic twin pregnancies: relationship to fetal growth, fetofetal transfusion syndrome, and pregnancy outcome. Am J Obstet Gynecol 2000;182:417e26. [9] Robertson EG, Neer KJ. Placental injection studies in twin gestation. Am J Obstet Gynecol 1983;147:170e4. [10] Kishore N, Sarkar SC. The arterial patterns of placenta. A postpartum radiologic study. J Obstet Gynaecol India 1967;17:9e13. [11] Umur A, van Gemert MJ, Nikkels PG, Ross MG. Monochorionic twins and twinetwin transfusion syndrome: the protective role of arterioarterial anastomoses. Placenta 2002;23:201e9.
[12] Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twinetwin transfusion syndrome. J Perinatol 1999; 19:550e5. [13] De Paepe ME, Friedman RM, Poch M, Hansen K, Carr SR, Luks FI. Placental findings after laser ablation of communicating vessels in twin-totwin transfusion syndrome (TTTS). Pediatr Dev Pathol 2004;7:159e65. [14] Nordenvall M, Sandstedt B, Ulmsten U. Relationship between placental shape, cord insertion, lobes and gestational outcome. Acta Obstet Gynecol Scand 1988;67:611e6. [15] Schellmann B, Kannegiesser-Wolf B. Distribution of the chorionic vessels of the human placenta and their arteriovenous crossings [author’s transl]. Zentralbl Allg Pathol 1976;120:210e23. [16] Geva E, Ginzinger DG, Zaloudek CJ, Moore DH, Byrne A, Jaffe RB. Human placental vascular development: vasculogenic and angiogenic (branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A, angiopoietin-1, and angiopoietin-2. J Clin Endocrinol Metab 2002;87:4213e24. [17] Reynolds LP, Redmer DA. Angiogenesis in the placenta. Biol Reprod 2001;64:1033e40. [18] Carter AM, Charnock Jones DS. Angiogenesis and blood flow: implications for pathobiology e a workshop report. Placenta 2001; 22(Suppl. A):S66e8. [19] Crawford JM. A study of human placental growth with observations on the placenta in erythroblastosis foetalis. J Obstet Gynaecol Br Emp 1959; 66:885e96. [20] Ruckhaberle KE, Viehweg B, Ruckhaberle B, Schlegel C, Leistner B, Ebert S, et al. Relationships between the macroscopic placentary condition and postnatal state of underweight neonates. A contribution to the correlational pathology of the placenta [author’s transl]. Zentralbl Gynakol 1978;100:226e34. [21] Nordenvall M, Ullberg U, Laurin J, Lingman G, Sandstedt B, Ulmsten U. Placental morphology in relation to umbilical artery blood velocity waveforms. Eur J Obstet Gynecol Reprod Biol 1991;40:179e90.
Vascular Distribution Patterns in Monochorionic Twin Placentas M. E. De Paepe*, P. DeKoninck and R. M. Friedman Department of Pathology, Women and Infants Hospital and Brown Medical School, 101 Dudley Street, Providence, RI 02905, United States Paper accepted 29 June 2004
Several recent publications have focused on the association between the occurrence of twin-to-twin transfusion syndrome (TTTS) in diamniotic-monochorionic twins and the presence of a number of selected anatomic placental characteristics (distribution of vascular territory, cord insertion, type and number of inter-twin anastomoses). In contrast, the potential importance of the vascular distribution patterns of the individual twins remains to be elucidated. Based on its gross architectural distribution pattern, chorionic vasculature is traditionally described as disperse, magistral or mixed. The aim of this study was (1) to determine the relative prevalence of these vascular distribution patterns in monochorionic twin placentas, and (2) to correlate these patterns with the presence of TTTS and known anatomic placental features linked to TTTS. The placentas of 89 consecutive diamnioticmonochorionic twins (15 with TTTS, 74 without TTTS), examined at Women and Infants Hospital, were studied. Disperse vascular patterns were seen in 53% of twins, and magistral or mixed patterns in 47%. The prevalence of magistral/mixed vascular patterns was significantly higher in TTTS gestations than in non-TTTS gestations (60% versus 44%, P ! 0.05) and, in TTTS gestations, much higher in donor twins than in recipient twins (87% versus 33%, P ! 0.005). A strong association was found between the presence of magistral/mixed patterns and marginal/velamentous cord insertion, low number of inter-twin anastomoses, and uneven distribution of the vascular territories. These findings suggest that the magistral/mixed vascular distribution pattern may represent an important placental architectural feature contributing to the complex pathophysiology of TTTS. Placenta (2005), 26, 471e475 Ó 2004 Published by Elsevier Ltd.
INTRODUCTION Approximately 10e20% of monochorionic twin gestations are complicated by severe chronic twin-to-twin transfusion syndrome (TTTS), characterized by a gradual shift of blood volume from the donor twin to the recipient twin through inter-twin vascular anastomoses. The pathogenesis of TTTS remains incompletely understood. However, the risk for development of TTTS in diamniotic-monochorionic twin gestations has been linked to a number of anatomic characteristics of the placenta, specifically, unequal sharing of the single-disc placenta, velamentous or marginal cord insertion, fewer anastomoses overall, and relative paucity of superficial artery-to-artery anastomoses in particular [1e5]. In view of its putative critical role in the pathogenesis of TTTS, the architecture of the inter-twin vascular communications has been the subject of numerous studies [1,5e8]. Placental vascular communications occur in virtually all monochorionic placentas [7e9] and are either superficial (artery-to-artery or vein-to-vein) or deep (artery-to-vein). * Corresponding author. Tel.: C1 401 274 1122x1544; fax: C1 401 453 7681. E-mail address: [email protected] (M.E. De Paepe). 0143e4004/$esee front matter
Whereas superficial artery-to-artery anastomoses are believed to protect against the development of TTTS, deep artery-tovein anastomoses are unidirectional and have been implicated in the unequal distribution of flow between the two twins. In contrast to the inter-twin vascular communications, no attention has been given thus far to the characteristics of the vascular distribution patterns of the individual diamnioticmonochorionic twins. Chorionic vascular patterns are traditionally described as disperse, magistral or mixed [6]. The ‘‘disperse’’ pattern is characterized by a fine network of vessels that branch out from the cord insertion to the various placental cotyledons. The ‘‘magistral’’ pattern has arteries of relatively uniform size that course across the placental surface nearly to the edge without diminishing in diameter. In singleton placentas, the disperse type of vessel distribution is more common (62%), while the magistral type occurs in 38% [6,10]. Placental vascular diameter, vascular resistance and flow patterns are widely believed to be determinants of TTTS in monochorionic placentas. In their mathematical model of monochorionic placental circulation, Umur et al. [11] have shown that vascular diameter and resistance are important determinants of hemodynamic imbalance in diamniotic-monochorionic placentas, especially in blood vessels with a high pressure differential, such as artery-to-vein anastomoses. We Ó 2004 Published by Elsevier Ltd.
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therefore speculated that the particular vascular distribution types, each characterized by specific vascular branching patterns and peripheral vascular diameters, may play an important role in the development of TTTS in monochorionic twins. The aim of this study was (1) to determine the relative prevalence of disperse and magistral vascular distribution patterns in monochorionic twin placentas, and (2) to correlate these patterns with the presence of TTTS and other anatomic placental characteristics linked to TTTS. Increased knowledge of the placental anatomy in diamniotic-monochorionic gestations may lead to a better understanding of the pathophysiology of TTTS, and may even be of prognostic value in this often lethal condition. MATERIALS AND METHODS The vascular distribution patterns were determined in a consecutive series of diamniotic-monochorionic twin placentas submitted to the Department of Pathology at Women and Infants Hospital (2001e2003). The accompanying charts were reviewed to determine whether the pregnancy was complicated by severe chronic TTTS, as defined by ultrasonographic evidence of severe polyhydramnios in one twin and concomitant oligohydramnios in the other, as well as additional signs (absence of bladder in the donor twin, critically abnormal Doppler studies, hydrops and/or demise of one or both twins) [12]. Gross examination of the placenta and injection of the placental vasculature were performed as previously described in detail [7]. The following anatomic variables were recorded for each placenta: the type of cord insertion (paracentral, marginal, velamentous), the relative distribution of the vascular territories, the number and type of inter-twin anastomoses, and the placental vascular distribution patterns of the individual twins. The vascular distribution patterns were categorized as disperse, magistral or mixed. The disperse pattern was defined as a superficial vascular arrangement characterized by regular, near-symmetric dichotomous branching, resulting in a progressive diminution of vascular caliber (Figure 1, top). For the purpose of this study, a pattern was categorized as disperse if R75% of the twin’s vascular territory showed this pattern. A vascular pattern was categorized as magistral if R75% of the vascular territory showed relatively large-sized vessels, extending from the insertion of the cord to the periphery without a significant reduction of diameter (Figure 1, bottom). A variable number of small-sized side branches extended from the main vessels in the magistral pattern. The mixed vascular distribution pattern was defined as the presence of combined disperse- and magistral-type vessels, with each type involving less than 75% of the individual twin’s territory. Determination of vascular pattern was performed by a single perinatal pathologist (MEDP) who had no knowledge of the clinical outcome. Results were expressed as percentages or mean G standard deviation where appropriate. The relative frequency of
Figure 1. Diagram representing disperse (top) and magistral (bottom) distribution patterns of placental chorionic vasculature.
findings in TTTS and non-TTTS groups and in placentas with magistral/mixed versus disperse patterns was compared using Fisher’s exact test. The number of vascular anastomoses in TTTS versus non-TTTS and in magistral/ mixed versus disperse groups was compared using unpaired Student t-test. A P value !0.05 was considered statistically significant. RESULTS Clinical data The vascular distribution patterns were studied in a consecutive series of 89 diamniotic-monochorionic twin placentas. Fifteen cases (17%) showed clinical and ultrasound evidence of severe chronic TTTS. Nine of these 15 twins had undergone fetoscopic laser coagulation of the communicating vessels. Seventy-four twins (83%) showed no evidence of TTTS and are designated as ‘non-TTTS’ cases. The gestational age at delivery ranged from 20 to 37 weeks for
De Paepe et al.: Vasculature in Monochorionic Placentas
TTTS twins (mean: 26 G 6 weeks) and from 24 to 40 weeks for non-TTTS twins (mean: 34 G 3 weeks). Analysis of vascular patterns The vascular distribution patterns were categorized as disperse, magistral, or mixed (combination of disperse and magistral) (Figure 2). In 68 of 89 (76%) placentas, at least one of the twins showed a magistral or mixed vascular pattern. In the remaining 21 placentas (24%), both twins showed disperse vascular patterns. When twins were considered separately, a disperse pattern was seen in 94/178 (53%) fetuses, a magistral pattern in 48/178 (27%), and a mixed pattern in 36/178 (20%). The prevalence of magistral or mixed magistral/disperse vascular patterns was significantly higher in twins with TTTS than in twins not affected by TTTS (60% versus 44%, respectively, P ! 0.05) (Figure 3A). Interestingly, the prevalence of magistral or mixed vascular patterns in TTTS twins was more than two-fold higher in donor twins than in recipient twins (13/15 (87%) versus 5/15 (33%), P ! 0.005) (Figure 3B). Correlation between vascular pattern and distribution of vascular territory Uneven distribution of vascular territory, defined as greater than 25% discordance between the two twin territories, was
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identified in 29/89 (33%) diamniotic-monochorionic placentas and was seen significantly more frequently in TTTS placentas than in non-TTTS placentas (73% versus 24%, P ! 0.005). The prevalence of magistral/mixed vascular patterns was significantly higher in placentas with uneven territorial distribution than in placentas with even distribution (Figure 3C). Indeed, 93% (27/29) of placentas with uneven distribution of vascular territories had magistral or mixed vascular patterns in at least one twin, compared with only 68% (41/60) of placentas with even territorial distribution (P ! 0.02, Fisher’s exact test). Correlation between vascular pattern and number of inter-twin vascular anastomoses The total number of inter-twin vascular anastomoses (arteryto-artery, vein-to-vein and artery-to-vein) was determined following color-coded dye injection of the placental vessels, as described [7]. Laser-coagulated TTTS placentas were excluded, as the number of grossly identifiable anastomoses has been shown to be significantly reduced after laser ablation [13]. Placentas in which both twins showed disperse vascular patterns had an average of 9.6 G 1.2 inter-twin anastomoses (range: 5e22). However, when at least one twin showed a magistral or mixed vascular pattern, the average number of anastomoses was only 6.1 G 0.4 (range: 1e17) (P ! 0.001, unpaired Student t-test).
Figure 2. Vascular distribution patterns in diamniotic-monochorionic twin placentas. (A) Placenta (non-TTTS) with bilateral disperse vascular patterns. The vasculature was injected with color-coded dye according to the following scheme. Left twin: yellow: artery, green: vein; right twin: yellow: artery (filled during injection of left twin through artery-to-artery anastomosis), red: vein. (B) Close-up of lower part of vascular equator, showing numerous bidirectional deep arteryto-vein anastomoses, as well as a single superficial artery-to-artery anastomosis (arrow). (C) Placenta (oligohydramnios/polyhydramnios) with magistral vascular pattern in one twin (left) and disperse pattern in the other (right). The following color code was applied for injection. Left twin: yellow: artery, blue: vein; right twin: red: artery, green: vein. Part of the arterial network of the right twin is filled with yellow dye, due to the presence of a small artery-to-artery anastomosis (arrow). (D) Close-up of the lower part of the vascular equator, showing relative paucity of inter-twin communications.
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Figure 3. Relative frequency of vascular distribution patterns in diamniotic-monochorionic twin placentas. (A) Relative frequency (in %) of the various vascular distribution patterns in twins with or without twin-to-twin transfusion syndrome (TTTS). The frequency of magistral/mixed vascularity was significantly higher in TTTS than in non-TTTS twins (P ! 0.05). (B) Relative frequency (in %) of the various vascular distribution patterns in donor and recipient twins with TTTS. *P ! 0.005 versus recipient. (C) Relative frequency (in %) of the various vascular distribution patterns in diamniotic-monochorionic twin placentas with even or uneven (O25% discordance) distribution of vascular territories. *P ! 0.02 versus even.
It has been suggested that the presence of artery-to-artery anastomoses has a protective effect on the development or severity of TTTS. We therefore determined the relationship between the presence or absence of AA anastomoses, the presence and severity of TTTS, and the various placental vascular types. Artery-to-artery anastomoses were present in 10/15 (67%) of TTTS placentas and in 65/74 (88%) of nonTTTS placentas (P ! 0.05). However, the presence or absence of artery-to-artery anastomoses did not correlate with a particular vascular distribution pattern, and the prevalence of magistral/mixed vascular patterns was virtually identical in placentas with or without artery-to-artery anastomoses (76% versus 78%, respectively). Correlation between vascular pattern and cord insertion The types of umbilical cord insertion were classified as either paracentral or marginal, the latter category including both marginal and velamentous (membranous) types of insertion. Of the 178 individual fetuses (89 sets of twins), 64 (36%) had marginal cord insertions, while 114 (64%) had paracentral cord insertions. In placentas with marginal cord insertion, the prevalence of magistral or mixed vascular patterns was more than two-fold higher than in placentas with paracentral cord insertion (75% versus 31%, P ! 0.0001, Fisher’s exact test). The prevalence of marginal cord insertion in our study was found to be equally high in TTTS and non-TTTS twins (37% versus 36%, respectively), suggesting that cord insertion may not be a critical determinant for the development of TTTS. Nevertheless, both TTTS and non-TTTS twins showed a strong correlation between type of cord insertion and vascular distribution pattern. Eleven of 30 (37%) twins with TTTS had a marginal cord insertion; nine of these 11 twins (82%) had magistral or mixed vasculature. Fifty-three of 148 (36%) twins without TTTS had a marginal cord insertion; 39 of these 53 twins (74%) had magistral or mixed vasculature.
DISCUSSION This study describes the relative frequency of disperse, magistral, or mixed vascular distribution patterns in diamniotic-monochorionic twin placentas. We found that the prevalence of magistral or mixed vascular types in monochorionic twin placentas was higher than that previously reported for singletons (47% versus 38%) [10]. In addition, we determined that the prevalence of magistral/mixed vascular types was significantly higher in placentas of twins with TTTS compared with those without TTTS (60% versus 44%). Furthermore, in twin pairs with TTTS, donor twins were significantly more likely to have magistral/mixed vascular patterns than recipients (87% versus 33%). These observations suggest that the presence of a magistral/mixed vascular distribution pattern in one or both diamniotic-monochorionic twins may be implicated in the development of TTTS. We determined that the presence of magistral/mixed vascular patterns was strongly linked to the presence of some, but not all, of the placental anatomic variables implicated in TTTS [1e5]. Specifically, a significant correlation was found between magistral/mixed vascularity and uneven distribution of vascular territory. In addition, the overall number of anastomoses (superficial and deep) was significantly lower in placentas with magistral/mixed vascular patterns in at least one twin. Finally, in concordance with similar findings in singleton placentas [10,14,15], we found that the magistral/ mixed vascular patterns were more frequently seen in association with marginal/velamentous cord insertion. The mechanisms underlying the preferential magistral patterning of chorionic vessels in diamniotic-monochorionic placentas with TTTS remain undetermined. While the regulation of uteroplacental (decidual and villous capillary) vasculogenesis and angiogenesis is increasingly being unraveled [16,17], our understanding of the regulation of fetoplacental (umbilical and chorionic) angiogenesis remains limited. Several lines of evidence suggest that placental angiogenesis,
De Paepe et al.: Vasculature in Monochorionic Placentas
analogous to angiogenesis in most organs and tissues, is regulated by the coordinated interaction of angiogenic (vascular endothelial growth factors (VEGFs) and their receptors, angiopoietin) and anti-angiogenic factors, in concert with local paracrine mediators, such as nitric oxide [16e18]. The higher prevalence of magistral patterns in TTTS donor twins is intriguing and suggests that additional physical factors, such as vascular pressure and flow and/or oxygen tension, may influence early vascular patterning. By analogy, oxygen gradients across the placental lobule have been shown to have differential effects on uteroplacental angiogenesis [18]. The hemodynamic implications of magistral versus disperse vascular patterns in the context of diamniotic-monochorionic twin gestation remain unclear. Most older studies [19,20] have suggested that, in singleton placentas, the nature of the chorionic vasculature has no effect on fetal or perinatal outcome. Recent pulsed Doppler ultrasound studies, however, have demonstrated that magistral or mixed chorionic vessel
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patterns in singleton placentas are correlated with enddiastolic zero flow in the umbilical artery [21]. The lower enddiastolic blood flow velocities in the magistral type have been attributed to the smaller peripheral vascular tree, resulting in higher resistance against the blood flow in the umbilical artery. It is tempting to speculate that lower flow velocities in magistral vessels may, especially when associated with other detrimental placental factors, be instrumental in ‘tipping’ the hemodynamic balance towards chronic TTTS. In summary, this study demonstrates that the prevalence of magistral/mixed vascular patterns is relatively high in diamniotic-monochorionic twin placentas, especially in those complicated by TTTS. We speculate that the presence of a magistral/mixed vascular distribution pattern in the donor part of the placenta, in concert with uneven territorial distribution and paucity of artery-to-artery anastomoses, may contribute to the development of TTTS in diamnioticmonochorionic twins.
ACKNOWLEDGEMENTS The authors wish to thank Francois I. Luks, M.D., Ph.D., for the artwork.
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