American Journal of Obstetrics & Gynecology
Volume 198, Issue 4 , Pages 382.e1-382.e8, April 2008

Twin-to-twin transfusion syndrome: an antiangiogenic state?

Presented at the 28th Annual Meeting of the Society for Maternal–Fetal Medicine, Dallas, TX, Jan. 28-Feb. 2, 2008.

  • Juan Pedro Kusanovic, MD

      Affiliations

    • Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI
    • Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
    • ,
  • Roberto Romero, MD

      Affiliations

    • Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI
    • Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI
    • Corresponding Author InformationReprints: Roberto Romero, MD, Perinatology Research Branch, NICHD, NIH, DHHS, Wayne State University/Hutzel Women’s Hospital, 3990 John R, Box 4, Detroit, MI 48201.
    • ,
  • Jimmy Espinoza, MD

      Affiliations

    • Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI
    • Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
    • ,
  • Jyh Kae Nien, MD

      Affiliations

    • Center for Perinatal Diagnosis and Research (CEDIP), Sotero del Rio Hospital, P. Universidad Catolica de Chile, Puente Alto, Chile
    • ,
  • Chong Jai Kim, MD

      Affiliations

    • Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI
    • Department of Pathology, Wayne State University, Detroit, MI
    • ,
  • Pooja Mittal, MD

      Affiliations

    • Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI
    • Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
    • ,
  • Sam Edwin, PhD

      Affiliations

    • Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI
    • ,
  • Offer Erez, MD

      Affiliations

    • Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI
    • ,
  • Francesca Gotsch, MD

      Affiliations

    • Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI
    • ,
  • Shali Mazaki-Tovi, MD

      Affiliations

    • Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
    • ,
  • Nandor G. Than, MD, PhD

      Affiliations

    • Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI
    • ,
  • Eleazar Soto, MD

      Affiliations

    • Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
    • ,
  • Natalia Camacho, MD

      Affiliations

    • Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI
    • Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI
    • ,
  • Ricardo Gomez, MD

      Affiliations

    • Center for Perinatal Diagnosis and Research (CEDIP), Sotero del Rio Hospital, P. Universidad Catolica de Chile, Puente Alto, Chile
    • ,
  • Ruben Quintero, MD

      Affiliations

    • Department of Obstetrics and Gynecology, University of South Florida, Tampa, FL.
    • ,
  • Sonia S. Hassan, MD

      Affiliations

    • Perinatology Research Branch, NICHD/NIH/DHHS, Bethesda, MD, and Detroit, MI
    • Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI

Received 2 December 2007; received in revised form 14 January 2008; accepted 6 February 2008.

Article Outline

Objective

An imbalanced chronic blood flow between the donor and recipient twin through placental vascular anastomoses is the accepted pathophysiology of twin-to-twin transfusion syndrome (TTTS). Vascular endothelial growth factor receptor-1 (VEGFR-1) mRNA is overexpressed only in the syncytiotrophoblast of the donor twin in some cases of TTTS. This study was conducted to determine maternal plasma concentrations of placental growth factor (PlGF), soluble VEGFR-1, and soluble endoglin (s-Eng) in monochorionic-diamniotic pregnancies with and without TTTS.

Study Design

This case-control study included monochorionic-diamniotic pregnancies between 16-26 weeks with and without TTTS. Maternal plasma concentrations of PlGF, sVEGFR-1, and s-Eng were determined with ELISA. A P value < .05 was considered statistically significant.

Results

Patients with TTTS had higher median plasma concentrations of s-Eng (14.8 ng/mL vs 7.8 ng/mL; P < .001) and sVEGFR-1 (6383.1 pg/mL vs 3220.1 pg/mL; P < .001]; and lower median plasma concentrations of PlGF (115.5 pg/mL vs 359.3 pg/mL; P = .002) than those without TTTS.

Conclusion

We propose that an antiangiogenic state may be present in some cases of TTTS.

Key words: angiogenesis, angiogenic factors, birthweight discordancy, endoglin, monochorionic, placental growth factor, PlGF, sFlt1, sVEGFR-1, TTTS, twin pregnancy

 

Chorionicity, rather than zygosity, is the main determinant of pregnancy outcome in twin gestation.1, 2, 3 Indeed, monochorionic (MC) twins have a higher risk of miscarriage, fetal death, preterm delivery, intrauterine growth restriction, birthweight discordancy,2, 4, 5, 6, 7 as well as a higher rate of cerebral palsy and neurologic morbidity8, 9 than dichorionic (DC) twins. These differences have been attributed to abnormalities in the placental angioarchitecture, including abnormal umbilical cord insertion,10, 11, 12 unequal placental sharing,13 and to the presence of placental vascular anatomoses that lead to the twin-to-twin transfusion syndrome (TTTS) and its consequences.3, 14

For Editors’ Commentary, see Table of Contents

The conventional view is that a chronic blood flow imbalance from the donor to the recipient twin due to a net unidirectional blood flow through placental vascular anastomoses15, 16, 17 is responsible for the development of TTTS. However, the presence of vascular anastomosis is necessary but not sufficient to induce TTTS. Indeed, almost all monochorionic twin placentas have vascular anastomoses16, 17, 18; however, TTTS is present only in 5-15% of these pregnancies,19, 20, 21 and no more than 25% of the MC twin pairs with TTTS have > 15% of hemoglobin discordance.22 Thus, although placental vascular anastomoses are a sine qua non requirement for the development of TTTS, the pathophysiology of TTTS may not be explained only on the basis of placental vascular anastomoses.

Angiogenesis plays a central role in normal placental development,23, 24, 25 and accumulating evidence indicates that angiogenic factors, such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), and antiangiogenic factors such as soluble VEGF receptor-1 (sVEGFR-1, also referred to as sFlt1) and the soluble form of Endoglin (s-Eng) are involved in the pathophysiology of preeclampsia,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 small for gestational age (SGA),31, 54, 55, 56, 57, 58, 59 placental abruption,60 “mirror syndrome,”61, 62, 63 preeclampsia with parvovirus-induced hydrops,64 and unexplained fetal death.65 Recently, it has been reported that VEGFR-1 mRNA is overexpressed in the syncytiotrophoblast of the donor but not in that of the recipient twin in some cases of TTTS,66 suggesting that this antiangiogenic factor may play a role in TTTS. The objective of this study was to determine if there are changes in the maternal plasma concentrations of angiogenic (PlGF), and antiangiogenic factors (sVEGFR-1 and s-Eng) in monochorionic-diamniotic twin pregnancies with and without TTTS.

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Materials and Methods 

Study design and population 

A case-control study was designed to examine the maternal plasma concentration of angiogenic and antiangiogenic factors in monochorionic twins with and without TTTS. We searched our clinical database, bank of biological samples, and digital library of ultrasound images to identify patients with monochorionic-diamniotic twin pregnancies between 16 and 26 weeks of gestation with and without TTTS. Patients with the diagnosis of preeclampsia at the time of venipuncture or fetal congenital anomalies were excluded.

Definitions 

Monochorionic placentation was diagnosed by ultrasonography before 20 weeks of gestation based on the presence of a single placental mass, same fetal gender, absence of the twin-peak sign, and dividing membrane thickness < 2 mm,67, 68, 69, 70 confirmed with placental histopathology. TTTS was defined as oligohydramnios (maximum vertical pocket [MVP] of amniotic fluid < 2 cm) in the donor twin and polyhydramnios (MVP > 8 cm) in the recipient twin. Preterm delivery was defined as delivery before 37 completed weeks of gestation. Preeclampsia was diagnosed in the presence of systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg on at least 2 occasions 4 hours to 1 week apart, after the 20th week of gestation, and proteinuria > 300 mg in a 24-hour urine collection, or 2 random urine specimens obtained 4 hours to 1 week apart containing ≥ 1+ protein by dipstick71, 72 or 1 dipstick measurement ≥ 2+ protein.73 Fetal death was considered to have occurred in the absence of fetal heart activity after 20 weeks of gestation. Intrauterine growth restriction was defined as a birthweight below the 10th percentile.74, 75

All patients provided written informed consent before participating in the study. The collection and utilization of samples, and the use of clinical and ultrasound data for research purposes was approved by the Institutional Review Boards of the Sotero del Rio Hospital (a major affiliate of the Catholic University, Santiago, Chile), Wayne State University, and the National Institute of Child Health and Human Development (NICHD/NIH/DHHS).

Sample collection and human PlGF, sVEGFR-1, and s-Eng immunoassays 

Samples of peripheral blood were obtained by venipuncture and collected in tubes containing EDTA. The samples were centrifugated at 4°C for 10 minutes and stored at −70°C until assay. Maternal plasma concentrations of sVEGFR-1, PlGF, and soluble endoglin were determined by specific and sensitive enzyme-linked immunoassays (R&D Systems, Minneapolis, MN). Briefly, plasma samples were incubated in duplicate wells of the microtiter plates, which have been precoated with antigen specific (PlGF, sVEGFR-1, or s-Eng) monoclonal antibodies. During this incubation, PlGF, sVEGFR-1, or s-Eng present in the standards or maternal plasma samples was immobilized by their specific precoated antibodies (form antigen-antibody complexes). Repeated washing and aspiration removed all other unbound materials from the assay plate. This step was followed by incubation with a specific antibody-enzyme reagent for a specified amount of time. Following a wash to remove excess and unbound materials, a substrate solution was added to the wells of the microtiter plate and color developed in proportion to the amount of antigen bound in the initial step of the individual assays. The color development was stopped with the addition of an acid solution and the intensity of color was read using a programmable microtiter plate spectrophotometer (SpectraMax M2 micro plate workstation, Molecular Devices Corporation, Sunnyvale, CA). The concentrations of PlGF, sVEGFR-1, or s-Eng in maternal plasma samples were determined by interpolation from individual standard curves composed of purified human PlGF, sVEGFR-1, or s-Eng. The calculated interassay coefficients of variation for s-Eng, sVEGFR-1, and PlGF in our laboratory were 3.3%, 5.3%, and 7%, respectively. The calculated intraassay coefficients of variation for s-Eng, sVEGFR-1, and PlGF were 2.7%, 2.2%, and 5.8%, respectively. The sensitivity was calculated to be 0.04 ng/mL for s-Eng, 13.1 pg/mL for sVEGFR-1, and 5.5 pg/mL for PlGF assays.

Statistical analysis 

The Kolmogorov–Smirnov test was used to test for normal distribution of the data. Comparisons among groups were performed using Mann-Whitney U test for continuous variables, and Chi-square or Fisher exact test for categorical variables. A P value < .05 was considered statistically significant. The statistical package used was SPSS v.14.0 (SPSS Inc, Chicago, IL).

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Results 

Sixty-nine monochorionic-diamniotic twin pregnancies with (n = 16) and without (n = 53) TTTS at 16-26 weeks of gestation were included in this study. In the TTTS group, all maternal blood samples were collected at the time of the clinical presentation and before treatment. Staging of TTTS was scored according to a previously described system.76 There were 2 patients in stage I, 6 in stage II, 7 in stage III, and 1 in stage V. There were no patients with stage IV.

Table 1 displays the demographic and clinical characteristics of the study population. Patients with TTTS had a significantly lower proportion of primigravidae (12.5% [2/16] vs 39.6% [21/53]; P = .04) and delivered earlier (31 weeks [IQR: 31.9-37.5] vs 35.6 weeks [IQR: 22.7-34.2]; P = .009) than those without TTTS.

TABLE. Demographic and clinical characteristics of patients with monochorionic-diamniotic twin pregnancies between 16 and 26 weeks of gestation
No TTTS (n = 53)TTTS (n = 16)P
Maternal age (y)27(22–34)28.5(23–33)NS
Primigravida39.6(21/53)12.5(2/16).04
Height (cm)155(152–160)155.5(152–162)NS
Weight (kg)58(55–68)59.5(53–68)NS
Prepregnancy BMI (kg/m2)24.0(21.9–27)23.8(22.5–28.9)NS
Smoking9.4(5/53)12.5(2/16)NS
Gestational age at blood draw (wk)21.7(19.8–23.3)21.3(19.5–23.5)NS
SBP (mmHg)a110(104–125)110(110–120)NS
DBP (mmHg)a70(65–80)70(60–72)NS
Preeclampsia11.8(6/45)0(0/15)NS
Gestational age at delivery (wk)35.6(31.9–37.5)31(22.7–34.2).009
Preterm delivery (wk)
< 3764.2(34/53)84.6(11/13)NS
< 3430.2(16/53)69.2(9/13).009
< 3224.5(13/53)61.5(8/13).01
IUGR39.6(21/53)60(6/10)NS
Fetal deathb7.5(8/106)10(3/30)NS
Sample storage time (y)4.1(2.4–6)2.7(1.3–5.8)NS

Values are expressed as percentage (number) or median (interquartile range).

BMI, body mass index; DBP, diastolic blood pressure; IUGR, intrauterine growth restriction; NS, not significant; SBP, systolic blood pressure; TTTS, twin-to-twin transfusion syndrome.

Kusanovic. Twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2008.

aSystolic and diastolic blood pressures at the time of blood draw.

bValues are expressed as percentage (number/total number of fetuses).

FIGURE 1, FIGURE 2, FIGURE 3 display the median maternal plasma concentrations of s-Eng, sVEGFR-1, and PlGF, respectively, in patients with monochorionic-diamniotic pregnancies with and without TTTS between 16 and 26 weeks of gestation.

  • View full-size image.
  • FIGURE 1. 

    Median maternal plasma concentrations of soluble Endoglin (s-Eng) among patients with monochorionic-diamniotic pregnancies with and without TTTS between 16 and 26 weeks of gestation

  • Patients with TTTS had a significantly higher median plasma concentration of s-Eng (14.8 ng/mL [IQR: 9.6-33.5] vs 7.8 ng/mL [IQR: 6.7-9.5]; P < .001) than those without TTTS.

  • Kusanovic. Twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2008.

  • View full-size image.
  • FIGURE 2. 

    Median maternal plasma concentrations of soluble vascular endothelial growth factor (sVEGFR-1) among patients with monochorionic-diamniotic pregnancies with and without TTTS between 16 and 26 weeks of gestation

  • Patients with TTTS had a significantly higher median plasma concentration of sVEGFR-1 (6383.1 pg/mL [IQR: 4874.5-18,047.8] vs 3220.1 pg/mL [IQR: 2310.1-5172.1]; P < .001) than those without TTTS.

  • Kusanovic. Twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2008.

  • View full-size image.
  • FIGURE 3. 

    Median maternal plasma concentrations of placental growth factor (PlGF), respectively, among patients with monochorionic-diamniotic pregnancies with and without TTTS between 16 and 26 weeks of gestation

  • Patients with TTTS had a significantly lower median maternal plasma concentration of PlGF (115.5 pg/mL [IQR: 51.9-357.4] vs. 359.3 pg/mL [IQR: 224.6-693.9]; P = .002) than those without TTTS.

  • Kusanovic. Twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2008.

Patients with TTTS had a significantly higher median plasma concentration of s-Eng (14.8 ng/mL [IQR: 9.6-33.5] vs 7.8 ng/mL [IQR: 6.7-9.5]; P < .001) and sVEGFR-1 (6383.1 pg/mL [IQR: 4874.5-18,047.8] vs 3220.1 pg/mL [IQR: 2310.1-5172.1]; P < .001), and a significantly lower median maternal plasma concentration of PlGF (115.5 pg/mL [IQR: 51.9-357.4] vs 359.3 pg/mL [IQR: 224.6-693.9]; P = .002) than those without TTTS.

Among patients without TTTS, a subanalysis was performed to determine the maternal plasma concentrations of PlGF, sVEGFR-1, and s-Eng at the time of delivery between those with (n = 18) and without (n = 24) IUGR. Among patients with IUGR, 11 had 1 IUGR fetus, whereas in 7 cases both fetuses were IUGR. No significant differences were observed in the median maternal plasma concentrations of PlGF (IUGR: 162.5 pg/mL [IQR: 105.8-226.2] vs no IUGR: 184.5 pg/mL [IQR: 134.5-290.2]; P = .3), sVEGFR-1 (IUGR: 13543.5 pg/mL [IQR: 6909.5-23,448] vs no IUGR: 16,140.7 pg/mL [IQR: 9105.7-22,785.7]; P = .4), and s-Eng (IUGR: 35 ng/mL [IQR: 18.8-41.2] vs no IUGR: 30.2 ng/mL [IQR: 23.1-44.7]; P = .98).

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Comment 

Principal findings of this study 

Patients with monochorionic twin pregnancies complicated by TTTS between 16 to 26 weeks of gestation have significantly higher median maternal plasma concentrations of S-ENG and sVEGFR-1, and a significantly lower median maternal plasma concentration of PlGF than those without TTTS.

Placental vascular anastomoses and TTTS 

Almost all monochorionic placentas have vascular anastomoses, which are either superficial or deep.16, 17, 18 The traditional view of the pathophysiology of TTTS is that there is an imbalance of blood volume exchange from the donor to the recipient twin through these placental vascular anastomoses.15, 16, 17

Although almost all monochorionic twin placentas have vascular anastomoses,16, 17, 18 TTTS is present only in a small proportion of these pregnancies.19, 20, 21 It has been proposed that the number, type, and size of the anastomoses are the key factors that allow the hemodynamic stability among monochorionic twins.77 Virtually all placentas from patients with TTTS have at least 1 arteriovenous anastomosis from the donor to the recipient, and approximately 96% have an arteriovenous anastomosis from recipient to donor. In addition, approximately 20% of placentas of patients with TTTS have a superficial anastomosis.78 Interestingly, TTTS can also develop through superficial anastomoses in the absence of deep vascular communications, suggesting that superficial anastomoses may be the cause of TTTS in a subset of patients.79

It has been proposed that the pathophysiology of TTTS is due to multiple pathologic processes80, 81, 82 and a growing body of evidence suggests that other mechanisms may play a role in the pathophysiology and clinical presentation of TTTS: 1) recipient twins have higher concentrations of atrial natriuretic peptide and endothelin-1 than donor twins, which has been associated with cardiac dysfunction in the recipient twin83; 2) overexpression of renin in the kidney of the donor twin and severe arterial and glomerular lesions like hypertension-induced microangiopathy in the kidney of the recipient have been reported in pregnancies complicated by TTTS84; and 3) donor twins have lower cord blood concentrations of leptin85 and insulin-like growth factor-II86 than the recipient twins, suggesting that discordant placental metabolic function may be the cause of the growth restriction in those twins and, because placental dysfunction is related with increased feto-placental resistance, that could be an explanation for transfusion from the growth-retarded donor to the recipient twin.80 Whether these conditions are causative or an epiphenomenon is not clear.

Twin-to-twin transfusion syndrome: An antiangiogenic state? 

There is a paucity of data regarding maternal plasma or serum concentrations of pro- and antiangiogenic factors in twin pregnancies. The study reported herein demonstrated that women with monochorionic twin pregnancies complicated by TTTS between 16 to 26 weeks of gestation have significantly higher median maternal plasma concentrations of the antiangiogenic factors soluble Endoglin and sVEGFR-1, and a significantly lower median maternal plasma concentration of the angiogenic factor PlGF than those without TTTS. This finding is novel and it is in keeping with a study reporting that VEGFR-1 mRNA is overexpressed in the villi of the donor, but not in that of the recipient twin in some cases of TTTS.66 The villi of the donor showed increased syncytiotrophoblastic knots, shrinkage of villi, increased perivillous fibrin deposition, villous infarction, and villous hypercapillarization. The authors suggest that, in some cases of TTTS, this may represent a hypoxic/ischemic state in the donor villi due to fetal villous hypoperfusion rather than an abnormal utero-placental circulation.66

In this study, among monochorionic-diamniotic twin pregnancies without TTTS, the prevalence of preeclampsia was 11.8%. In contrast to what was expected, no patients in the TTTS group developed preeclampsia. It is possible that these patients did not have enough time to develop preeclampsia, since the median gestational age at delivery in the TTTS group was 31 weeks of gestation and almost 70% of patients with TTTS delivered before 34 weeks.

Since we do not have longitudinal maternal blood samples available in the TTTS group, it is not possible to determine if the maternal plasma concentrations of angiogenic (PlGF) and antiangiogenic factors (sVEGFR-1 and s-Eng) in the third trimester were low and high enough, respectively, to be associated with the development of preeclampsia.

Recently, Nevo et al87 examined the mRNA and protein expression of sFlt-1 in placentas of twin pregnancies complicated by IUGR of 1 twin or preeclampsia. In dichorionic twins complicated by twin birthweight discordancy (defined as intertwin birthweight difference > 25%), the sFlt-1 mRNA expression was significantly higher in the IUGR twin placenta compared to the normal twin pair placenta. Similar findings were observed in monochorionic twin pregnancies when the sFlt-1 mRNA placental expression was compared to the normal twin pair placenta as well as to normal control twins without IUGR. Control twins did not have changes in sFlt-1 mRNA expression. Of interest, the authors demonstrated that the sFlt-1 mRNA expression is higher in the dichorionic than the monochorionic IUGR placenta, and postulated that findings in dichorionic placentas are probably associated with impaired placental development as occurs in singleton pregnancies with IUGR, while in monochorionic twins the presence of vascular anastomoses and unequal placental sharing further complicate the placental findings. In addition, sFlt-1 mRNA expression was significantly higher in the placentas of dichorionic and monochorionic IUGR twins than that of their normal twin pairs and control twins without IUGR.87 Among dichorionic twin pregnancies with preeclampsia, but without birthweight discordancy, sFlt-1 mRNA expression was higher in 1 placenta compared to the other, suggesting discordancy in sFlt-1 expression between twin pairs. The same results were found for sFlt-1 protein expression. The authors proposed that 1 placenta may elicit the onset of preeclampsia in these patients.87 This interpretation is consistent with previous reports of clinical resolution of preeclampsia following the death of the IUGR or hydropic fetus in twin pregnancies.88, 89, 90, 91, 92

In conclusion, the study reported herein demonstrates that patients with TTTS had a significantly higher median maternal plasma concentration of s-Eng and sVEGFR-1 (both antiangiogenic factors), and a significantly lower median maternal plasma concentration of PlGF (an angiogenic factor) than those without TTTS. We propose that an antiangiogenic state may be present in some cases of TTTS. Further longitudinal studies93 are required to define the subset of TTTS patients in which this occurs and to determine whether this is a cause or consequence of TTTS.

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References 

  1. Bajoria R, Kingdom J. The case for routine determination of chorionicity and zygosity in multiple pregnancy. Prenat Diagn. 1997;17:1207–1225
  2. Dube J, Dodds L, Armson BA. Does chorionicity or zygosity predict adverse perinatal outcomes in twins?. Am J Obstet Gynecol. 2002;186:579–583
  3. Carroll SG, Tyfield L, Reeve L, Porter H, Soothill P, Kyle PM. Is zygosity or chorionicity the main determinant of fetal outcome in twin pregnancies?. Am J Obstet Gynecol. 2005;193:757–761
  4. Sebire NJ, Snijders RJ, Hughes K, Sepulveda W, Nicolaides KH. The hidden mortality of monochorionic twin pregnancies. BJOG. 1997;104:1203–1207
  5. Gonzalez-Quintero VH, Luke B, O’Sullivan MJ, et al. Antenatal factors associated with significant birth weight discordancy in twin gestations. Am J Obstet Gynecol. 2003;189:813–817
  6. Leduc L, Takser L, Rinfret D. Persistance of adverse obstetric and neonatal outcomes in monochorionic twins after exclusion of disorders unique to monochorionic placentation. Am J Obstet Gynecol. 2005;193:1670–1675
  7. Sperling L, Kiil C, Larsen LU, et al. Naturally conceived twins with monochorionic placentation have the highest risk of fetal loss. Ultrasound Obstet Gynecol. 2006;28:644–652
  8. Bejar R, Vigliocco G, Gramajo H, et al. Antenatal origin of neurologic damage in newborn infants (II. Multiple gestations). Am J Obstet Gynecol. 1990;162:1230–1236
  9. Adegbite AL, Castille S, Ward S, Bajoria R. Neuromorbidity in preterm twins in relation to chorionicity and discordant birth weight. Am J Obstet Gynecol. 2004;190:156–163
  10. Fries MH, Goldstein RB, Kilpatrick SJ, Golbus MS, Callen PW, Filly RA. The role of velamentous cord insertion in the etiology of twin-twin transfusion syndrome. Obstet Gynecol. 1993;81:569–574
  11. Machin GA. Velamentous cord insertion in monochorionic twin gestation (An added risk factor). J Reprod Med. 1997;42:785–789
  12. Hanley ML, Ananth CV, Shen-Schwarz S, Smulian JC, Lai YL, Vintzileos AM. Placental cord insertion and birth weight discordancy in twin gestations. Obstet Gynecol. 2002;99:477–482
  13. Fick AL, Feldstein VA, Norton ME, Wassel FC, Caughey AB, Machin GA. Unequal placental sharing and birth weight discordance in monochorionic diamniotic twins. Am J Obstet Gynecol. 2006;195:178–183
  14. Patten RM, Mack LA, Harvey D, Cyr DR, Pretorius DH. Disparity of amniotic fluid volume and fetal size: problem of the stuck twin—US studies. Radiology. 1989;172:153–157
  15. Bajoria R, Wigglesworth J, Fisk NM. Angioarchitecture of monochorionic placentas in relation to the twin-twin transfusion syndrome. Am J Obstet Gynecol. 1995;172:856–863
  16. Bajoria R. Vascular anatomy of monochorionic placenta in relation to discordant growth and amniotic fluid volume. Hum Reprod. 1998;13:2933–2940
  17. 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;182:417–426
  18. Wee LY, Taylor M, Watkins N, Franke V, Parker K, Fisk NM. Characterisation of deep arterio-venous anastomoses within monochorionic placentae by vascular casting. Placenta. 2005;26:19–24
  19. Sebire NJ, Talbert D, Fisk NM. Twin-to-twin transfusion syndrome results from dynamic asymmetrical reduction in placental anastomoses: a hypothesis. Placenta. 2001;22:383–391
  20. Lutfi S, Allen VM, Fahey J, O’Connell CM, Vincer MJ. Twin-twin transfusion syndrome: a population-based study. Obstet Gynecol. 2004;104:1289–1297
  21. De Paepe ME, DeKoninck P, Friedman RM. Vascular distribution patterns in monochorionic twin placentas. Placenta. 2005;26:471–475
  22. Denbow M, Fogliani R, Kyle P, Letsky E, Nicolini U, Fisk N. Haematological indices at fetal blood sampling in monochorionic pregnancies complicated by feto-fetal transfusion syndrome. Prenat Diagn. 1998;18:941–946
  23. Mayhew TM. Fetoplacental angiogenesis during gestation is biphasic, longitudinal and occurs by proliferation and remodelling of vascular endothelial cells. Placenta. 2002;23:742–750
  24. Charnock-Jones DS, Kaufmann P, Mayhew TM. Aspects of human fetoplacental vasculogenesis and angiogenesis (I. Molecular regulation). Placenta. 2004;25:103–113
  25. Kaufmann P, Mayhew TM, Charnock-Jones DS. Aspects of human fetoplacental vasculogenesis and angiogenesis (II. Changes during normal pregnancy). Placenta. 2004;25:114–126
  26. Lyall F, Greer IA, Boswell F, Fleming R. Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in pre-eclampsia. BJOG. 1997;104:223–228
  27. Kupferminc MJ, Daniel Y, Englender T, et al. Vascular endothelial growth factor is increased in patients with preeclampsia. Am J Reprod Immunol. 1997;38:302–306
  28. Torry DS, Wang HS, Wang TH, Caudle MR, Torry RJ. Preeclampsia is associated with reduced serum levels of placenta growth factor. Am J Obstet Gynecol. 1998;179:1539–1544
  29. Tidwell SC, Ho HN, Chiu WH, Torry RJ, Torry DS. Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia. Am J Obstet Gynecol. 2001;184:1267–1272
  30. Zhou Y, McMaster M, Woo K, et al. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol. 2002;160:1405–1423
  31. Tsatsaris V, Goffin F, Munaut C, et al. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab. 2003;88:5555–5563
  32. Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111:649–658
  33. Koga K, Osuga Y, Yoshino O, et al. Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J Clin Endocrinol Metab. 2003;88:2348–2351
  34. McKeeman GC, Ardill JE, Caldwell CM, Hunter AJ, McClure N. Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop. Am J Obstet Gynecol. 2004;191:1240–1246
  35. Krauss T, Pauer HU, Augustin HG. Prospective analysis of placenta growth factor (PlGF) concentrations in the plasma of women with normal pregnancy and pregnancies complicated by preeclampsia. Hypertens Pregnancy. 2004;23:101–111
  36. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350:672–683
  37. Chaiworapongsa T, Romero R, Espinoza J, et al. Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia (Young Investigator Award). Am J Obstet Gynecol. 2004;190:1541–1547
  38. Thadhani R, Mutter WP, Wolf M, et al. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin Endocrinol Metab. 2004;89:770–775
  39. Maynard SE, Venkatesha S, Thadhani R, Karumanchi SA. Soluble Fms-like tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of preeclampsia. Pediatr Res. 2005;57:1R–7R
  40. Chaiworapongsa T, Romero R, Kim YM, et al. Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia. J Matern Fetal Neonatal Med. 2005;17:3–18
  41. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308:1592–1594
  42. Bdolah Y, Karumanchi SA, Sachs BP. Recent advances in understanding of preeclampsia. Croat Med J. 2005;46:728–736
  43. Levine RJ, Thadhani R, Qian C, et al. Urinary placental growth factor and risk of preeclampsia. JAMA. 2005;293:77–85
  44. Rajakumar A, Michael HM, Rajakumar PA, et al. Extra-placental expression of vascular endothelial growth factor receptor-1, (Flt-1) and soluble Flt-1 (sFlt-1), by peripheral blood mononuclear cells (PBMCs) in normotensive and preeclamptic pregnant women. Placenta. 2005;26:563–573
  45. Levine RJ, Karumanchi SA. Circulating angiogenic factors in preeclampsia. Clin Obstet Gynecol. 2005;48:372–386
  46. Shibata E, Rajakumar A, Powers RW, et al. Soluble fms-like tyrosine kinase 1 is increased in preeclampsia but not in normotensive pregnancies with small-for-gestational-age neonates: relationship to circulating placental growth factor. J Clin Endocrinol Metab. 2005;90:4895–4903
  47. Staff AC, Braekke K, Harsem NK, Lyberg T, Holthe MR. Circulating concentrations of sFlt1 (soluble fms-like tyrosine kinase 1) in fetal and maternal serum during pre-eclampsia. Eur J Obstet Gynecol Reprod Biol. 2005;122:33–39
  48. Espinoza J, Nien JK, Kusanovic JP, et al. The combined use of uterine artery Doppler and maternal plasma placental growth factor concentrations identifies patients at risk for early onset and/or severe preeclampsia. Ultrasound Obstet Gynecol. 2006;28:387–388
  49. Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006;12:642–649
  50. Robinson CJ, Johnson DD, Chang EY, Armstrong DM, Wang W. Evaluation of placenta growth factor and soluble Fms-like tyrosine kinase 1 receptor levels in mild and severe preeclampsia. Am J Obstet Gynecol. 2006;195:255–259
  51. Aggarwal PK, Jain V, Sakhuja V, Karumanchi SA, Jha V. Low urinary placental growth factor is a marker of pre-eclampsia. Kidney Int. 2006;69:621–624
  52. Levine RJ, Lam C, Qian C, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med. 2006;355:992–1005
  53. Levine RJ, Qian C, Maynard SE, Yu KF, Epstein FH, Karumanchi SA. Serum sFlt1 concentration during preeclampsia and mid trimester blood pressure in healthy nulliparous women. Am J Obstet Gynecol. 2006;194:1034–1041
  54. Crispi F, Dominguez C, Llurba E, Martin-Gallan P, Cabero L, Gratacos E. Placental angiogenic growth factors and uterine artery Doppler findings for characterization of different subsets in preeclampsia and in isolated intrauterine growth restriction. Am J Obstet Gynecol. 2006;195:201–207
  55. Malamitsi-Puchner A, Boutsikou T, Economou E, et al. Vascular endothelial growth factor and placenta growth factor in intrauterine growth-restricted fetuses and neonates. Mediators Inflamm. 2005;2005:293–297
  56. Boutsikou T, Malamitsi-Puchner A, Economou E, Boutsikou M, Puchner KP, Hassiakos D. Soluble vascular endothelial growth factor receptor-1 in intrauterine growth restricted fetuses and neonates. Early Hum Dev. 2006;82:235–239
  57. Girardi G, Yarilin D, Thurman JM, Holers VM, Salmon JE. Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction. J Exp Med. 2006;203:2165–2175
  58. Padavala S, Pope N, Baker P, Crocker I. An imbalance between vascular endothelial growth factor and its soluble receptor in placental villous explants of intrauterine growth-restricted pregnancies. J Soc Gynecol Investig. 2006;13:40–47
  59. Wallner W, Sengenberger R, Strick R, et al. Angiogenic growth factors in maternal and fetal serum in pregnancies complicated by intrauterine growth restriction. Clin Sci (Lond). 2007;112:51–57
  60. Signore C, Mills JL, Qian C, et al. Circulating angiogenic factors and placental abruption. Obstet Gynecol. 2006;108:338–344
  61. Espinoza J, Nien JK, Kusanovic JP, et al. A role of the anti-angiogenic factor sVEGFR-1 in the ’mirror syndrome’ (Ballantyne’s syndrome). Am J Obstet Gynecol. 2005;193:S134
  62. Espinoza J, Romero R, Nien JK, et al. A role of the anti-angiogenic factor sVEGFR-1 in the ’mirror syndrome’ (Ballantyne’s syndrome). J Matern Fetal Neonatal Med. 2006;19:607–613
  63. Rana S, Venkatesha S, DePaepe M, Chien EK, Paglia M, Karumanchi SA. Cytomegalovirus-induced mirror syndrome associated with elevated levels of circulating antiangiogenic factors. Obstet Gynecol. 2007;109:549–552
  64. Stepan H, Faber R. Elevated sFlt1 level and preeclampsia with parvovirus-induced hydrops. N Engl J Med. 2006;354:1857–1858
  65. Espinoza J, Chaiworapongsa T, Romero R, et al. Unexplained fetal death: another anti-angiogenic state. J Matern Fetal Neonatal Med. 2007;20:495–507
  66. Kumazaki K, Nakayama M, Suehara N, Wada Y. Expression of vascular endothelial growth factor, placental growth factor, and their receptors Flt-1 and KDR in human placenta under pathologic conditions. Hum Pathol. 2002;33:1069–1077
  67. Scardo JA, Ellings JM, Newman RB. Prospective determination of chorionicity, amnionicity, and zygosity in twin gestations. Am J Obstet Gynecol. 1995;173:1376–1380
  68. Sepulveda W, Sebire NJ, Hughes K, Odibo A, Nicolaides KH. The lambda sign at 10-14 weeks of gestation as a predictor of chorionicity in twin pregnancies. Ultrasound Obstet Gynecol. 1996;7:421–423
  69. Wood SL, St OR, Connors G, Elliot PD. Evaluation of the twin peak or lambda sign in determining chorionicity in multiple pregnancy. Obstet Gynecol. 1996;88:6–9
  70. Bracero LA, Byrne DW. Ultrasound determination of chorionicity and perinatal outcome in twin pregnancies using dividing membrane thickness. Gynecol Obstet Invest. 2003;55:50–57
  71. Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000;183:S1–S22
  72. ACOG practice bulletin (Diagnosis and management of preeclampsia and eclampsia). No. 33, January 2002 Obstet Gynecol. 2002;99:159–167
  73. Sibai BM, Ewell M, Levine RJ, et al. Risk factors associated with preeclampsia in healthy nulliparous women. The Calcium for Preeclampsia Prevention (CPEP) Study Group Am J Obstet Gynecol. 1997;177:1003–1010
  74. Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M. A United States national reference for fetal growth. Obstet Gynecol. 1996;87:163–168
  75. Gonzalez RP, Gomez RM, Castro RS, et al. [A national birth weight distribution curve according to gestational age in Chile from 1993 to 2000]. Rev Med Chil. 2004;132:1155–1165
  76. Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol. 1999;19:550–555
  77. Quintero RA, Quintero L, Pivatelli A, Bornick PW, Allen M, Johnson P. The donor-recipient (D-R) score: in vivo endoscopic evidence to support the hypothesis of a net transfer of blood from donor to recipient in twin-twin transfusion syndrome. Prenat Neonat Med. 2000;5:84–91
  78. Bermudez C, Becerra CH, Bornick PW, Allen MH, Arroyo J, Quintero RA. Placental types and twin-twin transfusion syndrome. Am J Obstet Gynecol. 2002;187:489–494
  79. Bermudez C, Becerra C, Bornick PW, Allen MH, Arroyo J, Quintero RA. Twin-twin transfusion syndrome with only superficial placental anastomoses: endoscopic and pathological evidence. J Matern Fetal Neonatal Med. 2002;12:138–140
  80. Lewi L, Van SD, Gratacos E, Witters I, Timmerman D, Deprest J. Monochorionic diamniotic twins: complications and management options. Curr Opin Obstet Gynecol. 2003;15:177–194
  81. Galea P, Jain V, Fisk NM. Insights into the pathophysiology of twin-twin transfusion syndrome. Prenat Diagn. 2005;25:777–785
  82. Harkness UF, Crombleholme TM. Twin-twin transfusion syndrome: where do we go from here?. Semin Perinatol. 2005;29:296–304
  83. Bajoria R, Ward S, Chatterjee R. Natriuretic peptides in the pathogenesis of cardiac dysfunction in the recipient fetus of twin-twin transfusion syndrome. Am J Obstet Gynecol. 2002;186:121–127
  84. Mahieu-Caputo D, Dommergues M, Delezoide AL, et al. Twin-to-twin transfusion syndrome (Role of the fetal renin-angiotensin system). Am J Pathol. 2000;156:629–636
  85. Sooranna SR, Ward S, Bajoria R. Discordant fetal leptin levels in monochorionic twins with chronic midtrimester twin-twin transfusion syndrome. Placenta. 2001;22:392–398
  86. Bajoria R, Gibson MJ, Ward S, Sooranna SR, Neilson JP, Westwood M. Placental regulation of insulin-like growth factor axis in monochorionic twins with chronic twin-twin transfusion syndrome. J Clin Endocrinol Metab. 2001;86:3150–3156
  87. Nevo O, Many A, Xu J, et al. Placental expression of sFlt-1 is increased in singletons and twin pregnancies with intrauterine growth restriction. J Clin Endocrinol Metab. 2008;93:285–292
  88. Heyborne KD, Chism DM. Reversal of Ballantyne syndrome by selective second-trimester fetal termination (A case report). J Reprod Med. 2000;45:360–362
  89. Audibert F, Salomon LJ, Castaigne-Meary V, Alves K, Frydman R. Selective termination of a twin pregnancy as a treatment of severe pre-eclampsia. BJOG. 2003;110:68–69
  90. Heyborne KD, Porreco RP. Selective fetocide reverses preeclampsia in discordant twins. Am J Obstet Gynecol. 2004;191:477–480
  91. Pirhonen JP, Hartgill TW. Spontaneous reversal of mirror syndrome in a twin pregnancy after a single fetal death. Eur J Obstet Gynecol Reprod Biol. 2004;116:106–107
  92. Audibert F, Saloman LJ, Frydman R. Selective fetocide reverses preeclampsia in discordant twins. Am J Obstet Gynecol. 2005;193:894–895
  93. Romero R, Nien JK, Espinoza J, et al. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic/soluble endoglin and soluble endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small-for-gestational-age neonate. J Matern Fetal Neonatal Medicine. 2008;21:9–23

 This research was supported in part by the Intramural Research Program of the National Institute of Child Health and Human Development, NIH, DHHS.

 Cite this article as: Kusanovic JP, Romero R, Espinoza J, et al. Twin-to-twin transfusion syndrome: an antiangiogenic state? Am J Obstet Gynecol 2008;198:382.e1-382.e8.

PII: S0002-9378(08)00152-X

doi:10.1016/j.ajog.2008.02.016

American Journal of Obstetrics & Gynecology
Volume 198, Issue 4 , Pages 382.e1-382.e8, April 2008

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