DOI: 10.1002/pd.4458
ORIGINAL ARTICLE
Prenatal management and outcomes in mirror syndrome associated with twin–twin transfusion syndrome Hanjing Chai, Qun Fang, Xuan Huang, Yi Zhou and Yanmin Luo* Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China *Correspondence to: Yanmin Luo. E-mail: [email protected]
ABSTRACT Objective The aim of this article is to investigate the prevalence, clinical presentation, prenatal management, and prognosis of mirror syndrome associated with twin–twin transfusion syndrome (TTTS) treated by amnioreduction or selective fetocide. Method A retrospective study of twin pregnancies with TTTS was conducted. The prevalence of mirror syndrome, defined as severe maternal edema related to fetal hydrops and placental edema, was calculated for TTTS, and data on clinical characteristics, treatment, and outcomes of the patients were reviewed.
Results We observed mirror syndrome in 4.85% (5/103) of pregnancies with TTTS and 26.32% (5/19) of pregnancies with TTTS Stage IV. Most cases (4/5) of mirror syndrome associated with TTTS were diagnosed before 24 weeks of gestation. The patients manifested edema, anemia, hemodilution, and hypoproteinemia (5/5); proteinuria (4/5); complicated postpartum hemorrhage (4/5); and pulmonary edema and congestive heart failure (2/5). Maternal hemoglobin, hematocrit, and plasma protein dropped after amnioreduction. The perinatal survival rate at 28 days was 28.57% (2/7), and only one infant born after selective feticide survived beyond 18 months.
Conclusion TTTS carries a high risk of mirror syndrome, a disease with significant materno-fetal mortality and morbidity. Amnioreduction alone or with selective feticide in mirror syndrome may transiently aggravate anemia and hemodilution and lead to severe maternal complications. © 2014 John Wiley & Sons, Ltd.
Funding sources: This work was supported in part by the National Natural Science Foundation of China (no. 81270705) and the PhD Start-up Fund of Natural Science Foundation of Guangdong Province, China (no. S2011040004280). Conflicts of interest: None declared
INTRODUCTION
METHODS
Mirror syndrome, also known as Ballantyne syndrome, was first described by John William Ballantyne in 1892.1 The syndrome is characterized by maternal edema related to serious fetal hydrops or placental edema, and the mother ‘mirrors’ the fetal state of hydrops in utero. The syndrome is associated to both immune and nonimmune causes of fetal hydrops, such as Rh isoimmunization, fetal arrhythmias, and twin–twin transfusion syndrome (TTTS). Mirror syndrome is a potentially life-threatening disease with high fetal mortality and maternal morbidity.2 TTTS is a serious complication of monochorionic pregnancy, which may be associated with fetal hydrops in the so-called Quintero Stage IV. Few cases of mirror syndrome associated with TTTS have been reported,2 and the clinical characteristics of this association remain unclear. In this study, we retrospectively analyze the clinical data from mirror syndrome cases associated with TTTS and discuss the management of this clinical condition.
All pregnant women with TTTS managed at the First Affiliated Hospital, Sun Yat-sen University from January 2010 to July 2012 were included. This study was approved by the Institutional Review Board. Twin–twin transfusion syndrome was defined as polyhydramnios in the recipient’s amniotic cavity [the maximum vertical pocket (MVP) ≥8 cm at or before 20 weeks of gestation or ≥10 cm after 20 weeks of gestation] and oligohydramnios in the donor’s sac (MVP ≤2 cm) in a monochorionic twin pregnancy.3 Severity was assessed according to the Quintero staging system as follows: Stage I, oli-poly sequence; Stage II, the bladder of the donor twin is no longer visible; Stage III, Doppler studies are critically abnormal in either of the twins and are characterized by absent or reverse end-diastolic velocity in the umbilical artery, reverse flow in the ductus venosus, or pulsatile umbilical venous flow; Stage IV, fetal hydrops; and Stage V, demise of one or both fetuses.4 The diagnosis of mirror syndrome was based on the presence of
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maternal edema (skin and/or pulmonary edema) related to fetal hydrops and placental edema.5–7 Fetal hydrops was defined as excessive fetal fluid accumulation in at least two serous cavities (abdomen, pleura, and pericardium) or in the body tissue (subcutaneous edema).8 Physical examinations and echocardiography were performed on patients after admission. All fetuses had a detailed sonographic assessment, including Doppler investigation of blood flow velocity waveforms. TTTS Stage I-II was managed expectantly or by amnioreduction when the MVP was greater than 12 cm or the patient developed abdominal distension. Severe cases of TTTS (Stage III-IV) were treated with either selective feticide with bipolar cord coagulation or amnioreduction; fetoscopic coagulation of placental anastomoses was not feasible in our hospital at the time of the study. Bipolar cord coagulation was conducted for feticide of recipients, followed by rapid amnioreduction, as reported previously.9 Amnioreduction was performed under ultrasonography using a 16-G needle inserted percutaneously into the recipient’s amniotic sac, and amniotic fluid was removed until the MVP of the recipient twin was below 8 cm. Maternal complete blood count and plasma proteins were assessed prior to and after any fetal therapies. Perinatal outcomes were recorded, including gestational age at delivery, neonatal mortality, and infant survival at 1 year.
Blood pressure was considered elevated when greater than or equal to 140/90 mmHg. Oliguria was defined as a urine output less than 400 mL daily. Normal references are as follows: hemoglobin (Hb) 110 to 150 g/L, hematocrit (Hct) 0.330 to 0.450, total protein 60 to 87 g/L, albumin (Alb) 35 to 50 g/L, proteinuria , alanine aminotransferase 1 to 40 U/L, and aspartate aminotransferase 1 to 37 U/L.
RESULTS A total of 103 monochorionic diamniotic twin pregnancies with TTTS were diagnosed, and 19 were classified as Quintero Stage IV. Of these 19 cases, five developed mirror syndrome. The prevalence of mirror syndrome was 4.85% (5/103) in all twin pregnancies with TTTS and 26.32% (5/19) in TTTS Stage IV pregnancies. The characteristics and outcomes of the five cases of mirror syndrome associated with TTTS are summarized in Tables 1 and 2. The gestational age at diagnosis of TTTS-associated mirror syndrome ranged from 19.4 to 28.2 weeks of gestation. Three cases (Patients 1, 2, and 5) were diagnosed with mirror syndrome at the moment of diagnosis of TTTS; the maternal symptoms of Patient 1 and Patient 2 worsened after selective feticide. Two cases (Patient 3 and Patient 4) were diagnosed with mirror syndrome after amnioreduction. All patients presented with marked edema in the ankles and legs. Slightly
Table 1 Clinical characteristics of mirror syndrome associated with twin–twin transfusion syndrome Gestational weeks at mirror Patient syndrome no. diagnosis 1
24.0
Laboratory data at mirror syndrome diagnosis
Oliguria
Blood pressure (mmHg)
Hb (g/L)
Hct
TP (g/L)
Alb ALT (g/L) Proteinuria (U/L)
LEE
No
121/70–141/78
86
0.272
57.1
33.1
Edema
++
AST (U/L)
19
22
2
23.6
LEE, Vulval edema
Yes
100/60–144/93
96
0.283
50.2
27.6
+
19
30
3
28.2
LEE
No
95/65–139/80
85
0.256
45.6
27.1
+
119
107
+
4
21.3
LEE
Yes
110/52–148/95
75
0.226
45.8
23.9
5
19.4
LEE
No
99/59–121/67
87
0.251
53.9
29.1
58
45
24
19
Hb, hemoglobin; Hct, hematocrit; TP, total protein; Alb, albumin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LEE, lower extremity edema. Oliguria is defined as urine output less than 400 mL daily. Normal references: Hb 110 to 150 g/L, Hct 0.330 to 0.450, TP 60 to 87 g/L, Alb 35 to 50 g/L, proteinuria 1 to 40 U/L, and AST 1 to 37 U/L.
, ALT
Table 2 Treatment and outcomes of mirror syndrome associated with twin–twin transfusion syndrome Patient no.
Treatment
Gestational weeks at treatment
Gestational weeks at delivery
Perinatal outcomes Recipient
Donor
Maternal complications
Maternal recovery
1
SF
24.2
29
SF
Survived beyond 18 months
8 days after SF
2
SF
24.1
25.1
SF
Neonatal death after delivery
Pulmonary edema, congestive heart failure, PPH
8 days after cesarean section
3
Cesarean section
28.4
28.4
Neonatal death after delivery
Infant death at 7 months
PPH
10 days after cesarean section
4
IOL
21.3
21.3
Miscarriage
Miscarriage
Pulmonary edema, congestive heart failure, PPH
4 days after delivery
5
Amnioreduction and IOL
21.2
21.4
IUD
Miscarriage
PPH
2 days after delivery
SF, selective feticide; IOL, induction of labor; PPH, postpartum hemorrhage; IUD, intrauterine death.
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elevated blood pressure (3/5) occasionally occurred, as well as oliguria (2/5). Laboratory data revealed anemia and hemodilution (5/5), hypoproteinemia (5/5), proteinuria (4/5), and elevated liver enzymes (2/5). Severe maternal complications included postpartum hemorrhage (4/5), as well as pulmonary edema and congestive heart failure (2/5). The perinatal outcomes were poor. The overall perinatal survival at 28 days was 28.57% (2/7) among seven fetuses who were alive in utero after selective feticide or amnioreduction, and only one infant born after selective feticide survived beyond 18 months. Patient 1 and Patient 2 presented with marked edema in the ankles and legs when the ultrasonic examination confirmed fetal hydrops in recipient twins, including signs of skin edema, ascites, pleural effusion, and polyhydramnios. A bipolar cord occlusion procedure was performed on the recipient. In both, the maternal Hb and Hct values decreased dramatically on postoperative day (POD) 1 (Table 3 and Figure 1). No signs of internal hemorrhage were identified on ultrasonography, and the blood pressure of the patients was normal. The Hb and Hct levels did not improve even after transfusion with 200 to 400 mL erythrocytes. Patient 1 developed tachycardia and cardiomegaly after selective feticide and improved on POD 2, whereas maternal anemia improved (Hb 102 g/L, Hct 0.318) until POD 8. The co-twin was born at 29 weeks of gestation and was healthy at 18 months of age. The changes in Hb, Hct, and total plasma protein in Patient 2 are shown in Figure 1. Unfortunately, after selective feticide, Patient 2 presented with progressive generalized marked edema, including severe edema of the legs, external genitalia, and abdominal skin, and abdominal distention. On POD 3, uterine contractions were intermittently developed and were accompanied by a filling jugular vein, bilateral basilar pulmonary rales, and oliguria. Arterial blood gas values revealed a pH 7.39, PO2 75 mmHg, PCO2 30.2 mmHg, and HCO3 18.5 mmol/L. The patient was transferred to an intensive care unit and managed with nasal oxygenation, transfusion, Alb administration, and diuresis under close observation. On POD 6, the patient developed dyspnea, pulmonary edema, and uterine contractions; was treated with inotropic agents, diuretics, and fluid restriction; and delivered abdominally on POD 7. The placenta was edematous and large, weighing 830 g, and the percentage of the recipient was approximately 70% (Figure 2); the donor twin died immediately after delivery. Maternal pulmonary and systemic edema began
to resolve, and maternal anemia, hypoproteinemia (Figure 1), and proteinuria improved on the day following delivery, and she recovered on POD 8. Both Patient 3 and Patient 4 were diagnosed with mirror syndrome after amnioreduction. Patient 3 was admitted as TTTS Stage IV without maternal edema at 27.3 weeks of gestation. After amnioreduction, the patient developed severe edema of the legs, moderate anemia, elevated liver enzymes, and cardiomegaly. Emergent cesarean section was performed at 28.4 weeks of gestation. The patient recovered 10 days after delivery. The donor twin survived beyond 28 days of life but died of asphyxia at 7 months; the recipient twin was hydropic (skin and scalp edema) and died within 10 min of the delivery. Patient 4 was admitted as TTTS Stage II and presented with edema of the legs and oliguria at 21 weeks of gestation. Both maternal and fetal conditions worsened 2 days after amnioreduction. The patient suffered from dyspnea and tachycardia. The chest X-ray revealed bilateral middle and lower pulmonary lobe infiltration and pleural effusions. Because pulmonary edema and early signs of congestive heart failure were suspected, labor was induced. Four hours later, two dead fetuses were delivered, and skin edema and pleural effusions were confirmed in the recipient twin. The dyspnea and tachycardia were resolved after delivery, and the edema was resolved on POD 4. Patient 5 exhibited severe edema of the legs 3 days before the ultrasound showed that the hydropic recipient died in utero at 20 weeks of gestation. Because the patient developed progressive anemia, amnioreduction and induction of labor were performed at 21.2 weeks of gestation. The patient recovered from mirror syndrome 2 days post-delivery. In all the cases, laboratory values demonstrated decreases in Hb, Hct, plasma protein, and Alb after amnioreduction (Table 3), independent of the volume of drained amniotic fluid (range, 1100–4850 mL). The mean differences in Hb, Hct, plasma protein, and Alb before and after amnioreduction were 22.8 g/L, 0.06, 8.3 g/L, and 5.6 g/L, respectively.
DISCUSSION The TTTS affects 10% to 15% of monochorionic diamniotic twin pregnancies,10 and about 6% to 18% of cases in reported studies were Stage IV.11–13 Mirror syndrome associated with TTTS has been rarely reported.2 However, the incidence of this
Table 3 Changes in maternal blood components following amnioreduction
Patient no.
Volume of drained amniotic fluid (mL)
Hb (g/L) Before AR
Hct
TP (g/L)
After AR
Before AR
After AR
Before AR
Alb (g/L)
After AR
Before AR
After AR
1
3950
86
77
0.272
0.243
57.1
2
2000
96
70
0.283
0.217
50.2
45.0
27.6
20.0
3
4850
118
85
0.345
0.256
57.4
45.6
33.1
27.1
4
3600
113
75
0.326
0.226
51.1
45.8
26.9
23.9
5
1100
87
79
0.251
0.237
53.9
43.0
29.1
23.4
Mean differences between before/after AR
22.8
0.060
8.3
33.1
5.6
Hb, hemoglobin; Hct, hematocrit; TP, total protein; Alb, Albumin; AR, amnioreduction.
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Figure 2 Macroscopic view of the edematous placenta of Patient 2. The placenta weighed 830 g and was edematous in the region of recipient
Figure 1 Maternal hemoglobin (A), hematocrit (B), and total protein (C) levels before and after selective feticide and after Cesarean section in Patient 2. POD, postoperative day; PPD, postpartum day
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associated condition is unknown, and no large series has been reported. In the present study, 103 twin pregnancies with TTTS were included. Mirror syndrome affected approximately 4.8% of these TTTS cases or 26.3% of the TTTS Stage IV cases, indicating that mirror syndrome was not rare in twin pregnancies with TTTS Stage IV. The pathogenesis and pathophysiology of mirror syndrome associated with TTTS are not completely understood. Maternal circulating antiangiogenic factors, including soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), are increased in mirror syndrome.14–16 These factors may be responsible for the endothelial dysfunction that in turn causes mirror syndrome. Higher maternal plasma concentrations of sFlt-1 and sEng and lower placental growth factor levels were also found in monochorionic diamniotic pregnancies with TTTS compared with those without TTTS.17 Levels of sFlt-1 and sEng were further increased in the cases of TTTS with mirror syndrome compared with those without mirror syndrome.14 In addition, fetal edema is frequently associated with villous edema.15 Edematous villi may narrow the intervillous space and compress the villous blood vessels, which may reduce oxygen exchange and blood flow through the villi. Hypoxia of the villous trophoblast leads to increased production and the release of sFlt-1 into the maternal circulation, resulting in maternal endothelial injury.14 In a review of 56 mirror syndrome cases, the most common maternal symptoms were weight gain and maternal edema (89.3%), followed by elevated blood pressure (60.7%), mild anemia and hemodilution (46.4%), proteinuria (42.9%), elevated uric acid and creatinine (25%), mild elevated liver enzymes (19.6%), oliguria (16.1%), and headache and visual disturbances (14.3%).2 In the present study, the key maternal symptoms of mirror syndrome associated with TTTS were edema, anemia, hemodilution, hypoproteinemia, and proteinuria. However, slightly elevated blood pressure was observed in only three cases, which may be due to the early onset of mirror syndrome associated with TTTS. The differential diagnosis between preeclampsia and mirror syndrome is difficult. In mirror syndrome, maternal hemodilution is common and clinically presents as anemia. However, patients with preeclampsia usually present with hemoconcentration (high Hb and Hct). The presence of hemodilutional anemia in mirror syndrome may be explained by the elevated blood volume associated with high maternal serum levels of vasopressin and © 2014 John Wiley & Sons, Ltd.
Mirror syndrome in twin–twin transfusion syndrome
atrial natriuretic factor.18,19 Additionally, preeclampsia often occurs at a later stage of pregnancy. The youngest gestational age at which mirror syndrome has been reported is 16 weeks.20 Preeclampsia is seldom diagnosed before 24 weeks of gestation. The earliest time point of mirror syndrome diagnosis in our cases was 19.4 weeks of gestation (Patient 5). In addition, in mirror syndrome, the platelet count is usually unaffected; this parameter may be used to distinguish mirror syndrome from hemolysis, elevated liver enzymes, and low platelet count syndrome.21 The prognosis of the combination of TTTS and mirror syndrome in our study was poor for both the mother and the fetus. In this study, the severe maternal complications included postpartum hemorrhage, pulmonary edema, and congestive heart failure. Other maternal complications previously reported are placental abruption, disseminated intravascular coagulation; hemolysis, elevated liver enzymes, and low platelet count syndrome; and acute kidney failure.22 In our study, the perinatal survival rate was 28.57% (2/7), similar to that of mirror syndrome associated with other causes.2,23 For singleton pregnancies, maternal symptoms associated with mirror syndrome disappeared shortly after treatment of fetal symptoms or termination of the pregnancy (mean 8.9 days).2,24,25 In a case of dichorionic twin pregnancy with mirror syndrome, maternal edema was resolved after the hydropic fetus died,21 which suggested selective feticide as another option for treating mirror syndrome in twin pregnancies. Patient 1 recovered from mirror syndrome 8 days after selective feticide and delivered a healthy baby. Nevertheless, the maternal symptoms worsened after selective feticide in both Patient 1 and Patient 2, and Patient 2 suffered from pulmonary edema and congestive heart failure. We speculate that the reason for maternal deterioration is the associated amnioreduction. Relief of maternal abdominal pressure by amnioreduction increases venous return to the heart, which when combined with transfusion, increased cardiac preload, resulting in congestive heart failure. This hypothesis is supported by the dramatically aggravated anemia and hemodilution after amnioreduction as shown in Table 3 and Figure 1. Further, both Patient 3 and Patient 4 developed mirror syndrome after amnioreduction without selective feticide. Moreover, hydropic placenta is crucial for the development of mirror syndrome, and production of certain substances (such as sFLT-1 and sEng) by hydropic villi causes endothelial dysfunction and the clinical manifestation of mirror syndrome.18,26,27 We speculate that amnioreduction can reduce the intra-amniotic and placental intravascular
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pressures, potentially facilitating blood flow through the hydropic placenta, which most likely increases the release of sFlt-1 and sEng transiently to the maternal circulation and thus leads to the maternal deterioration. This hypothesis may explain why severe complications such as pulmonary edema and congestive heart failure were observed after amnioreduction in our study. A similar phenomenon was described in which maternal edema worsened shortly after fetoscopic laser photocoagulation in the case of TTTS when amnioreduction was performed before or after laser surgery.6,28 Further studies have to be carried out to approve this hypothesis. Huber et al.29 found a significant correlation between the amount of amniotic fluid drained and the decrease in maternal Hb and Hct. However, this phenomenon was not observed in our limited series. Careful fluid balance, with rational administration of intravenous fluids based on hemodynamic indices and endorgan function, will reduce the risk of acute pulmonary edema.30 A limitation of this study is that the rate of TTTS Stage IV was high (18.45%), which may be because some advanced cases were transferred to our center from local hospitals and that fetoscopic coagulation of the placental anastomoses was not yet feasible at the time of the study. Successful laser surgery for severe TTTS has been used to treat mirror syndrome with complete resolution of fetal hydrops.6
CONCLUSIONS The TTTS carries a high risk of mirror syndrome, a disease with significant fetal mortality and maternal morbidity. In our study, we observed that amnioreduction alone or with selective feticide transiently aggravated anemia and hemodilution, which may lead to severe maternal complications such as pulmonary edema and congestive heart failure. WHAT’S ALREADY KNOWN ABOUT THIS TOPIC? • Mirror syndrome associated with twin–twin transfusion syndrome is a rare and life-threatening disease resulting in substantial increases in materno-fetal mortality and morbidity.
WHAT DOES THIS STUDY ADD? • Mirror syndrome associated with twin–twin transfusion syndrome mostly occurs before 24 weeks of gestation, with key maternal signs including edema, anemia, hemodilution, hypoproteinemia, and proteinuria. Amnioreduction alone or with selective feticide may transiently aggravate anemia and hemodilution and may increase the risk of severe maternal complications.
REFERENCES 1. Dunn PM. Dr John Ballantyne (1861–1923): perinatologist extraordinary of Edinburgh. Arch Dis Child 1993;68:66–7. 2. Braun T, Brauer M, Fuchs I, et al. Mirror syndrome: a systematic review of fetal associated conditions, maternal presentation and perinatal outcome. Fetal Diagn Ther 2010;27:191–203. 3. Van Mieghem T, Eixarch E, Gucciardo L, et al. Outcome prediction in monochorionic diamniotic twin pregnancies with moderately discordant amniotic fluid. Ultrasound Obstet Gynecol 2011;37:15–21.
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4. Quintero RA, Morales WJ, Allen MH, et al. Staging of twin–twin transfusion syndrome. J Perinatol 1999;19:550–5. 5. Brochot C, Collinet P, Provost N, Subtil D. Mirror syndrome due to parvovirus b19 hydrops complicated by severe maternal pulmonary effusion. Prenat Diagn 2006;26:179–80. 6. Matsubara M, Nakata M, Murata S, et al. Resolution of mirror syndrome after successful fetoscopic laser photocoagulation of communicating placental vessels in severe twin–twin transfusion syndrome. Prenat Diagn 2008;28:1167–8.
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7. Takahashi H, Matsubara S, Kuwata T, et al. Maternal manifestation of Ballantyne’s syndrome occurring concomitantly with the development of fetal congenital mesoblastic nephroma. J Obstet Gynaecol Res 2014;40:1114–7. 8. Warsof SL, Nicolaides KH, Rodeck C. Immune and non-immune hydrops. Clin Obstet Gynecol 1986;29:533–42. 9. He ZM, Fang Q, Yang YZ, et al. Fetal reduction by bipolar cord coagulation in managing complicated monochorionic multiple pregnancies: preliminary experience in china. Chin Med J (Engl) 2010;123:549–54. 10. Mosquera C, Miller RS, Simpson LL. Twin–twin transfusion syndrome. Semin Perinatol 2012;36:182–9. 11. Simpson LL. Twin–twin transfusion syndrome. Am J Obstet Gynecol 2013;208:3–18. 12. Pruetz JD, Sklansky M, Detterich J, et al. Twin–twin transfusion syndrome treated with laser surgery: postnatal prevalence of congenital heart disease in surviving recipients and donors. Prenat Diagn 2011;31:973–7. 13. Chmait RH, Kontopoulos EV, Korst LM, et al. Stage-based outcomes of 682 consecutive cases of twin–twin transfusion syndrome treated with laser surgery: the USFetus experience. Am J Obstet Gynecol 2011;204:393.e1–6. 14. Prefumo F, Pagani G, Fratelli N, et al. Increased concentrations of antiangiogenic factors in mirror syndrome complicating twin-to-twin transfusion syndrome. Prenat Diagn 2010;30:378–9. 15. 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;19:607–13. 16. Lobato G, Nakamura-Pereira M. Reversion of the Ballantyne syndrome despite fetal hydrops persistence. Fetal Diagn Ther 2008;24:474–7. 17. Kusanovic JP, Romero R, Espinoza J, et al. Twin-to-twin transfusion syndrome: an antiangiogenic state? Am J Obstet Gynecol 2008;198:382.e1–8. 18. Carbillon L, Oury JF, Guerin JM, et al. Clinical biological features of Ballantyne syndrome and the role of placental hydrops. Obstet Gynecol Surv 1997;52:310–4.
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19. Gherman RB, Incerpi MH, Wing DA, Goodwin TM. Ballantyne syndrome: is placental ischemia the etiology? J Matern Fetal Med 1998;7:227–9. 20. Heyborne KD, Chism DM. Reversal of Ballantyne syndrome by selective second-trimester fetal termination. A case report. J Reprod Med 2000;45:360–2. 21. 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;116:106–7. 22. Wu LL, Wang CH, Li ZQ. Clinical study of 12 cases with obstetric mirror syndrome. Zhonghua Fu Chan Ke Za Zhi 2012;47:175–8. 23. Zhao Y, Liu G, Wang J, et al. Mirror syndrome in a Chinese hospital: diverse causes and maternal fetal features. J Matern Fetal Neonatal Med 2013;26:254–8. 24. Simpson JM, Sharland GK. Fetal tachycardias: management and outcome of 127 consecutive cases. Heart 1998;79:576–81. 25. Frohn-Mulder IM, Stewart PA, Witsenburg M, et al. The efficacy of flecainide versus digoxin in the management of fetal supraventricular tachycardia. Prenat Diagn 1995;15:1297–302. 26. Llurba E, Marsal G, Sanchez O, et al. Angiogenic and antiangiogenic factors before and after resolution of maternal mirror syndrome. Ultrasound Obstet Gynecol 2012;40:367–9. 27. Graham N, Garrod A, Bullen P, Heazell AE. Placental expression of antiangiogenic proteins in mirror syndrome: a case report. Placenta 2012;33:528–31. 28. Hayashi S, Sago H, Hayashi R, et al. Manifestation of mirror syndrome after fetoscopic laser photocoagulation in severe twin-twin transfusion syndrome. Fetal Diagn Ther 2006;21:51–4. 29. Huber A, Diehl W, Zikulnig L, et al. Amniotic fluid and maternal blood characteristics in severe mid-trimester twin–twin transfusion syndrome. Fetal Diagn Ther 2004;19:504–9. 30. Dennis AT, Solnordal CB. Acute pulmonary oedema in pregnant women. Anaesthesia 2012;67:646–59.
© 2014 John Wiley & Sons, Ltd.
ORIGINAL ARTICLE
Prenatal management and outcomes in mirror syndrome associated with twin–twin transfusion syndrome Hanjing Chai, Qun Fang, Xuan Huang, Yi Zhou and Yanmin Luo* Fetal Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China *Correspondence to: Yanmin Luo. E-mail: [email protected]
ABSTRACT Objective The aim of this article is to investigate the prevalence, clinical presentation, prenatal management, and prognosis of mirror syndrome associated with twin–twin transfusion syndrome (TTTS) treated by amnioreduction or selective fetocide. Method A retrospective study of twin pregnancies with TTTS was conducted. The prevalence of mirror syndrome, defined as severe maternal edema related to fetal hydrops and placental edema, was calculated for TTTS, and data on clinical characteristics, treatment, and outcomes of the patients were reviewed.
Results We observed mirror syndrome in 4.85% (5/103) of pregnancies with TTTS and 26.32% (5/19) of pregnancies with TTTS Stage IV. Most cases (4/5) of mirror syndrome associated with TTTS were diagnosed before 24 weeks of gestation. The patients manifested edema, anemia, hemodilution, and hypoproteinemia (5/5); proteinuria (4/5); complicated postpartum hemorrhage (4/5); and pulmonary edema and congestive heart failure (2/5). Maternal hemoglobin, hematocrit, and plasma protein dropped after amnioreduction. The perinatal survival rate at 28 days was 28.57% (2/7), and only one infant born after selective feticide survived beyond 18 months.
Conclusion TTTS carries a high risk of mirror syndrome, a disease with significant materno-fetal mortality and morbidity. Amnioreduction alone or with selective feticide in mirror syndrome may transiently aggravate anemia and hemodilution and lead to severe maternal complications. © 2014 John Wiley & Sons, Ltd.
Funding sources: This work was supported in part by the National Natural Science Foundation of China (no. 81270705) and the PhD Start-up Fund of Natural Science Foundation of Guangdong Province, China (no. S2011040004280). Conflicts of interest: None declared
INTRODUCTION
METHODS
Mirror syndrome, also known as Ballantyne syndrome, was first described by John William Ballantyne in 1892.1 The syndrome is characterized by maternal edema related to serious fetal hydrops or placental edema, and the mother ‘mirrors’ the fetal state of hydrops in utero. The syndrome is associated to both immune and nonimmune causes of fetal hydrops, such as Rh isoimmunization, fetal arrhythmias, and twin–twin transfusion syndrome (TTTS). Mirror syndrome is a potentially life-threatening disease with high fetal mortality and maternal morbidity.2 TTTS is a serious complication of monochorionic pregnancy, which may be associated with fetal hydrops in the so-called Quintero Stage IV. Few cases of mirror syndrome associated with TTTS have been reported,2 and the clinical characteristics of this association remain unclear. In this study, we retrospectively analyze the clinical data from mirror syndrome cases associated with TTTS and discuss the management of this clinical condition.
All pregnant women with TTTS managed at the First Affiliated Hospital, Sun Yat-sen University from January 2010 to July 2012 were included. This study was approved by the Institutional Review Board. Twin–twin transfusion syndrome was defined as polyhydramnios in the recipient’s amniotic cavity [the maximum vertical pocket (MVP) ≥8 cm at or before 20 weeks of gestation or ≥10 cm after 20 weeks of gestation] and oligohydramnios in the donor’s sac (MVP ≤2 cm) in a monochorionic twin pregnancy.3 Severity was assessed according to the Quintero staging system as follows: Stage I, oli-poly sequence; Stage II, the bladder of the donor twin is no longer visible; Stage III, Doppler studies are critically abnormal in either of the twins and are characterized by absent or reverse end-diastolic velocity in the umbilical artery, reverse flow in the ductus venosus, or pulsatile umbilical venous flow; Stage IV, fetal hydrops; and Stage V, demise of one or both fetuses.4 The diagnosis of mirror syndrome was based on the presence of
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maternal edema (skin and/or pulmonary edema) related to fetal hydrops and placental edema.5–7 Fetal hydrops was defined as excessive fetal fluid accumulation in at least two serous cavities (abdomen, pleura, and pericardium) or in the body tissue (subcutaneous edema).8 Physical examinations and echocardiography were performed on patients after admission. All fetuses had a detailed sonographic assessment, including Doppler investigation of blood flow velocity waveforms. TTTS Stage I-II was managed expectantly or by amnioreduction when the MVP was greater than 12 cm or the patient developed abdominal distension. Severe cases of TTTS (Stage III-IV) were treated with either selective feticide with bipolar cord coagulation or amnioreduction; fetoscopic coagulation of placental anastomoses was not feasible in our hospital at the time of the study. Bipolar cord coagulation was conducted for feticide of recipients, followed by rapid amnioreduction, as reported previously.9 Amnioreduction was performed under ultrasonography using a 16-G needle inserted percutaneously into the recipient’s amniotic sac, and amniotic fluid was removed until the MVP of the recipient twin was below 8 cm. Maternal complete blood count and plasma proteins were assessed prior to and after any fetal therapies. Perinatal outcomes were recorded, including gestational age at delivery, neonatal mortality, and infant survival at 1 year.
Blood pressure was considered elevated when greater than or equal to 140/90 mmHg. Oliguria was defined as a urine output less than 400 mL daily. Normal references are as follows: hemoglobin (Hb) 110 to 150 g/L, hematocrit (Hct) 0.330 to 0.450, total protein 60 to 87 g/L, albumin (Alb) 35 to 50 g/L, proteinuria , alanine aminotransferase 1 to 40 U/L, and aspartate aminotransferase 1 to 37 U/L.
RESULTS A total of 103 monochorionic diamniotic twin pregnancies with TTTS were diagnosed, and 19 were classified as Quintero Stage IV. Of these 19 cases, five developed mirror syndrome. The prevalence of mirror syndrome was 4.85% (5/103) in all twin pregnancies with TTTS and 26.32% (5/19) in TTTS Stage IV pregnancies. The characteristics and outcomes of the five cases of mirror syndrome associated with TTTS are summarized in Tables 1 and 2. The gestational age at diagnosis of TTTS-associated mirror syndrome ranged from 19.4 to 28.2 weeks of gestation. Three cases (Patients 1, 2, and 5) were diagnosed with mirror syndrome at the moment of diagnosis of TTTS; the maternal symptoms of Patient 1 and Patient 2 worsened after selective feticide. Two cases (Patient 3 and Patient 4) were diagnosed with mirror syndrome after amnioreduction. All patients presented with marked edema in the ankles and legs. Slightly
Table 1 Clinical characteristics of mirror syndrome associated with twin–twin transfusion syndrome Gestational weeks at mirror Patient syndrome no. diagnosis 1
24.0
Laboratory data at mirror syndrome diagnosis
Oliguria
Blood pressure (mmHg)
Hb (g/L)
Hct
TP (g/L)
Alb ALT (g/L) Proteinuria (U/L)
LEE
No
121/70–141/78
86
0.272
57.1
33.1
Edema
++
AST (U/L)
19
22
2
23.6
LEE, Vulval edema
Yes
100/60–144/93
96
0.283
50.2
27.6
+
19
30
3
28.2
LEE
No
95/65–139/80
85
0.256
45.6
27.1
+
119
107
+
4
21.3
LEE
Yes
110/52–148/95
75
0.226
45.8
23.9
5
19.4
LEE
No
99/59–121/67
87
0.251
53.9
29.1
58
45
24
19
Hb, hemoglobin; Hct, hematocrit; TP, total protein; Alb, albumin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LEE, lower extremity edema. Oliguria is defined as urine output less than 400 mL daily. Normal references: Hb 110 to 150 g/L, Hct 0.330 to 0.450, TP 60 to 87 g/L, Alb 35 to 50 g/L, proteinuria 1 to 40 U/L, and AST 1 to 37 U/L.
, ALT
Table 2 Treatment and outcomes of mirror syndrome associated with twin–twin transfusion syndrome Patient no.
Treatment
Gestational weeks at treatment
Gestational weeks at delivery
Perinatal outcomes Recipient
Donor
Maternal complications
Maternal recovery
1
SF
24.2
29
SF
Survived beyond 18 months
8 days after SF
2
SF
24.1
25.1
SF
Neonatal death after delivery
Pulmonary edema, congestive heart failure, PPH
8 days after cesarean section
3
Cesarean section
28.4
28.4
Neonatal death after delivery
Infant death at 7 months
PPH
10 days after cesarean section
4
IOL
21.3
21.3
Miscarriage
Miscarriage
Pulmonary edema, congestive heart failure, PPH
4 days after delivery
5
Amnioreduction and IOL
21.2
21.4
IUD
Miscarriage
PPH
2 days after delivery
SF, selective feticide; IOL, induction of labor; PPH, postpartum hemorrhage; IUD, intrauterine death.
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elevated blood pressure (3/5) occasionally occurred, as well as oliguria (2/5). Laboratory data revealed anemia and hemodilution (5/5), hypoproteinemia (5/5), proteinuria (4/5), and elevated liver enzymes (2/5). Severe maternal complications included postpartum hemorrhage (4/5), as well as pulmonary edema and congestive heart failure (2/5). The perinatal outcomes were poor. The overall perinatal survival at 28 days was 28.57% (2/7) among seven fetuses who were alive in utero after selective feticide or amnioreduction, and only one infant born after selective feticide survived beyond 18 months. Patient 1 and Patient 2 presented with marked edema in the ankles and legs when the ultrasonic examination confirmed fetal hydrops in recipient twins, including signs of skin edema, ascites, pleural effusion, and polyhydramnios. A bipolar cord occlusion procedure was performed on the recipient. In both, the maternal Hb and Hct values decreased dramatically on postoperative day (POD) 1 (Table 3 and Figure 1). No signs of internal hemorrhage were identified on ultrasonography, and the blood pressure of the patients was normal. The Hb and Hct levels did not improve even after transfusion with 200 to 400 mL erythrocytes. Patient 1 developed tachycardia and cardiomegaly after selective feticide and improved on POD 2, whereas maternal anemia improved (Hb 102 g/L, Hct 0.318) until POD 8. The co-twin was born at 29 weeks of gestation and was healthy at 18 months of age. The changes in Hb, Hct, and total plasma protein in Patient 2 are shown in Figure 1. Unfortunately, after selective feticide, Patient 2 presented with progressive generalized marked edema, including severe edema of the legs, external genitalia, and abdominal skin, and abdominal distention. On POD 3, uterine contractions were intermittently developed and were accompanied by a filling jugular vein, bilateral basilar pulmonary rales, and oliguria. Arterial blood gas values revealed a pH 7.39, PO2 75 mmHg, PCO2 30.2 mmHg, and HCO3 18.5 mmol/L. The patient was transferred to an intensive care unit and managed with nasal oxygenation, transfusion, Alb administration, and diuresis under close observation. On POD 6, the patient developed dyspnea, pulmonary edema, and uterine contractions; was treated with inotropic agents, diuretics, and fluid restriction; and delivered abdominally on POD 7. The placenta was edematous and large, weighing 830 g, and the percentage of the recipient was approximately 70% (Figure 2); the donor twin died immediately after delivery. Maternal pulmonary and systemic edema began
to resolve, and maternal anemia, hypoproteinemia (Figure 1), and proteinuria improved on the day following delivery, and she recovered on POD 8. Both Patient 3 and Patient 4 were diagnosed with mirror syndrome after amnioreduction. Patient 3 was admitted as TTTS Stage IV without maternal edema at 27.3 weeks of gestation. After amnioreduction, the patient developed severe edema of the legs, moderate anemia, elevated liver enzymes, and cardiomegaly. Emergent cesarean section was performed at 28.4 weeks of gestation. The patient recovered 10 days after delivery. The donor twin survived beyond 28 days of life but died of asphyxia at 7 months; the recipient twin was hydropic (skin and scalp edema) and died within 10 min of the delivery. Patient 4 was admitted as TTTS Stage II and presented with edema of the legs and oliguria at 21 weeks of gestation. Both maternal and fetal conditions worsened 2 days after amnioreduction. The patient suffered from dyspnea and tachycardia. The chest X-ray revealed bilateral middle and lower pulmonary lobe infiltration and pleural effusions. Because pulmonary edema and early signs of congestive heart failure were suspected, labor was induced. Four hours later, two dead fetuses were delivered, and skin edema and pleural effusions were confirmed in the recipient twin. The dyspnea and tachycardia were resolved after delivery, and the edema was resolved on POD 4. Patient 5 exhibited severe edema of the legs 3 days before the ultrasound showed that the hydropic recipient died in utero at 20 weeks of gestation. Because the patient developed progressive anemia, amnioreduction and induction of labor were performed at 21.2 weeks of gestation. The patient recovered from mirror syndrome 2 days post-delivery. In all the cases, laboratory values demonstrated decreases in Hb, Hct, plasma protein, and Alb after amnioreduction (Table 3), independent of the volume of drained amniotic fluid (range, 1100–4850 mL). The mean differences in Hb, Hct, plasma protein, and Alb before and after amnioreduction were 22.8 g/L, 0.06, 8.3 g/L, and 5.6 g/L, respectively.
DISCUSSION The TTTS affects 10% to 15% of monochorionic diamniotic twin pregnancies,10 and about 6% to 18% of cases in reported studies were Stage IV.11–13 Mirror syndrome associated with TTTS has been rarely reported.2 However, the incidence of this
Table 3 Changes in maternal blood components following amnioreduction
Patient no.
Volume of drained amniotic fluid (mL)
Hb (g/L) Before AR
Hct
TP (g/L)
After AR
Before AR
After AR
Before AR
Alb (g/L)
After AR
Before AR
After AR
1
3950
86
77
0.272
0.243
57.1
2
2000
96
70
0.283
0.217
50.2
45.0
27.6
20.0
3
4850
118
85
0.345
0.256
57.4
45.6
33.1
27.1
4
3600
113
75
0.326
0.226
51.1
45.8
26.9
23.9
5
1100
87
79
0.251
0.237
53.9
43.0
29.1
23.4
Mean differences between before/after AR
22.8
0.060
8.3
33.1
5.6
Hb, hemoglobin; Hct, hematocrit; TP, total protein; Alb, Albumin; AR, amnioreduction.
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Figure 2 Macroscopic view of the edematous placenta of Patient 2. The placenta weighed 830 g and was edematous in the region of recipient
Figure 1 Maternal hemoglobin (A), hematocrit (B), and total protein (C) levels before and after selective feticide and after Cesarean section in Patient 2. POD, postoperative day; PPD, postpartum day
Prenatal Diagnosis 2014, 34, 1213–1218
associated condition is unknown, and no large series has been reported. In the present study, 103 twin pregnancies with TTTS were included. Mirror syndrome affected approximately 4.8% of these TTTS cases or 26.3% of the TTTS Stage IV cases, indicating that mirror syndrome was not rare in twin pregnancies with TTTS Stage IV. The pathogenesis and pathophysiology of mirror syndrome associated with TTTS are not completely understood. Maternal circulating antiangiogenic factors, including soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), are increased in mirror syndrome.14–16 These factors may be responsible for the endothelial dysfunction that in turn causes mirror syndrome. Higher maternal plasma concentrations of sFlt-1 and sEng and lower placental growth factor levels were also found in monochorionic diamniotic pregnancies with TTTS compared with those without TTTS.17 Levels of sFlt-1 and sEng were further increased in the cases of TTTS with mirror syndrome compared with those without mirror syndrome.14 In addition, fetal edema is frequently associated with villous edema.15 Edematous villi may narrow the intervillous space and compress the villous blood vessels, which may reduce oxygen exchange and blood flow through the villi. Hypoxia of the villous trophoblast leads to increased production and the release of sFlt-1 into the maternal circulation, resulting in maternal endothelial injury.14 In a review of 56 mirror syndrome cases, the most common maternal symptoms were weight gain and maternal edema (89.3%), followed by elevated blood pressure (60.7%), mild anemia and hemodilution (46.4%), proteinuria (42.9%), elevated uric acid and creatinine (25%), mild elevated liver enzymes (19.6%), oliguria (16.1%), and headache and visual disturbances (14.3%).2 In the present study, the key maternal symptoms of mirror syndrome associated with TTTS were edema, anemia, hemodilution, hypoproteinemia, and proteinuria. However, slightly elevated blood pressure was observed in only three cases, which may be due to the early onset of mirror syndrome associated with TTTS. The differential diagnosis between preeclampsia and mirror syndrome is difficult. In mirror syndrome, maternal hemodilution is common and clinically presents as anemia. However, patients with preeclampsia usually present with hemoconcentration (high Hb and Hct). The presence of hemodilutional anemia in mirror syndrome may be explained by the elevated blood volume associated with high maternal serum levels of vasopressin and © 2014 John Wiley & Sons, Ltd.
Mirror syndrome in twin–twin transfusion syndrome
atrial natriuretic factor.18,19 Additionally, preeclampsia often occurs at a later stage of pregnancy. The youngest gestational age at which mirror syndrome has been reported is 16 weeks.20 Preeclampsia is seldom diagnosed before 24 weeks of gestation. The earliest time point of mirror syndrome diagnosis in our cases was 19.4 weeks of gestation (Patient 5). In addition, in mirror syndrome, the platelet count is usually unaffected; this parameter may be used to distinguish mirror syndrome from hemolysis, elevated liver enzymes, and low platelet count syndrome.21 The prognosis of the combination of TTTS and mirror syndrome in our study was poor for both the mother and the fetus. In this study, the severe maternal complications included postpartum hemorrhage, pulmonary edema, and congestive heart failure. Other maternal complications previously reported are placental abruption, disseminated intravascular coagulation; hemolysis, elevated liver enzymes, and low platelet count syndrome; and acute kidney failure.22 In our study, the perinatal survival rate was 28.57% (2/7), similar to that of mirror syndrome associated with other causes.2,23 For singleton pregnancies, maternal symptoms associated with mirror syndrome disappeared shortly after treatment of fetal symptoms or termination of the pregnancy (mean 8.9 days).2,24,25 In a case of dichorionic twin pregnancy with mirror syndrome, maternal edema was resolved after the hydropic fetus died,21 which suggested selective feticide as another option for treating mirror syndrome in twin pregnancies. Patient 1 recovered from mirror syndrome 8 days after selective feticide and delivered a healthy baby. Nevertheless, the maternal symptoms worsened after selective feticide in both Patient 1 and Patient 2, and Patient 2 suffered from pulmonary edema and congestive heart failure. We speculate that the reason for maternal deterioration is the associated amnioreduction. Relief of maternal abdominal pressure by amnioreduction increases venous return to the heart, which when combined with transfusion, increased cardiac preload, resulting in congestive heart failure. This hypothesis is supported by the dramatically aggravated anemia and hemodilution after amnioreduction as shown in Table 3 and Figure 1. Further, both Patient 3 and Patient 4 developed mirror syndrome after amnioreduction without selective feticide. Moreover, hydropic placenta is crucial for the development of mirror syndrome, and production of certain substances (such as sFLT-1 and sEng) by hydropic villi causes endothelial dysfunction and the clinical manifestation of mirror syndrome.18,26,27 We speculate that amnioreduction can reduce the intra-amniotic and placental intravascular
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pressures, potentially facilitating blood flow through the hydropic placenta, which most likely increases the release of sFlt-1 and sEng transiently to the maternal circulation and thus leads to the maternal deterioration. This hypothesis may explain why severe complications such as pulmonary edema and congestive heart failure were observed after amnioreduction in our study. A similar phenomenon was described in which maternal edema worsened shortly after fetoscopic laser photocoagulation in the case of TTTS when amnioreduction was performed before or after laser surgery.6,28 Further studies have to be carried out to approve this hypothesis. Huber et al.29 found a significant correlation between the amount of amniotic fluid drained and the decrease in maternal Hb and Hct. However, this phenomenon was not observed in our limited series. Careful fluid balance, with rational administration of intravenous fluids based on hemodynamic indices and endorgan function, will reduce the risk of acute pulmonary edema.30 A limitation of this study is that the rate of TTTS Stage IV was high (18.45%), which may be because some advanced cases were transferred to our center from local hospitals and that fetoscopic coagulation of the placental anastomoses was not yet feasible at the time of the study. Successful laser surgery for severe TTTS has been used to treat mirror syndrome with complete resolution of fetal hydrops.6
CONCLUSIONS The TTTS carries a high risk of mirror syndrome, a disease with significant fetal mortality and maternal morbidity. In our study, we observed that amnioreduction alone or with selective feticide transiently aggravated anemia and hemodilution, which may lead to severe maternal complications such as pulmonary edema and congestive heart failure. WHAT’S ALREADY KNOWN ABOUT THIS TOPIC? • Mirror syndrome associated with twin–twin transfusion syndrome is a rare and life-threatening disease resulting in substantial increases in materno-fetal mortality and morbidity.
WHAT DOES THIS STUDY ADD? • Mirror syndrome associated with twin–twin transfusion syndrome mostly occurs before 24 weeks of gestation, with key maternal signs including edema, anemia, hemodilution, hypoproteinemia, and proteinuria. Amnioreduction alone or with selective feticide may transiently aggravate anemia and hemodilution and may increase the risk of severe maternal complications.
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4. Quintero RA, Morales WJ, Allen MH, et al. Staging of twin–twin transfusion syndrome. J Perinatol 1999;19:550–5. 5. Brochot C, Collinet P, Provost N, Subtil D. Mirror syndrome due to parvovirus b19 hydrops complicated by severe maternal pulmonary effusion. Prenat Diagn 2006;26:179–80. 6. Matsubara M, Nakata M, Murata S, et al. Resolution of mirror syndrome after successful fetoscopic laser photocoagulation of communicating placental vessels in severe twin–twin transfusion syndrome. Prenat Diagn 2008;28:1167–8.
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