Twin anemia polycythemia sequence from a prenatal perspective

PRENATAL DIAGNOSIS

Prenat Diagn 2010; 30: 438–442. Published online 5 April 2010 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/pd.2491

Twin anemia polycythemia sequence from a prenatal perspective† L´eonardo Gucciardo1 , Liesbeth Lewi1 , Pascal Vaast2 , Marzena Debska3 , Luc De Catte1 , Tim Van Mieghem1 , Elisa Done1 , Roland Devlieger1 and Jan Deprest1 * 1

Department of Obstetrics and Gynecology, University Hospitals, Leuven, Belgium Department of Obstetrics and Gynecology, CHU Jeanne de Flandre, Lille, France 3 Klinika Połoznictwa i Ginekologii CMKP, Szpital Bielanski, Warszaw, Poland 2

Objectives To describe the prevalence, management and outcome of spontaneous twin anemia polycythemia sequence (TAPS) diagnosed in the prenatal period. Method Retrospective analysis of 142 consecutive monochorionic twin pregnancies not diagnosed with twin to twin transfusion syndrome. TAPS cases were identified based on the presence of discordant middle cerebral artery peak systolic velocity (MCA-PSV) measurements and signs suggestive of a chronic intertwin transfusion imbalance: either an elevated reticulocyte count in the anemic twin or the presence of few small unidirectional anastomoses during fetoscopy or at postnatal placental examination. Results Three cases were identified, giving an estimated prevalence of 2%. Prenatal interventions were tailored to the characteristics of each case and consisted of intrauterine transfusion and interruption of the shared circulation by cord coagulation or laser separation. Conclusion In monochorionic twin pregnancies, TAPS is an uncommon prenatal finding. Nonetheless, its incidence seems high enough to recommend screening for this disease by MCA-PSV measurements. Copyright  2010 John Wiley & Sons, Ltd. KEY WORDS:

prenatal; monochorionic twin pregnancy; anemia; polycythemia; fetoscopic laser; cord coagulation; middle cerebral artery; intrauterine transfusion

INTRODUCTION Monochorionic twin pregnancies nearly all have intertwin anastomoses connecting the fetal circulations. In most cases, the intertwin transfusion is balanced. However, imbalances may occur, leading to a number of complications (Lewi et al., 2008b). Twin to twin transfusion syndrome (TTTS) is the best known clinical entity, with a well described ultrasound appearance of oligoand polyhydramnios and its diagnosis is based on strict sonographic criteria defining the amniotic fluid discordance (Senat et al., 2004). TTTS is usually explained as a chronic net intertwin transfusion process. However, as the majority of twins diagnosed with TTTS do not have severe intertwin hemoglobin (Hb) differences (Denbow et al., 1998), hormonal factors are likely to be involved as well (Mahieu-Caputo et al., 2000). Severe intertwin Hb differences can nevertheless also occur in monochorionic twin pregnancies in the absence of severe amniotic fluid discordance typical for TTTS (Lopriore et al., 2005). Twin anemia polycythemia sequence (TAPS) was suggested as a separate clinical entity (Lopriore et al., 2007). TAPS can occur *Correspondence to: Jan Deprest, Department of Obstetrics and Gynecology, University Hospitals, Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected] † This work was presented at the ISUOG 2009 World Congress, Hamburg, Germany.

Copyright  2010 John Wiley & Sons, Ltd.

spontaneously in previously uncomplicated monochorionic twin pregnancies. It is, however, better known in its iatrogenic form as a complication of incomplete laser treatment for TTTS (Robyr et al., 2006). In both instances, the placentas typically show few, tiny and mostly unidirectional anastomoses (Lewi et al., 2008a; Lopriore et al., 2008). TAPS probably reflects a pure net intertwin transfusion, with a slow transfer of blood over these tiny anastomoses. Whereas the prenatal diagnosis, incidence and management of iatrogenic TAPS have been reported previously (Robyr et al., 2006), no information is yet available on the management of prenatally diagnosed spontaneous TAPS (i.e. not occurring after laser therapy). We therefore reviewed the prevalence, management and outcome of TAPS in previously uncomplicated monochorionic twin pregnancies. METHODS We conducted a retrospective analysis of our database including all monochorionic diamniotic twin pregnancies assessed in our unit during the year 2007. We excluded cases diagnosed with TTTS defined as a polyuric polyhydramnios in one twin [deepest vertical pocket (DVP) more than 8 cm before 20 weeks and more than 10 cm after 20 weeks] in one twin and an oligouric oligohydramnios (DVP less than 2 cm) in the other. TAPS was diagnosed as the presence of discordant middle cerebral artery peak systolic velocity Received: 15 October 2009 Revised: 14 January 2010 Accepted: 24 January 2010 Published online: 5 April 2010

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(MCA-PSV) measurements in combination with features suggestive of a chronic intertwin transfusion imbalance. In our center, we routinely measure MCA-PSV in all monochorionic twin pregnancies from 15 weeks of gestation until birth. Discordant MCA-PSV measurements were defined as a measurement over 1.5 MoM (multiples of the median) in one twin in combination with an MCA-PSV less than 0.8 MoM in its co-twin (Robyr et al., 2006). An increased MCA-PSV suggests fetal anemia, whereas a decreased MCA-PSV is an indicative of polycythemia. A chronic rather than an acute intertwin transfusion was diagnosed by an elevated reticulocyte count in the anemic twin or the presence of few small unidirectional anastomoses typical for TAPS as identified during fetoscopy or on placental injection studies after birth. Information on the pregnancy and neonatal outcome was obtained from the referring clinicians. The pregnancy and perinatal outcomes of part of this series were included in a larger prospective study reported elsewhere (Lewi et al., 2008b). Part of the MCA-PSV measurements from this cohort was included in a prospective longitudinal study performed in our unit (Klaritsch et al., 2009).

RESULTS In 2007, 142 monochorionic twin pregnancies without TTTS were evaluated. Three cases fulfilled the criteria of spontaneous TAPS (prevalence 2%, 95% confidence interval 0.44–6.3). The prenatal characteristics and neonatal outcomes are summarized in Tables 1 and 2, respectively. Placental examination confirmed monochorionicity and Kleihauer–Betke test, TORCH

screening and fetal karyotype were normal in all cases. Particularities of each individual case are described below.

Case 1 A 35-year-old G2P1 was referred at 26 weeks because of suspected TTTS. The mother was diagnosed with preeclampsia at the time of referral. On ultrasound, there was discordant growth, with a hydropic smaller fetus presenting with oligohydramnios (DVP of 1 cm). Doppler measurements were unremarkable, except for an elevated MCA-PSV (70 cm/s, 2.08 MoM). Also, its placental part was hydropic (Figure 1). The appropriately grown co-twin had a low MCA-PSV (22.6 cm/s, 0.67 MoM) with normal amniotic fluid (DVP less than 6 cm), umbilical artery and ductus venosus Dopplers. An intrauterine transfusion of the anemic donor (Hb: 3.7 g/dL; reticulocyte count: 553 109 /L—normal values 20–100 109 /L) was performed. The maternal situation deteriorated quickly with progression to severe HELLP syndrome. Intravenous antihypertensive drugs and magnesium sulfate were started, as well as a course of steroids. An emergency cesarean section was required due to pulmonary edema. The smaller twin weighed 650 g and had an Hb of 4.6 g/dL. In contrast, the larger twin weighed 950 g and had an Hb of 20.2g/dL. The smaller twin was transfused immediately after birth. The baby was oxygen dependent at 28 days of life (bronchopulmonary dysplasia) and later required a lobectomy for a lung abscess. Neonatal course of the larger twin was uneventful. Both had normal brain scans until discharge. The mother had an uneventful recovery with normal blood pressures within 7 days. Placental fragmentation precluded injection of the chorionic plate vessels.

Table 1—Prenatal characteristics. When two values are displayed, the first is from the recipient (polycythemic fetus) and the second is from the donor (anemic fetus)

Prenatal findings GA at diagnosis (weeks) MCA-PSV (MoM) (R/D) DVP (cm) (R/D) Growth discordance (%) Prenatal findings (R)

Prenatal findings fetus (D)

Prenatal Hb (g/dL) and reticulocyte count (×10 exp 9/L) (D) Prenatal interventions

Case 1

Case 2

Case 3

25 + 6 0.7/2.1 4.4/1 23.8 No abnormalities

23 + 5 0.3/2.0 8/1 28 Umbilical vein pulsations Structural heart defect Ascites Pericardial effusion.

28 + 6 0.7/1.5 12/3.5 23.6 Hypocontractility of the heart MPI of 0.44 (normal ≤0.43)

Cardiothoracic index 0.4 Hypocontractility Pericardial effusion, Subcutaneous edema Placental hydrops (7 cm) 3.7/553

IUT of the anemic fetus

No abnormalities

Placental hydrops (7 cm)

3.1/442

4.4/NA

Cord coagulation (R) IUT (D)

Laser coagulation Hemodilution (R) IUT (D)

D, donor; DVP, deepest vertical pocket; Hb, hemoglobin; IUT, intrauterine transfusion; MCA-PSV, middle cerebral artery peak systolic velocity; MPI, myocardial performance index; MoM, multiples of the median; NA, not available; R, recipient. Copyright  2010 John Wiley & Sons, Ltd.

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Table 2—Neonatal outcome. When two values are displayed, the first one is from the recipient (polycythemic) and the second is from the donor (anemic) neonate Neonatal findings Gestational age at birth Neonatal weight R/D (g) Neonatal Hb R/D (g/dL) Absolute reticulocyte count (D) (10exp9/L)

Case 1

Case 2

Case 3

26 weeks 950/660 20.2/4.6 521

27 weeks and 3 days 995 12 N/A

34 weeks 2 days 1805/1525 21.5/14.2 116

D, donor; Hb, hemoglobin; N/A, not available; R, recipient.

Case 3

Figure 1—Case 1: hydropic placental territory of the donor (anemic fetus)

However, pathological examination confirmed placental edema without features of placental abruption.

Case 2 A 30-year-old G3P2 was referred at 24 weeks of gestation for suspected TTTS. Both twins had normal growth but there was a marked amniotic fluid discordance. One twin had an elevated MCA-PSV (60 cm/s, 1.95 MoM) with oligohydramnios (DVP of 1 cm). Umbilical artery and ductus venosus Dopplers were normal. Its placental part was hydropic. The co-twin had a low MCA-PSV (8 cm/s, 0.26 MoM) as well as polyhydramnios (DVP of 8 cm). The a-wave in the ductus venosus was positive and there was monophasic pulsatility in the umbilical vein. Ascites was associated with severe cardiomegaly, significant tricuspid regurgitation and a morphologically abnormal ascending aorta. The parents opted for selective fetocide of the recipient. We performed a cord occlusion and concomitant transfusion of the co-twin (Hb: 3.1 g/dL; reticulocyte count: 442 109 /L). Following that, its MCA-PSV returned to 40 cm/s. The patient delivered at 27 weeks because of preterm rupture of the membranes followed by spontaneous labor. The newborn weighed 995 g and was extubated after 3 days with nasal oxygen support for 10 weeks. Hb at the time of birth was 15.5 g/dL. The immediate neonatal period was marked by symptomatic cardiogenic shock and grade II intraventricular hemorrhage with spontaneous resolution on day 12. One red blood cell transfusion and two platelet transfusions were required before discharge. Copyright  2010 John Wiley & Sons, Ltd.

This 32-year-old G3P2 was referred for mild discordant growth at 16 weeks with normal amniotic fluid. At 22 weeks, the larger fetus developed polyhydramnios (DVP of 9 cm) and MCA-PSV was 20 cm/s (0.71 MoM). The smaller twin had an MCA-PSV of 32 cm/s (1.14 MoM) with low normal amniotic fluid (DVP of 3 cm). A progressive increase of the growth discordance was noticed. At 29 weeks, the criteria for prenatal TAPS were met. The larger twin [estimated fetal weight (EFW): 1241 g] had an MCA-PSV of 28 cm/s (0.7 MoM) whereas its co-twin (EFW: 948 g) had an MCA-PSV of 58 cm/s (1.5 MoM). The polyhydramnios of the larger twin had increased to a DVP of 12 cm. There were also signs of heart failure as evidenced by an increased myocardial performance index (Van Mieghem et al., 2009). The anemic twin still had normal fluid. Steroids for lung maturation were initiated and in- as well as ex-utero therapeutic options were discussed. The parents opted for an attempt of laser coagulation of vascular anastomoses, as well as intrauterine transfusion of the anemic twin combined with hemodilution of the polycythemic co-twin. All this was foreseen with back up cesarean section. Three tiny arteriovenous anastomoses were identified and coagulated and 3 L of amniotic fluid was drained. The anemic twin (Hb: 4.4g/dL) was transfused and hemodilution was performed in the polycythemic co-twin (Hb: 22.2 g/dL; hematocrit of 67%) by replacing 11 mL of fetal blood with 8 mL of 20% albumin solution (Baxter). During follow-up, MCA-PSV normalized in both twins, and there was catch-up growth of the formerly anemic twin. The patient was electively delivered at 34 weeks. The former donor weighed 1525 g, its neonatal Hb was 14.2 g/dL. The former recipient weighed 1805 g with an Hb of 21.5 g/dL. Both babies had an uneventful neonatal course with normal brain scans until discharge. On placental injection (Figure 2), there were no residual anastomoses. CONCLUSION This is the first case series describing the prevalence, clinical presentation and management of spontaneously occurring TAPS diagnosed during pregnancy. We tailored therapy according to the clinical characteristics of each case. Symptomatic treatment always consisted of intrauterine transfusion of the anemic twin. In one case, laser therapy was used as a causative treatment. In Prenat Diagn 2010; 30: 438–442. DOI: 10.1002/pd

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Figure 2—Placenta injection with color dye (case 4). Left image: the donor (anemic fetus, twin 2, 2 clamps) has blue arteries and red veins. The recipient (polycythemic fetus, twin 1, 1 clamp) has purple colored arteries and white veins. Right image: the white arrow shows one of the three coagulated arteriovenous anastomoses

another, selective feticide was offered because of associated anomalies, arresting the intertwin transfusion at the same time. The simultaneous occurrence of anemia and polycythemia in monochorionic twins has been described both in the prenatal and postnatal periods, however, with diverging definitions. As mentioned above, TAPS is thought to result from a chronic net intertwin transfusion across tiny unidirectional anastomoses. Although a consensual definition is still lacking, we defined TAPS as the occurrence of discordant MCA-PSV measurements. To differentiate TAPS from an acute fetofetal transfusion, an elevated reticulocyte count suggesting chronic anemia or the presence of the typical few small anastomoses as evidenced by fetoscopy or on postnatal placental injection studies were added to the inclusion criteria. The association between severe anemia and MCAPSV above 1.5 MoM has been well established in singletons. However, prior to 18 weeks, MCA-PSV values are somewhat higher in monochorionic twins than in singletons. Therefore, in order to avoid false-positive diagnoses of suspected anemia, it seems better to use reference ranges specific for monochorionic twins in early gestation (Klaritsch et al., 2009). Another caveat is that an elevated MCA-PSV in the presence of growth restriction does not necessarily imply that the fetus is anemic (Mari et al., 2007). Also, the association of MCA-PSV below 0.8 MoM with polycythemia still requires validation. It would seem important to exclude other causes of fetal anemia, such as alloimmunization, congenital infection or fetomaternal hemorrhage. Also, in the absence of a validated correlation, it seems mandatory to confirm the presence of severe anemia in the donor twin by cordocentesis before embarking on any causative invasive intervention. Our cases were all diagnosed between 24 and 29 weeks. In the prenatal period, TAPS seems to be less far common than TTTS (2 vs 10%, respectively)(Lewi et al., 2008b). However, postnatal data suggest a more common condition, affecting up to 4% of pregnancies, all diagnosed beyond 30 weeks. In one of the pregnancies complicated by TAPS, fetal demise of the anemic twin occurred at 33 weeks (Lewi et al., 2008a,b). Because TAPS seems to occur primarily in the third Copyright  2010 John Wiley & Sons, Ltd.

trimester, large prospective follow-up studies with documentation of the MCA-PSV until birth are required to document its exact incidence and natural history. In the longitudinal study of 50 monochorionic twins that were booked for delivery in our hospital, we were able to document MCA-PSV measurements until birth (Klaritsch et al., 2009). However, none of these patients developed TAPS, which supports the observation that TAPS is indeed rather uncommon. Nevertheless, because undiagnosed TAPS may lead to intrauterine demise, MCA-PSV measurements appear as a simple and useful tool to identify TAPS in the prenatal period. All our cases had complicating features other than discordant MCA-PSV measurements, which may be due to a referral bias and again larger prospective series are needed to document the exact incidence and natural history of TAPS in previously uncomplicated monochorionic twin pregnancies. In conclusion, this case series provides an opportunity to inform fetal medicine specialists about TAPS as a potential complication of monochorionic pregnancies and the tools available for its diagnosis and management. The prevalence and possible implications of TAPS seem to justify routine MCA-PSV measurements in every monochorionic twin pregnancy. ACKNOWLEDGEMENTS

E. Don´e (MEST CT2005 019707), L. Gucciardo (EuroSTEC; LSHC-CT-2006-037409) as well as L. Lewi (QLG1-CT-2002-01632 EuroTwin2Twin) receive grants from the European Commission. J. Deprest is a ‘Fundamental Clinical Researcher’ and receives a grant of the Fonds Wetenschappelijk Onderzoek-Vlaanderen (1.8.012.07.N.02). T. Van Mieghem is beneficiary of a grant of the Flemish Government (Instituut voor Wetenschap en Technologie; IWT 070715). REFERENCES Denbow M, Fogliani R, Kyle P, Letsky E, Nicolini U, Fisk N. 1998. Haematological indices at fetal blood sampling in monochorionic pregnancies complicated by feto-fetal transfusion syndrome. Prenat Diagn 18: 941–946. Klaritsch P, Deprest J, Van Mieghem T, et al. 2009. Reference ranges for middle cerebral artery peak systolic velocity in monochorionic Prenat Diagn 2010; 30: 438–442. DOI: 10.1002/pd

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Prenat Diagn 2010; 30: 438–442. DOI: 10.1002/pd