OBSTETRICS
Perinatal Outcomes of Twin Anemia–
Polycythemia Sequence: A Systematic Review
A. Cristina Rossi, MD,1 Federico Prefumo, MD, PhD2
Department of Obstetrics and Gynecology, University of Bari, Bari, Italy
1
Maternal-Fetal Medicine Unit, Department of Obstetrics and Gynecology, University of Brescia, Brescia, Italy
2
Abstract
Objective: To analyze outcomes of monochorionic twins with twin
anemia-polycythemia sequence (TAPS).
Data Sources: PubMed, EMBASE, Medline, and reference list.
Study Selection: We included reports of TAPS defined prenatally with
abnormal Doppler studies of middle cerebral artery and normal
amniotic fluid volume which reported data as proportional rates.
Data Extraction: Abstracted outcomes were postnatal hemoglobin
levels, postnatal procedures, and survival rates. Outcomes were
analyzed for gestational age at diagnosis of TAPS (15 to 23 weeks,
24 to 29 weeks, > 29 weeks), in utero therapy, and nature of onset
(isolated TAPS, or following twin-to-twin transfusion syndrome). The
review was performed using MOOSE guidelines. Differences were
significant if P < 0.05.
Data Synthesis: We assessed data on 28 pregnancies with TAPS.
Diagnosis at 15 to 23 weeks’ gestation and in utero therapy
were associated with the highest mean levels of hemoglobin in
anemic twins (P = 0.021), the lowest levels in polycythemic twins
(P = 0.025), and the lowest frequency of postnatal procedures
(P < 0.001). Survival rate was independent of gestational age at
diagnosis and in utero therapy. In cases of TAPS following twin-to-
twin transfusion, the mean hemoglobin level was higher in donors
than in anemic twins with isolated TAPS (P = 0.029) and similar
between recipients and polycythemic twins with isolated TAPS
(P = 0.135). Twins with TAPS following twin-to-twin transfusion
received in utero therapy more frequently than isolated TAPS twins
(P = 0.030) and required a postnatal procedure less often
(P < 0.001). Survival rates were similar in each group.
Conclusion: Diagnosis of TAPS at an early gestational age is
associated with more favourable outcomes than later diagnosis. In
utero therapy improves neonatal hemoglobin levels but does not
change survival rates. Previous twin-to-twin transfusion syndrome
does not worsen outcomes.
J Obstet Gynaecol Can 2014;36(8):701–707
Key Words: Monochorionic pregnancy, twins, anemia
polycythemia sequence, twin transfusion syndromes
Competing Interests: None declared.
Received on November 2, 2013
Accepted on February 12, 2014
Résumé
Objectif : Analyser les issues que connaissent les jumeaux monozygotes
qui présentent une séquence anémie-polyglobulie gémellaire
(twin anemia-polycythemia sequence ou TAPS).
Sources de données : PubMed, EMBASE, Medline et liste de références.
Sélection des études : Nous avons inclus les études ayant porté sur la
TAPS établie avant la naissance (obtention de résultats anormaux aux
études Doppler visant l’artère cérébrale moyenne et constatation d’un
volume normal de liquide amniotique) qui signalaient leurs données
sous forme de taux proportionnels.
Extraction des données : Les issues résumées ont été les suivantes :
taux postnataux d’hémoglobine, interventions postnatales et taux de
survie. Les issues ont été analysées en fonction de l’âge gestationnel
au moment du diagnostic de TAPS (15-23 semaines, 24-29 semaines,
> 29 semaines), de la présence d’un traitement in utero et de la nature
de l’apparition de la TAPS (TAPS isolée ou apparaissant à la suite du
syndrome transfuseur-transfusé). L’analyse a été menée au moyen
des lignes directrices MOOSE. Les différences ont été considérées
significatives lorsque P < 0,05.
Synthèse des données : Nous avons évalué des données portant sur
28 grossesses présentant une TAPS. Le diagnostic à 15-23 semaines
de gestation et le traitement in utero ont été associés aux taux moyens
d’hémoglobine les plus élevés chez les jumeaux anémiques (P =
0,021), aux taux moyens d’hémoglobine les plus bas chez les jumeaux
présentant une polyglobulie (P = 0,025) et à la fréquence d’interventions
postnatales la plus basse (P < 0,001). Le taux de survie ne dépendait
ni de l’âge gestationnel au moment du diagnostic ni de la présence
d’un traitement in utero. Dans les cas de TAPS suivant le syndrome
transfuseur-transfusé, le taux moyen d’hémoglobine était plus élevé
chez les transfuseurs (par comparaison avec la situation constatée chez
les jumeaux anémiques dans les cas de TAPS isolée [P = 0,029]) et il
était semblable chez les transfusés (par comparaison avec la situation
constatée chez les jumeaux présentant une polyglobulie dans les
cas de TAPS isolée [P = 0,135]). Les jumeaux présentant une TAPS
constatée à la suite du syndrome transfuseur-transfusé ont reçu un
traitement in utero plus fréquemment (P = 0,030) et ont nécessité une
intervention postnatale moins souvent (P < 0,001) que les jumeaux
présentant une TAPS isolée. Les taux de survie étaient semblables d’un
groupe à l’autre.
Conclusion : L’établissement d’un diagnostic de TAPS à un âge
gestationnel précoce est associé à des issues plus favorables que
l’établissement d’un diagnostic de TAPS à un âge gestationnel plus
tardif. L’administration d’un traitement in utero améliore les taux
néonataux d’hémoglobine, mais ne modifie en rien les taux de survie.
La présence d’un syndrome transfuseur-transfusé au préalable
n’aggrave en rien les issues.
AUGUST JOGC AOÛT 2014 l 701
Obstetrics
INTRODUCTION
T win anemia-polycythemia sequence is a specific
complication of monochorionic twin pregnancy. It
has been classified as isolated TAPS or TAPS associated
with twin-to-twin transfusion syndrome. Both TAPS and
TTTS are typical features of monochorionic pregnancies.
TTTS is characterized by polyhydramnios in the recipient
sac and oligohydramnios in the donor sac, whereas TAPS
is characterized by polycythemia in the recipient and
anemia in the donor twin, but amniotic fluid volume is
normal in both sacs. These characteristics are used to
distinguish between the two conditions. TAPS can occur
in isolation or may arise when laser therapy for TTTS
is followed by the persistence of vascular anastomoses,
leading again to anemia and polycythemia but with
normal amniotic fluid volumes.1 TAPS is diagnosed
prenatally by Doppler measurement of the peak systolic
velocity of the middle cerebral artery in each twin. PSV
in the MCA > 1.5 MoM in one twin and < 0.8 MoM in
the other are generally used to identify the anemic and
polycythemic twin, respectively.2,3 Prenatal diagnosis is
confirmed at birth by measurement of each neonate’s
hemoglobin concentration, and thresholds of < 110 g/L
and > 200 g/L are applied for diagnosis of anemia
and polycythemia, respectively.4 Postnatal TAPS can be
classified according to the criteria proposed by Lopriore,
which are based on differences in Hb levels between
twins.5 The incidence of TAPS in monochorionic
pregnancies is estimated at 3% to 5% for the isolated
forms4 and at 2% to 13% after laser therapy for TTTS.3
Because of the relatively low incidence, the literature is
limited to the description of small series or case reports
of twins affected by TAPS. The aim of this review was
to collect and pool published case reports of perinatal
outcomes of TAPS identified prenatally, in order to
obtain a larger sample size.
ABBREVIATIONS
aTAPS TAPS following TTTS
Hb hemoglobin
iTAPS isolated TAPS
MCA middle cerebral artery
MoM multiple of the median
MVP maximum vertical pocket
PSV peak systolic velocity
TAPS twin anemia-polycythemia sequence
TTTS twin-to-twin transfusion syndrome
702 l AUGUST JOGC AOÛT 2014
METHODS
We searched PubMed, Embase, Medline, Clinicaltrials.org,
and reference lists to identify articles that described
perinatal outcomes of TAPS, from the inception of these
databases to November 2012. Key words used in the search
were twins, monochorionic pregnancies, twin anemia-
polycythemia sequence, twin-to-twin transfusion syndrome,
placental anastomoses, recurrent TTTS, fetal anemia, and
fetal polycythemia. Each author independently selected
articles, and discordance was resolved by consensus. The
MOOSE guidelines were followed. This meta-analysis was
based on case reports with raw data described for each case;
the data were collected and pooled as a single large study.
Where data were missing, we attempted to contact the
corresponding author to obtain unpublished data. When
more than one article was published by the same authors,
we selected the article with the largest sample size in order
to avoid overlap of population. Overlap of population was
assessed according to the authors and institution where the
study was performed and the year of publication.
Inclusion criteria for study selection were:
1. prenatal diagnosis of TAPS based on MCA-PSV
> 1.5 MoM in one twin and < 0.8 MoM in the second
with normal amniotic fluid volumes, and
2. confirmation of the diagnosis at birth with Hb levels
< 110 g/L for the anemic twin and > 200 g/L for the
polycythemic twin. Monoamniotic twin pregnancies
were excluded.
Outcomes of interest were Hb concentration and
reticulocyte count at birth, postnatal procedures, neonatal
morbidity, and overall survival rates. Postnatal procedures
comprised blood exchange in the polycythemic twin and
blood transfusion in the anemic twin. Overall survival rate
was defined as the number of survivors at least 28 days after
birth. Outcomes were stratified according to gestational
age at diagnosis of TAPS, performance of intrauterine
therapy, mode of onset, and presence of patent vascular
anastomoses on placental histological examination.
Gestational age at diagnosis was arbitrarily divided into
three intervals: 15 to 23 weeks, 24 to 29 weeks, and > 29
weeks. Intrauterine therapy included laser therapy of
placental vascular anastomoses, blood transfusion by
cordocentesis, and umbilical cord occlusion. The mode
of onset consisted of isolated TAPS or TAPS associated
with previous laser therapy for TTTS.
We used the Mann-Whitney U, Kruskall-Wallis, and Fisher
exact test, as appropriate, in GraphPad Prism (GraphPad
Software Inc., La Jolla CA) for statistical analysis. Statistical
 Perinatal Outcomes of Twin Anemia–Polycythemia Sequence: A Systematic Review

Flow chart for study selection

Potentially relevant observational Observatinal studies excluded

studies concerning perinatal because were not published during
outcomes of TAPS the study period
N = 1203 n = 407

Observational studies excluded based

Observational studies retrieved for on title or abstract (case reports,
more detailed evaluation reviews, personal communications)
n = 36 n = 14

Observational studies excluded

Potentially appropriate because did not meet the
observational studies to be inclusion criteria
included in the meta-analysis n = 12
n = 22

Observational studies with usable

information included in the
meta-analysis
n = 10

significance was reached with two-sided P values < 0.05.
We addressed quality issues in the description of studies
and in the discussion of findings.
RESULTS
The steps taken for study selection are shown in the Figure.
Of 36 articles retrieved for detailed evaluation, 10 articles
were selected for inclusion in the analysis; these described
28 monochorionic twin pregnancies affected by TAPS (56
fetuses).1,3,6–13 The characteristics of each study are described
in Table 1. Median gestational age at diagnosis was 24 weeks
(range 15 to 33 weeks). In 17 pregnancies (61%), TAPS was
diagnosed after laser treatment of TTTS. Intrauterine therapy
was performed in 20 pregnancies (71%); this consisted of
laser treatment of placental vascular anastomoses (4 cases,
20%), blood transfusion in the anemic twin by cordocentesis
(13 cases, 65%), and umbilical cord occlusion for impending
intrauterine death (3 cases, 15%).
At birth, the mean (± SD) Hb levels were 108.9 ± 54.4 g/L
and 203.7 ± 46.2 g/L in the anemic and polycythemic
twins, respectively. Blood exchange was required in seven
polycythemic twins (30%) and blood transfusion was
required in nine anemic twins (39%). The overall survival
rate was 82% (46/56); of these survivors, 50% (23/46) were
the anemic twin and 50% (23/46) were the polycythemic
twin. For each twin set, there were no survivors in 3%
of pregnancies (1/28), one survivor in 28% (8/28),
and two survivors in 68% (19/28). Neonatal morbidity
affected five newborns (9%) and was represented by
thrombocytopenia, neurologic disease, skin necrosis, mild
hypotonia, and respiratory distress. In two cases, neonatal
morbidity was fatal. Placental examination was performed
in 11 of 28 pregnancies (39%) and revealed patent vascular
anastomoses in seven (64%); two of these had previously
undergone laser therapy for TTTS.
Diagnosis at 15 to 23 weeks’ gestation was associated with
more normal Hb levels. When TAPS was diagnosed at > 29
weeks, conservative management was more likely than
with earlier diagnosis, but postnatal procedures were more
frequently performed. The overall survival rates did not
differ according to gestational age at diagnosis (Table 2).
Comparison between TAPS treated in utero and
TAPS managed conservatively showed that the former
significantly improved Hb levels at birth and reduced the

AUGUST JOGC AOÛT 2014 l 703

Obstetrics

Table 1. Characteristics of the studies

Type of GA at diagnosis In utero Residual Postnatal Survivors,
Author Cases TAPS of TAPS therapy anastomoses procedure n
Lopriore et al.12 Case 1 Isolated 15 No NA None 1
Groussolles et al. 8
Case 1 Associated 18 II Laser Absent None 2
Herway et al.10 Case 1 Associated 20 Transfusion Present E/T 2
Weingertner et al.13 Case 1 Isolated 32 No Present E/T 2
  Case 2 Isolated 32 No Present E/T 2
  Case 3 Isolated 32 No Present E/T 2
  Case 4 Isolated 23 Laser Absent E/T 2
Gucciardo et al.9 Case 1 Isolated 26 Transfusion NA T 2
  Case 2 Isolated 24 UCO NA T 1
Transfusion
  Case 3  Isolated 29 Laser Absent None 2
Transfusion
Hemodilution
Fratelli et al. 7 Case 1 Associated 27 No Present E/T 2
Lopriore et al. 1
Case 1 Isolated 33 No Present T 2
  Case 2  Isolated na No Present E/T 2
Robyr et al.3 Case 1 Associated 27 Transfusion NA None 2
  Case 2  Associated 24 Transfusion NA None 2
  Case 3 Associated 20 Transfusion NA None 1
  Case 4  Associated 19 Transfusion NA None 1
  Case 5  Associated 26 Transfusion NA None 2
  Case 6 Associated 23 Transfusion NA None 1
  Case 7 Associated 21 Transfusion NA NA 1
  Case 8 Associated 25 UCO NA None 1
  Case 9 Associated 23 Transfusion NA None 0
  Case 10 Associated 22 Transfusion NA None 2
  Case 11 Associated 24 Transfusion NA None 2
  Case 12 Associated 18 Transfusion NA None 2
  Case 13 Associated 28 Transfusion NA None 2
Lopriore et al. 11
Case 1 Associated 20 No Absent None 2
Assaf et al. 6 Case 1 Isolated 19 Laser NA None 1
UCO: umbilical cord occlusion; E: blood exchange in the polycythemic twin; T: blood transfusion in the anemic twin; NA: not available

Table 2. Outcomes according to gestational age at diagnosis of TAPS

Gestational age at diagnosis of TAPS
15 to 23 weeks 24 to 29 weeks 32 to 33 weeks
13 pregnancies 10 pregnancies 4 pregnancies
N (26 twins) (20 twins) (8 twins) P
Hb anemic twin, g/L, mean ± SD 146 ± 60.1 98.6 ± 35.1 60.7 ± 20.7 0.021
Hb polycythemic twin g/L, mean ± SD 171 ± 46.7 227 ± 34.1 216.8 ± 9.4 0.025
In utero therapy, n (%) 10/13 (77) 9/10 (90) 0/4 (0) 0.003
Overall survival, n (%) 18/26 (69) 18/20 (90) 8/8 (100) 0.068
Postnatal procedures, n (%) 4/26 (15) 4/20 (20) 7/8 (87) < 0.001

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 Perinatal Outcomes of Twin Anemia–Polycythemia Sequence: A Systematic Review
risk of postnatal procedures. Survival rates did not differ
significantly, either in overall survival or according to the
number of surviving twins (Table 3).
When compared with iTAPS, cases of aTAPS were treated
in utero more often and required postnatal procedures less
frequently. Gestational age at diagnosis of TAPS, Hb levels
at birth, and survival rates did not differ between the two
groups. We observed more normal Hb levels in neonates
after aTAPS than after iTAPS In Table 4, this comparison
is shown with twins classified as follows:
● Donor twin: donor twin with TAPS following TTTS
treated with laser therapy
● Anemic twin: donor twin with TAPS without previous
TTTS
● Recipient twin: recipient twin with TAPS following
TTTS treated with laser therapy
● Polycythemic twin: recipient twin with TAPS without
previous TTTS
Finally, the Hb levels were not influenced by the patency
of vascular anastomoses (Table 5).
DISCUSSION
In this review we found that the overall survival rate in twins
affected by TAPS was 82% and was similar for the anemic
and the polycythemic twin. Neonatal morbidity occurred
in 9% of cases, and in a very few it was severe enough to
cause neonatal death. We also observed that more normal
Hb levels at birth were related to early diagnosis (gestational
age 15 to 23 weeks), probably because this allows specific
management and intrauterine therapy. However, we noted
that survival rates increased from 69% to 100% in association
with increasing gestational age at diagnosis.
In addition, previous TTTS did not worsen neonatal
outcomes. Indeed, TAPS after laser therapy for TTTS was
associated with more normal Hb levels in both anemic
and polycythemic twins than isolated TAPS. It may be
speculated that laser therapy provides protection by
reducing the severity of later TAPS.
It is generally believed that TAPS results from inter-twin
blood transfusion through small vascular anastomoses.1 In
the cases in our review, placental histological assessment
(which should be mandatory in monochorionic twin
pregnancies complicated by TAPS or TTTS) was performed
in only 39%. Histological assessment did not reveal patent
vascular anastomoses in 36% of the examined placentas.
Because patent anastomoses are necessary for inter-twin
transfusion, it is likely that thrombotic events, probably
secondary to polycythemia, closed small anastomoses.
Therefore, failure to demonstrate patent vessels on
placental examination is not a requirement for excluding
the diagnosis of TAPS.
We found that neonatal anemia and polycythemia do not
depend on the patency of vascular anastomoses. However,
in anemic neonates with patent placental anastomoses
detected by placental histological examination, the mean
Hb was lower (85.1 g/L) than in anemic neonates without
patent anastomoses (167.5 g/L). This difference might
be clinically relevant, although it did not reach statistical
significance (likely because of the small sample size).
The key limitation of our review was the paucity of
information available in the literature. Although we observed
better outcomes for twins with TAPS treated in utero, there
are no standard criteria for selecting the initial treatment for
TAPS. Doppler surveillance of the middle cerebral artery
every four weeks has been suggested,3 but the threshold
value for intervention has not been established. Intrauterine
blood transfusion, laser ablation of placental anastomoses,
umbilical cord occlusion, and expectant management have
been described,1,3,6–13 but the numbers in case series have
been too small to compare the different methods. Moreover,
the limited number of cases in our dataset did not allow us
to perform multivariable analyses.
Reticulocyte count is essential for the postnatal diagnosis
of TAPS,5 but in the articles we reviewed there was no
consensus about units or values. In fact, the reticulocyte
count was reported as a percentage in some articles,10–12
as an absolute value in others,1,7–9,13 and was sometimes
unreported,3,6 making it impossible to pool data in a single
meta-analysis.
TAPS associated with TTTS might have a different natural
history from isolated TAPS, although the definition is
similar. Therefore, further studies are needed to clarify
what management and treatment should be performed for
these two entities.
In our opinion, the main limitation of assessing conditions
associated with inter-twin transfusion is that it is still
difficult to determine when inter-twin blood exchange
becomes unequal. It is generally believed that blood
transfusion becomes pathological (and unequal) when a
twin oligo/polyhydramnios sequence develops. However,
the definition of oligo/polyhydramnios (MVP < 2 cm
for oligohydramnios and > 8 cm for polyhydramnios) is
subjective,14 since to our knowledge there have been no
studies comparing amniotic fluid volumes in normal and
abnormal monochorionic twins. In addition, the definition
AUGUST JOGC AOÛT 2014 l 705
Obstetrics

Table 3. Outcomes according to prenatal management

Conservative
In utero therapy management
20 pregnancies 8 pregnancies  
N (40 twins) (16 twins) P
Hb anemic twin, g/L, mean ± SD 129.1 ± 50.0 71.0 ± 43.5 0.011
Hb polycythemic twin, g/L, mean ± SD 190.3 ± 50.1 230.5 ± 20.1 0.018
Overall survival, n (%) 31/40 (77) 15/24 (62) 0.254
No survivors, n (%) 1/20 (20) 0/8 NS
1 survivor, n (%) 7/20 (35) 1/8 (12) 0.053
2 survivors, n (%) 12/20 (60) 7/8 (87) 0.502
Postnatal procedures, n (%) 6/40 (15) 12/24 (50) 0.004
NS: not significant

Table 4. Outcomes according to mode of onset

aTAPS iTAPS
17 pregnancies 11 pregnancies
N (34 twins) (22 twins) P
Hb donor vs. anemic twin, g/L, mean ± SD 130.5 ± 53.6 80.8 ± 42.9 0.029
Hb recipient vs polycythemic twin, g/L, mean ± SD 192.7 ± 53.5 221.9 ± 22.9 0.135
Hb donor vs polycythemic twin, g/L, mean ± SD 130.5 ± 53.6 221.9 ± 22.9 < 0.001
Hb recipient vs anemic twin, g/L, mean ± SD 192.7 ± 53.5 80.8 ± 42.9 < 0.001
GA at diagnosis of TAPS, weeks, mean ± SD 22.65 ± 3.23 26.50 ± 6.20 0.07
In utero therapy, n (%) 15/17 (88) 5/11 (50) 0.03
Overall survival, n (%) 27/34 (79) 19/22 (86) 0.723
No survivors, n (%) 1/17 (16) 0/11 NS
1 survivor, n (%) 5/17 (29) 3/11 (27) NS
2 survivors 11/17 (65) 8/11 (73) NS
Postnatal procedures 3/34 (9) 14/22 (64) < 0.001

Table 5. Hemoglobin levels according to patency of vascular anastomoses assessed by

placental examination
Patent No patent
anastomoses anastomoses
N 7 placentas 4 placentas  P
Hb anemic twin, g/L, mean ± SD 85.1 ± 27.0 167.5 ± 26.1 0.072
Hb polycythemic twin, g/L, mean ± SD 209.4 ± 53.4 199.0 ± 55.1 0.412

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 Perinatal Outcomes of Twin Anemia–Polycythemia Sequence: A Systematic Review
does not include gestational age. In a recent study
reporting percentiles of amniotic fluid volume in normal
monochorionic diamniotic twins, Dekoninck et al. found
that from 15 to 37 gestational weeks, the MVP at the 2.5th
centile ranges from 2.01 to 2.83 cm.15 Therefore, using a
definition of oligohydramnios < 2 cm would miss cases
from 15 to 37 weeks. Similarly, polyhydramnios (MVP at
the 97.5th centile) was > 8 cm only from 23 to 31 weeks.15
Moreover, at any gestational age, out-of-range MVP was
never < 2 cm and > 8 cm at the same time, as required
to define pathological inter-twin transfusion.14 We believe
that a better definition would be helpful to understand why
some twins develop selective growth restriction, some the
twin oligo/polyhydramnios sequence, and some TAPS,
while most are normal.
In addition, it has been suggested that the pathophysiology
of TAPS is the slow transfusion of blood through a few
small vascular anastomoses1. If inter-twin blood exchange
becomes unequal, anemia and polycythemia develop,
manifested by abnormal Doppler velocimetry of the
middle cerebral artery; however, amniotic fluid volume
remains normal in both sacs, indicating blood flow
depletion in the fetal brain but normal renal function.
Nevertheless, because cerebral impairment is the late stage
of fetal distress, it is unlikely that cerebral impairment
would occur before impairment of renal function.
We suggest that these conditions may be considered as a
single entity and probably occur in sequence:
● No inter-twin transfusion of blood: normal twins
● Mild inter-twin transfusion: selective intrauterine
growth restriction
● Moderate inter-twin transfusion: abnormal renal
function leading to amniotic fluid discordance (TTTS)
● Severe inter-twin transfusion: abnormal cerebral
perfusion (TAPS).
Because of the relatively low incidence of monochorionic
twin pregnancies and related complications, large
multicentre studies are needed in order to investigate the
natural history of monochorionic twins.
CONCLUSION
Improved hematological outcomes in both the anemic and
polycythemic twins affected by TAPS are associated with
early gestational age at diagnosis, intrauterine therapy, and
previous laser therapy for TTTS. Due to the low incidence
of TAPS, large multicentre studies would be useful to
develop standards for the management of twins affected
by TAPS.
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