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com

Original article

Intertwin cardiac status at 10-year follow-up after

intrauterine laser coagulation therapy of severe
twintwin transfusion syndrome: comparison
of donor, recipient and normal values
Ulrike Herberg,1 Julian Bolay,1 Pauline Graeve,2 Kurt Hecher,3 Peter Bartmann,2
Johannes Breuer1
1

Division of Pediatric
Cardiology, University of Bonn,
Bonn, Germany
2
Division of Neonatology,
University of Bonn, Bonn,
Germany
3
Department of Obstetrics and
Fetal Medicine, University
Medical Center HamburgEppendorf, Hamburg, Germany
Correspondence to
Dr Ulrike Herberg, Division of
Pediatric Cardiology, University
of Bonn, Adenauerallee 119,
Bonn D 53113, Germany;
Ulrike.Herberg@ukb.uni-bonn.de
Received 8 August 2013
Revised 1 May 2014
Accepted 31 May 2014
Published Online First
27 June 2014

ABSTRACT
Background In twin-to-twin transfusion syndrome
(TTTS), genetically identical twins are exposed to
different haemodynamic conditions during fetal life,
which are considered to be the cause of prenatal and
postnatal cardiovascular differences between the donor
and the recipient.
Objective To assess intertwin differences on childhood
cardiac outcome after intrauterine laser coagulation
therapy (LC) of severe TTTS.
Design and patients Prospective, detailed,
echocardiographic follow-up of 31 twin pairs aged 9.95
0.8 years (meanSD) with severe TTTS treated by LC,
and the comparison with reference values.
Results Cardiac function was normal and did not show
intertwin differences in twins without structural heart
disease. Discordant birth weight or birth weight <3rd
centile for gestational age had no inuence on blood
pressure and cardiac indices. Pulmonary stenosis was
more common (5/62; 8.1%) than in the general
population ( prevalence 0.066%, relative risk 134.4,
95% CI 42.1 to 428.8, p<0.0001) and affected both
donor and recipient. Intertwin differences in late diastolic
right ventricular lling ( peak velocities: recipient 0.51
0.11 m/s vs donor 0.450.10 m/s, mean difference
0.74 m/s, 95% CI 0.23 to 1.24, p=0.009) and early
septal relaxation (mean myocardial velocities: recipient
8.21.5 cm/s vs donor 8.91.2 cm/s, mean
difference 0.7 cm/s, 95% CI 0.02 to 1.38, p=0.044)
were found only when twins with right heart disease
were included.
Conclusions Despite severe prenatal cardiac
involvement, childhood cardiac function is normal in the
majority of surviving donors and recipients after
successful LC of severe TTTS. This underlines the
favourable impact of intrauterine LC on postnatal
cardiovascular performance.

INTRODUCTION

To cite: Herberg U, Bolay J,

Graeve P, et al. Arch Dis
Child Fetal Neonatal Ed
2014;99:F380F385.
F380

Twin-to-twin transfusion syndrome (TTTS) complicates 810% of monochorionic diamniotic twin

pregnancies.13 In TTTS, genetically identical twins
are exposed to different cardiac loading conditions
during fetal life. Unequal fetal haemodynamics
seems to be associated with an increased risk of
postnatal cardiovascular impairment, depending on
donor or recipient twin status.4 5 Therefore,
within-twin comparison of cardiovascular parameters is of special interest for long-term
outcomes.

What is already known on this topic

In twin-to-twin transfusion syndrome (TTTS),
genetically identical twins are exposed to different
haemodynamic loading conditions, leading to
severe cardiac compromise of the recipient twin.
Postnatal echocardiographic studies have shown
diastolic dysfunction of both ventricles in recipients
after repetitive amnioreduction, a symptomatic
therapy, which does not interrupt pathological
loading conditions. Selective fetoscopic laser
coagulation (LC) of placental anastomoses
interrupts intertwin blood transfer; however,
long-term studies of cardiac function after LC are
missing.

What this study adds

In the long term after LC of severe TTTS, cardiac
function and blood pressure are normal in the
majority of surviving twins. This indicates that
cardiac dysfunction regresses once LC has removed
the underlying cause. However, an increased
prevalence of pulmonary stenosis despite
successful LC justies the need for prenatal and
postnatal cardiac surveillance.

Placental vascular anastomoses provide the anatomical basis for the unbalanced intertwin transfusion from donor to recipient twin.1 3 In the
recipient, an increase in preload and afterload
results in systemic hypertension, myocardial hypertrophy, diastolic dysfunction and progressive
cardiac failure.3 6 7 Besides functional cardiac
impairment, right ventricular outow tract obstruction (RVOTO) has been reported in recipients and
is attributed to increased loading of the fetal right
ventricle (RV).810 In contrast, the smaller donor
shows less cardiac pathology but manifests moderate right ventricular diastolic impairment due to
increased placental resistance and poor renal perfusion.11 Cardiovascular changes occur early in pregnancy and progress with increasing gestational age,
potentially causing signicant impact on the development of the cardiovascular system.4 6

Herberg U, et al. Arch Dis Child Fetal Neonatal Ed 2014;99:F380F385. doi:10.1136/archdischild-2013-305034

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Original article
Selective fetoscopic laser coagulation (LC) of placental anastomoses ideally interrupts intertwin blood transfer and offers a
causal treatment.1 LC has been shown to signicantly improve
cardiac pathology in recipients.12 In contrast, donors have to
face an acute volume overload immediately after LC.13
However, even in successfully treated survivors, cardiovascular
impairment has been reported in the neonatal period, which
may persist throughout childhood.4 Despite successful intrauterine LC, sustained cardiomegaly and increased prevalence of
RVOTO has been found in a subset of recipient twins.810 14
Further important risk factors for cardiovascular diseases in
adulthood are unequal placental share, intrauterine growth
restriction and prematurity, all of which can coexist with
TTTS.1 4 1517 Therefore, follow-up studies of cardiovascular
function in TTTS are of great interest, but long-term cardiac
studies after LC are still lacking. We hypothesised that twins,
despite fetal LC, are at risk of long-term cardiac dysfunction. To
clarify this hypothesis, we studied the 10-year outcome in twin
survivors of severe TTTS treated by LC.

with standard German percentiles.19 Mean values of quantitative echocardiographic parameters were calculated from three
consecutive cardiac cycles and compared with normal values for
European children.22 23 Doppler velocities of the outow tracts,
great arteries and ventricular inow were compared with
age-related reference values.21 The myocardial performance
index, a sensitive and prognostic important marker for fetal
cardiac involvement in TTTS,7 was calculated to assess the combined systolic and diastolic function. On tissue Doppler
imaging, mean systolic and early and late diastolic myocardial
velocities were calculated at the basal interventricular septum,
the lateral mitral annulus and the tricuspid annulus (workstation
QLab 5.0).
3D left ventricular volumes, related to body size, were calculated from 3D full-volume datasets (QLab 5.0).25 26 Indices of
left ventricular lling and ejection were determined from 3D
volumetime curves.27 28

METHODS
Study population

Data were tabulated in SPSS (SPSS Inc, Chicago, USA), V.19.0.

The KolmogorovSmirnov test was used to indicate normal distribution. Intertwin comparisons were evaluated by means of
two-sample, paired t test (if normally distributed) and Wilcoxon
signed-tank test (in case of non-normal distribution). A onefactor, three-level ANOVA and Bonferroni-corrected post hoc
t test and a MannWhitney U-test were used to compare
donors, recipients and controls. Fishers exact test was used for
categorical variables ( prenatal cardiac ndings). p Values <0.05
indicated a statistical signicance. The local ethics committee
approved the study. Informed written consent was obtained.

This is a prospective follow-up of 31 twin pairs (36 male, 26

female) after intrauterine LC of severe TTTS, recruited from a
cohort of 69 surviving twin pairs who were consecutively operated between June 1997 and September 1999.18 Twelve pairs
living outside Germany were excluded, and 26 twins pairs were
lost or did not consent to the study. There was no signicant difference between the included and excluded cohorts with respect
to severity of TTTS, prenatal cardiac involvement or gestational
age at birth. In all cases, TTTS with a Quintero stage of III
(n=17), III (n=10) and IV (n=4) was diagnosed prenatally fullling the following criteria: gestational age <26 weeks, single
monochorionic placenta with massive polyhydamnios of the
recipient and severe oligohydramnios in the donor with small or
empty bladder.18 LC was performed at a median gestational age
of 20+4 weeks (table 1). Patients attended their local referring
hospital for follow-up and delivery. After delivery at a median
gestational age of 34+2 weeks, weight and length were recorded
and converted into z-scores adjusted to gestational age and
gender. Twins with intertwin difference in birth weight >1
z-score were classied as discordant (n=17 twin pairs).
Cardiac follow-up was performed at a median age of
9.83 years. The twin data were compared with reference
values1924 and a control group, which consisted of 15 singletons of the same age and gender to enable the verication of
formerly published reference values.

Investigations
All fetuses underwent detailed echocardiography and Doppler
sonography at the time of LC. At least mild myocardial hypertrophy was identied in all recipients; 10 had moderate to
severe tricuspid regurgitation, 4 had hydrops and 1 had functional pulmonary atresia (table 2). Seventeen recipients had no
further cardiac abnormalities before fetal intervention.
Postnatally, a single examiner, blinded for donor and recipient
status, performed a complete echocardiographic examination
according to published standards using a Philips ultrasound
system (ie, 33, transducer X7-2; S8; S5; Andover, USA).1720
Data were analysed by two examiners, blinded to age, body
surface and recipient or donor status.
The mean of three consecutive measurements of the blood
pressure (BP), recorded with an oscillometric sphygmomanometer in a supine position after 20 min of rest, was compared

Statistical analyses

RESULTS
Structural heart disease
Structural heart disease was found in 6 of 62 survivors (9.7%;
table 3). Pulmonary stenosis (PS) was more common (5/62;
8.1%) than in the general population ( prevalence 0.066%, relative risk 134.4, 95% CI 42.1 to 428.8, p<0.0001).29 PS was
found both in recipient and donor twins, with two donors
requiring balloon dilatation within the rst months of life.
There was no correlation between the postnatal occurrence of
structural heart disease and abnormal prenatal cardiac ndings
before LC (table 2).

Blood pressure
Systolic and diastolic BP did not differ between twins, twins and
controls or discordant twin pairs.
Low birth weight (<3rd centile, n=9, and <10th centile,
n=27) was not associated with increased BP.

Cardiac dimensions on M-Mode, 2D and 3D

echocardiography
Cardiac dimensions showed no signicant intertwin differences
and no signicant differences between study groups and controls, and were within normal ranges (table 4).

Flow velocities across aortic or pulmonary artery

Doppler velocities of the aortic valve were within reference
values. Regarding peak Doppler velocities of the pulmonary
valve, there was no statistically signicant intertwin difference
(p=0.82).

Herberg U, et al. Arch Dis Child Fetal Neonatal Ed 2014;99:F380F385. doi:10.1136/archdischild-2013-305034

F381

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Original article
Table 1 Perinatal and infant demographic profile in the three cohorts

GA at birth (weeks)
GA at LC (weeks)
LC-birth-period (days)
Weight at birth (g)
Height at birth (cm)
Weight at birth (z-score)
Height at birth (z-score)
Current age (years)
Current weight (kg)
Current height (cm)
Current BSA (m2)

Recipient (n=31)

Donor (n=31)

Control (n=15)

34.32.7 (range 29+238+0

20.61.8 (range 17+424+2)
9522
2174530
44.43.5
0.230.98
0.390.78
9.950.8 (range 8.8311.4)
33.345.80
140.88.5
1.1350.127

34.32.7 (range 29+238+0

20.61.8 (range 17+424+2)
9522
1734472
42.03.7
1.501.07
1.260.89
9.950.8 (range 8.8311.4)
30.776.49
139.48.1
1.0860.136

Intertwin
difference

p Value
RD

RC

DC

440315
2.42.4
1.270.93
0.890.86

<0.001
<0.001
<0.001
<0.001

2.573.29
1.482.85
0.050.08

<0.001
0.004
<0.001

<0.001
0.001
<0.001
0.001
ns
ns
ns
ns

<0.001
<0.001
<0.001
<0.001
ns
ns
ns
ns

Term

3333565
52.02.2
0.500.9
0.50.43
10.081.0 (range 8.5811.3)
34.396.71
141.97.7
1.1550.137

Values are meanSD; p Values by paired t test for intertwin analysis (RD, recipient to donor) and ANOVA for twin-control analysis (RC, recipient to control; DC, donor to control).
BSA, body surface area using the Haycock estimation; GA, gestational age; LC, laser coagulation; LC birth period, period between laser therapy and birth; ns, not significant.

Systolic and diastolic function

Variables of systolic cardiac function and the myocardial performance index did not differ between twins or twins and
control group, and were within the normal range (table 4).
Assessment of diastolic function by Doppler peak velocities of
left ventricular lling was normal. In contrast, signicant differences of peak velocities during late diastolic lling of the RV
(tricuspid A wave) were found between recipient and donor
twins ( p=0.009; table 4). However, after exclusion of twins
with PS and atrial septal defect (n=6), which can cause right
ventricular hypertrophy and may impair RV diastolic lling,
there was no signicant difference between donor and recipient
( p=0.119) (gure 1). In comparison to reference values, all
measures were within the upper level of the published normal
ranges in the twin cohort and the control group.21 These ndings may be attributed to different acquisition and measuring
techniques. Tricuspid E/A ratio was normal and without intertwin difference.

Due to the lengthy investigation time, myocardial function

could only be assessed in a smaller subset of twins (table 4).
Mean myocardial velocities of early myocardial relaxation at the
basal interventricular septum (mitral septal E0 ) were different
between recipient and donor twins ( p=0.045). After exclusion
of twins with PS and atrial septal defect (n=6), there was no signicant difference between donor and recipient ( p=0.202).
Recipients with mitral valve regurgitation had normal indices.
Tissue Doppler ratios E0 /A0 for left and right ventricular diastolic
lling showed no signicant intertwin differences (tricuspid E0 /A0
p=0.40 und Mitral E0 /A0 p=0.50). Discordant weight at birth
and low birth weight were not associated with signicant differences in systolic or diastolic function at the age of 10 years.

DISCUSSION
To our knowledge, this is the rst childhood follow-up study of
cardiac function in twin pairs after intrauterine laser therapy of

Table 3 Structural heart disease and minor cardiac abnormalities

in the study cohort
Recipient

Table 2 Prenatal hemodynamic findings and frequency of

postnatal structural congenital heart disease (CHD)
Prenatally
Abnormal finding
Recipients n=31
Hydrops fetalis
Mitral valve regurgitation
Tricuspid valve
regurgitation
Absent or reverse flow
during atrial contraction
in ductus venosus
Functional pulmonary
atresia

Present

CHD

Prenatally
Not
present

CHD

p
Value

4
3
10

1*
1*
1*

27
28
21

3
3
3

0.511
0.408
0.510

13

1*

18

0.518

30

0.846

See table 3 after exclusion of minor abnormalities, n=4.

Correlation between the postnatal occurrence of structural heart disease (CHD) and
abnormal prenatal cardiac findings before LC (present or not present) on Fishers
exact test. Significance is considered for p<0.05. One recipient with fetal hydrops and
functional pulmonary atresia had normal findings on postnatal follow-up. Another
recipient with fetal hydrops, mitral and tricuspid valve regurgitation presented with
moderate pulmonary stenosis postnatally (*).
LC, laser coagulation.

F382

PS and VSD*, n=2

Small perimembranous VSD
+moderate PS (Vmax 2.6 m/s)
Isolated PS, n=3
Moderate PS (Vmax 2.6 m/s), PR
Increased endocardial echogenicity
of the RV
Moderate PS (Vmax 2.8 m/s)
Other, n=2
ASD II (9 mm) with increased
endocardial echogenicity of the RV
Minor abnormalities, n=5
Minimal mitral valve prolapse, n=3
Borderline peak velocity of the
pulmonary valve, n=1 (Vmax
1.76 m/s)

Donor

Small muscular VSD+mild residual

PS (Vmax 1.8 m/s) and PR after
dilatation of severe PS
Minimal residual gradient (Vmax
1.7 m/s) after neonatal dilatation
of severe PS

PDA, coiled

Borderline peak velocity of the

pulmonary valve, n=1 (Vmax
1.63 m/s)

*Twin pair with VSD and PS both in donor and recipient.

ASD II, atrial septal defect; PR, pulmonary regurgitation; PS, pulmonary stenosis; RV,
right ventricle; VSD, ventricular septal defect; Vmax, peak Doppler velocity of the
pulmonary valve.

Herberg U, et al. Arch Dis Child Fetal Neonatal Ed 2014;99:F380F385. doi:10.1136/archdischild-2013-305034

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Original article
Table 4 Haemodynamic variables in recipients, donors and controls
Variable (meanSD)
Recipient
HR (bpm)
7811
BP sys z-score
0.830.87
BP dia z-score
0.080.96
M-mode echocardiography
IVSd z-score
1.441.39
LVPWd z-score
0.150.82
RVIDd z-score
0.261.58
LVIDd z-score
0.080.89
LA z-score
0.151.43
Ao z-score
0.140.94
FS MM (%)
37.76.3
Doppler echocardiography
Ao Vmax (m/s)
1.110.23
PA Vmax (m/s)
1.140.53
Mitral E wave (m/s)
0.960.14
Mitral A wave (m/s)
0.560.11
Mitral E/A ratio
1.80.4
Tricusp E wave (m/s)
0.740.12
Tricusp A wave (m/s)
0.510.11
Tricusp A wave no PS
0.490.09
Tricusp E/A-ratio
1.50.23
MPI LV
0.350.20
MPI RV
0.230.18
2D echocardiography
0.750.15
EDV/(aBSA1.38)
0.780.19
ESV/(bBSA1.37)
EF 2D (%)
60.06.2
3D echocardiography
0.720.12
EDV/(aBSA1.38)
0.820.14
ESV/(bBSA1.37)
EF 3D (%)
56.85.1
Volume-time-relation on 3D echocardiography
1/3 FR/EDV
2.30.72
PFR/EDV
3.00.5
TPFR (ms)
84.510.4
Tissue Doppler imaging
8.11.2
Mitral sept E0 (cm/s)
8.21.6
Mitral sept E0 no PS
Mitral sept A0 (cm/s)
3.01.1
122.67
Mitral sept E/E0
9.32.2
Mitral lat E0 (cm/s)
3.10.8
Mitral lat A0 (cm/s)
11.23.1
Mitral lat E/E0
7.81.8
Tricusp E0 (cm/s)
3.93.2
Tricusp A0 (cm/s)
9.82.7
Tricuspid E/E0

Intertwin difference

p Value

Donor

Control

Recipientdonor

RD

RC

DC

31
31
31

7811
0.600.55
0.040.51

31
31
31

768
0.420.51
0.010.43

15
15
15

0.2811.6
0.240.96
0.120.80

31
31
31

ns
ns
ns

ns
ns
ns

ns
ns
ns

30
30
29
30
30
30
30

1.181.46
0.070.81
0.261.40
0.031.02
0.490.85
0.040.99
37.37.4

31
31
31
31
29
29
31

1.580.98
0.130.71
0.661.87
0.051.10
0.121.44
0.180.59
38.17.1

15
15
15
15
14
14
15

0.272.08
0.201.10
0.492.24
0.081.22
0.391.50
0.010.85
0.489.10

30
30
29
30
29
29
30

ns
ns
ns
ns
ns
ns
ns

ns
ns
ns
ns
ns
ns
ns

ns
ns
ns
ns
ns
ns
ns

30
31
31
31
31
31
31
25
31
31
30

1.060.17
1.040.27
1.010.16
0.570.13
1.850.44
0.720.15
0.450.10
0.440.11
1.640.36
0.290.13
0.240.21

31
31
31
31
31
31
31
25
31
31
31

1.010.17
0.900.10
0.940.12
0.490.11
1.980.46
0.650.15
0.440.08
0.440.08
1.520.41
0.360.15
0.250.13

15
15
15
15
15
15
15
15
15
15
15

0.060.23
0.100.54
0.050.19
0.010.14
0.080.39
0.020.16
0.060.13
0.431.34
0.150.45
0.060.19
0.020.27

30
31
31
31
31
31
31
25
31
31
30

ns
ns
ns
ns
ns
ns
0.009
0.119
ns
ns
ns

ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns

ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns

29
29
29

0.760.16
0.780.22
60.76.8

29
29
29

0.680.12
0.700.13
60.05.4

15
15
15

0.010.18
0.020.28
1.266.9

27
27
27

ns
ns
ns

ns
ns
ns

ns
ns
ns

30
30
30

0.740.11
0.890.19
54.96.3

30
30
30

0.790.10
0.950.16
54.45.5

15
15
15

0.030.11
0.070.17
1.67.8

29
29
29

ns
ns
ns

ns
ns
ns

ns
ns
ns

30
30
30

2.40.5
3.00.5
85.714.2

30
30
30

2.30.7
3.10.5
84.311.91

15
15
15

0.10.8
0.10.7
0.616.6

29
29
29

ns
ns
ns

ns
ns
ns

ns
ns
ns

09
09
09
09
09
09
09
06
06
06

0.71.5
0.61.7
0.21.5
0.73.7
0.051.8
0.70.6
0.43.3
0.12.5
0.14.1
0.54.0

22
16
21
22
10
09
10
05
04
05

0.044
0.202
ns
ns
ns
ns
ns
ns
ns
ns

ns
ns
ns
ns
ns
ns
ns
ns
ns
ns

ns
ns
ns
ns
ns
ns
ns
ns
ns
ns

24
16
23
24
12
12
12
06
05
06

8.91.2
8.81.3
2.710.9
11.32.3
8.92.2
2.40.4
11.52.9
8.71.3
3.81.4
8.51.9

27
16
26
27
18
17
18
12
12
12

7.91.5
7.91.5
2.71.0
121.8
8.52.2
2.40.9
11.83.9
9.13.9
3.72.0
7.13.7

Data are meanSD.

Intertwin difference is recipients value minus donors value. Intertwin comparisons by paired t test and Wilcoxon signed-rank test (RD, recipient to donor). ANOVA and MannWhitney
U-test for analysis between twins and controls (RC, recipient to control; DC, donor to control). ns, not significant: p<0.05; no PS: exclusion of twin pairs with at least one suffering
from pulmonary stenosis.
a=77.5 for male, a=67.8 for female, b=29.7 for male, b=26.1 for female, c=47.4 for male, c=41.7 for female according to Buechel and colleagues.26
1/3 FR/EDV, 1/3 filling rate indexed to EDV; A0 , mean late diastolic myocardial velocity; A, maximal velocity at late diastolic filling velocity; Ao, aortic valve; Ao, diameter of the aorta;
BP dia, diastolic blood pressure; BP sys, systolic blood pressure; BSA, body surface area; E0 , mean early diastolic myocardial velocity; E, maximal velocity at early diastolic filling velocity;
EDV, end-diastolic volume; EF, ejection fraction ESV, end-systolic volume; FS MM, fractional shortening on M-Mode; HR, heart rate; IVSd, interventricular septum diameter in diastole;
LA, left atrial diameter, LV, left ventricle; LVIDd, left ventricular inner diameter in diastole; LVPWd, left ventricular posterior wall thickness in diastole; MPI, myocardial performance
index; PA, pulmonary artery; PFR/EDV, peak filling rate indexed to EDV; RV, right ventricle; RVIDd, right ventricular inner diameter in diastole; S0 , mean systolic myocardial velocity at the
lateral (lat) and septal (sept) mitral valve annulus respective tricuspid annulus; TPFR, time to peak filling rate; Vmax, maximal velocity on Doppler echocardiography.

severe TTTS. Ten years after LC, surviving twins without structural
heart disease had normal heart dimensions and normal systolic and
diastolic function. Despite unequal loading conditions and cardiac

impairment in utero, there were no differences in childhood cardiac

performance between donors and recipients. Discordance of birth
weight had no inuence on BP or cardiac function.

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Figure 1 Peak velocities during late diastolic lling of the right ventricle (TV-A Vmax) in the complete cohort including twins with pulmonary
stenosis and atrial septal defect (to the left) and in twin pairs without right ventricular heart disease (to the right). Lines connect the results within
each pair of twins. If twin pairs with right ventricular heart disease were excluded, there was no signicant intertwin difference.

Differences in right ventricular diastolic function were found

if twins with structural right ventricular heart disease, that is, PS
or atrial septal defect, were included.
PS was more common than in the general population and was
found in recipient and donor twins.
These ndings are consistent with prenatal30 and postnatal
ndings at early childhood8 after successful LC.
There is evidence that cardiovascular development in utero is
inuenced by genetic as well as environmental and hemodynamic factors such as blood ow, sheer stress, preload and
afterload.4 31 Although genetically identical, donor and recipient have to face different haemodynamic and environmental
factors, including different loading conditions and placental
inuences. The recipient faces increased preload and afterload.
In contrast, the donor shows mild cardiac involvement before
LC,11 but may be affected by unequal placental sharing, which
lead to growth discordance and intrauterine growth restriction.17 Epidemiological studies provide evidence that prenatal
haemodynamic or placental alterations are associated with
increased cardiovascular risk in adults, and cardiovascular
system programming takes place in utero.4 15 16 Postnatal
studies have shown diastolic dysfunction in recipients and
increased vascular stiffness in donors after repetitive amnioreduction.4 5 The inuence of early intervention with LC on this
parameter is of great interest. LC resolves the intertwin blood
transfer and thereby the existing pathological loading conditions, particularly for the recipient. However, placental anomalies such as unequal placental sharing and the risk of intrauterine
growth retardation, especially in the donor, may still remain.17
We compared our results with those of Halvorsen et al,5 who
investigated the cardiac outcome in twin pairs 10 years after
amnioreduction. The essential difference between the two treatments is that in amnioreduction the intrauterine TTTS and
thereby the pathological loading conditions remain until birth,
whereas with LC, intertwin transfusion is stopped. The intertwin comparison after amnioreduction in 11 twin pairs, including one recipient with PS, showed signicant intertwin
differences in ow velocities during early left and right ventricular lling (mitral and tricuspid E wave) as well as on the myocardial tissue Doppler (tricuspid and mitral E0 /A0 ). This was
interpreted as reduced early diastolic ventricular lling in the
recipient. The authors concluded that in the long term after
F384

TTTS, the recipient shows diastolic abnormalities of the right as

well as the left ventricle. In contrast to these results, we did not
nd reduced early diastolic ventricular lling after LC in the
recipient. Right and left ventricular early diastolic lling velocities were normal in recipient and donor twins. Using the comparison with the results of Halvorsen, we conclude that LC
appears to have a favourable long-term impact on cardiac
performance.30
In singleton pregnancies, fetal growth restriction is associated
with subclinical myocardial systolic and diastolic dysfunction
and higher BP in preschool children.15 We found no association
between intrauterine growth retardation and arterial hypertension or systolic or diastolic cardiac dysfunction. These ndings
conform with the population-based twin study of Oberg et al,31
who found no association between birth weight and cardiovascular disease in monozygotic twins. Therefore, genetic cofactors
rather than low birth weight per se seem to be involved.
The high prevalence of PS is a unique feature in TTTS and
predominantly affects the recipient twin.7 8 Ventricular hypertrophy in combination with myocardial dysfunction is thought
to reduce the ow across the pulmonary artery and may lead to
secondary PS.9 Treatment of TTTS by LC leads to regression of
hypertrophy and improvement of ventricular function.7 9 30
However, structural changes on the pulmonary valve may
persist and manifest later in pregnancy. In contrast to
Moon-Grady et al,9 who reported an incidence of PS of 23%
after LC, we observed PS with a frequency of about 810%.8
We are unable to draw any conclusions on intrauterine development of PS as the postinterventional pregnancies were mainly
attended in the referring centres. The occurrence of PS in
donors is particularly interesting and may be attributed to a
postinterventional deterioration of cardiac function secondary
to an acute increase in volume load after LC.7 13

Limitations
As this study only investigated surviving twin pairs after LC, but
no singleton survivors after intrauterine death of the co-twin,
no valid conclusion can be made for the complete collective of
all survivors with respect to cardiac and vascular risks. Because
our study design used an intertwin comparison, we may have
investigated a subgroup with better outcome.

Herberg U, et al. Arch Dis Child Fetal Neonatal Ed 2014;99:F380F385. doi:10.1136/archdischild-2013-305034

Downloaded from http://fn.bmj.com/ on February 9, 2015 - Published by group.bmj.com

Original article
It would be of particular interest to perform a comparative
investigation on twin pairs with severe TTTS, who have
received intrauterine amnioreduction. But as LC has become the
rst-line treatment for TTTS, we do not have access to an agematched collective treated by amnioreduction. In addition, a
control group of age-matched unaffected monochorionic twins
was not available.
Certainly pregnancies were followed up at the local referring
hospitals, but postinterventional and detailed neonatal data are
not completely available.
Our study placed particular emphasis on the investigation of left
ventricular function because according to the Barker hypothesis,
arterial hypertension, and therefore, left ventricular dysfunction,
was expected. Future studies should include the most sensitive
parameters of both right and left ventricular function in all twin
pairs. Investigation of global and segmental myocardial tissue
deformation of both ventricles in long-term survivors of TTTS
would be of interest.11 Given the high number of negative results
and only subtle differences between recipient and donor in this
cohort, further studies with a larger sample sizeespecially with
regard to diastolic dysfunctionare necessary.
Although this study is the largest long-term follow-up study
of survivors after LC of TTTS, we were not able to examine all
twin survivors eligible.

CONCLUSION
Ten years after LC of severe TTTS, the majority of surviving
donors and recipient twins had normal cardiac ndings. Despite
unequal loading conditions and cardiac impairment in utero,
there were no differences between donors and recipients longterm cardiac performance. Discordant birth weight or birth
weight <3rd centile had no inuence on BP or cardiac function.
This illustrates that cardiac dysfunction present in survivors after
serial amnioreduction is not found after LC and indicates that
cardiac dysfunction regresses once successful LC has removed
the underlying cause. However, long-term follow-up into adulthood is necessary to verify these ndings.
In addition, the increased prevalence of congenital heart
disease both in recipients and donors justies the need for prenatal and postnatal cardiac surveillance.
Contributors All authors contributed broadly to the work presented in this paper.
UH and JBr designed the study. PG, PB and KH were responsible for patient
acquisition. UH ran the clinical examinations, measured blood pressure and
performed echocardiography. Echocardiographic data analysis was performed by JB
and JBr Statistical evaluation was realised by UH and JB Anthropometric
measurement was conducted by PG Prenatal intervention was carried out by KH The
manuscript was supervised by JBr, KH and PB and edited by UH and JB.

7
8
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10

11

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13

14

15
16
17

18

19
20

21

22

23

24

25

Competing interests None.

Patient consent Obtained.

26

Ethics approval University of Bonn, Medical Faculty.

Provenance and peer review Not commissioned; externally peer reviewed.

27

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Herberg U, et al. Arch Dis Child Fetal Neonatal Ed 2014;99:F380F385. doi:10.1136/archdischild-2013-305034

F385

Downloaded from http://fn.bmj.com/ on February 9, 2015 - Published by group.bmj.com

Intertwin cardiac status at 10-year follow-up

after intrauterine laser coagulation therapy of
severe twintwin transfusion syndrome:
comparison of donor, recipient and normal
values
Ulrike Herberg, Julian Bolay, Pauline Graeve, Kurt Hecher, Peter
Bartmann and Johannes Breuer
Arch Dis Child Fetal Neonatal Ed 2014 99: F380-F385 originally
published online June 27, 2014

doi: 10.1136/archdischild-2013-305034
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