Original Paper

Fetal Diagn Ther Received: July 31, 2019

Accepted after revision: October 9, 2019
DOI: 10.1159/000504049 Published online: January 21, 2020

Prospective Validation of First-Trimester

Ultrasound Characteristics as Predictive Tools for
Twin-Twin Transfusion Syndrome and Selective
Intrauterine Growth Restriction in Monochorionic
Diamniotic Twin Pregnancies
Ritu Mogra a–c Rahmah Saaid a, d Jane Tooher a Lars Pedersen e–h
       

Greg Kesby a, b Jon Hyett a, c

   

a Sydney Institute for Women, Children and Their Families, Sydney Local Health District, Sydney, NSW, Australia;
b Monash
IVF-Sydney Ultrasound for Women, Sydney, NSW, Australia; c Discipline of Obstetrics, Gynaecology and
 

Neonatology, Faculty of Medicine, University of Sydney, Sydney, NSW, Australia; d Department of Obstetrics and
 

Gynaecology, University Malaya Medical Centre, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia;
e Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; f Department of Biomedicine, Aarhus
   

University, Aarhus, Denmark; g Department of Obstetrics and Gynaecology, Aarhus University Hospital, Aarhus,
 

Denmark; h Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark

 

Keywords rump length (CRL), nuchal translucency (NT) thickness, duc-

Monochorionic twins · Tricuspid regurgitation · Prenatal
ultrasound · Ultrasound · Twin-twin transfusion syndrome ·
Selective intrauterine growth restriction
Abstract
Objective: Monochorionic diamniotic (MCDA) twins are at
increased risk of adverse outcome due to unequal placental
sharing and placental vascular communications between
the fetal circulations. Most centres perform ultrasound ex-
amination every 2–3 weeks to identify these complications.
Identifying a high-risk cohort of MCDA twins in the first tri-
mester would allow more efficient surveillance. We have at-
tempted to validate first-trimester ultrasound characteristics
as predictive tools for twin-twin transfusion syndrome (TTTS)
and selective intrauterine growth restriction (sIUGR) in
MCDA twins. Material and Methods: This is a prospective
cohort study including MCDA twins enrolled at the time of
first-trimester combined screening. Differences in crown-
tus venosus pulsatility index for veins (DV PIV), presence or
absence of tricuspid regurgitation and right ventricular E/A
ratio were assessed. Receiver operating characteristic (ROC)
curves were used to assess the potential value of these mea-
sures as predictive tools for identifying a cohort of MCDA
pregnancies at high risk of adverse pregnancy outcome. Re-
sults: Sixty-five MCDA pregnancies were included in the
analysis. Nine (14%) developed TTTS, 17 (26%) developed
sIUGR. The best predictive marker for TTTS was NT discor-
dance of ≥20% (ROC AUC = 0.79; 95% CI 0.59–0.99). Combin-
ing measures did not improve performance (AUC = 0.80;
95% CI 0.62–0.99). Conclusion: NT discordance was the most
effective characteristic at predicting TTTS but still had a rela-
tively poor positive predictive value (36%). Intertwin differ-
ences in CRL, DV PIV and E/A ratio were not predictive of
subsequent pregnancy complications. None of these char-
acteristics have sufficient efficacy to be used to triage MCDA
twin pregnancies ongoing obstetric surveillance.
© 2020 S. Karger AG, Basel
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© 2020 S. Karger AG, Basel Dr. Ritu Mogra

RPA Women and Babies, Royal Prince Alfred Hospital
Missenden Road
E-Mail karger@karger.com
Camperdown, NSW 2050 (Australia)
Université de Paris

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E-Mail ritu.mogra @ health.nsw.gov.au

 Introduction
Monochorionic diamniotic (MCDA) twins are at sig-
nificantly increased risk of perinatal morbidity and mor-
tality due to shared placentation and the presence of in-
ter-twin placental vascular anastomoses [1, 2]. The 4
main risks are acute second-trimester twin-twin transfu-
sion syndrome (TTTS) (twin oligohydramnios-polyhy-
dramnios sequence [TOPS]; prevalence of 10–15%),
chronic TTTS (twin anaemia-polycythaemia sequence
[TAPS]; prevalence of 3–5%), sudden unanticipated
death of one or both twins (prevalence of approximate-
ly 5%) and selective intrauterine growth restriction
(sIUGR; prevalence of 15%) [3, 4]. As a very significant
minority (up to 40%) of MCDA twins may be affected by
at least 1 of these pathologies, an effective first-trimester
predictive test would assist in planning appropriate sur-
veillance.
The 4 main complications of monochorionicity vary
in presentation – in respect to both onset and severity.
Despite there being little evidence describing the most
appropriate form of surveillance of MCDA twins, the
practice of reviewing these pregnancies by ultrasound
every 2–3 weeks from 16 weeks’ gestation has been ad-
opted by most jurisdictions [5–7]. Identifying a “high-
risk” cohort of MCDA twins at the time of first-trimester
screening would facilitate the appropriate triaging of
women for future surveillance. It may, in the future, also
be of value in identifying women who would benefit from
preventative non-invasive placental separation therapies
[8, 9].
Complications of monochorionicity have been noted
in pregnancies where discrepancies in crown-rump
length (CRL), nuchal translucency (NT) and abnormali-
ties of the ductus venosus (DV) waveform had been ob-
served at 11–13+6 weeks’ gestation [10–14]. Some authors
have retrospectively reviewed the prevalence of such find-
ings and have suggested that these may be useful markers
for population screening. In this study, we prospectively
examined the potential value of these markers in addition
to assessment of the right ventricular E/A ratio (the E/A
ratio is a marker of the diastolic function of the right ven-
tricle of the heart; it represents the ratio of peak velocity
blood flow in early diastole [the E wave] to peak velocity
flow in late diastole caused by atrial contraction [the A
wave]) and the presence or absence of tricuspid incompe-
tence in the first trimester as screening tools for the pre-
diction of TTTS as a primary objective and whether these
markers were predictive of sIUGR as a secondary objec-
tive.
2 Fetal Diagn Ther
DOI: 10.1159/000504049
Table 1. Maternal and fetal characteristics of the cohort of MCDA
twin pregnancies (n = 65)
Mean maternal age, years 33
Assisted conception, n (%) 11 (17)
Mean gestational age at recruitment, weeks 12+3
Mean difference in CRL, mm 3.4
CRL discordance >10%, n (%) 6 (9)
Mean difference in NT, mm 0.49
Nuchal translucency thickness >95th centile, n (%) 12 (18)
NT discordance >20%, n (%) 24 (36)
Mean difference in DV PIV, mm 0.11
DV PIV discordance >20%, n (%) 14 (20)
DV reversal of “A” wave, n (%) 1 (1.5)
Tricuspid regurgitation, n fetuses (%) 3 (5)
E/A wave ratio >0.7, n (%) 14 (21)
Normal outcome 31
Twin-twin transfusion 9
IUGR 24
Unanticipated sudden IUFD 1
MCDA, monochorionic diamniotic; CRL, crown-rump length;
NT, nuchal translucency; DV, ductus venosus; PIV, pulsatility in-
dex for veins; IUGR, intrauterine growth restriction; IUFD, intra-
uterine fetal death.
Material and Methods
This was a prospective cross-sectional cohort study conducted
in an Australian metropolitan public hospital between January
2011 and December 2016. The study was approved by the ethics
committee (protocol number X11-0073). Women found to have
MCDA twin pregnancies on ultrasound assessment at 11–13+6
weeks’ gestation were invited to participate and consent. Diagnosis
of MCDA placentation was based on the presence of a single pla-
cental mass and absence of a twin peak sign [15]. Pregnancies in
which major structural malformation was present in one or both
twins were excluded.
Five potential characteristics for MCDA complications were
assessed: differences in the CRL and NT thicknesses, DV pulsatil-
ity index for veins (PIV) and cardiac function through assessment
of flow across the tricuspid valve (presence or absence of tricuspid
regurgitation [TR]) and evaluation of right ventricular E/A ratio.
All pregnancies had a CRL equivalent to an average gestation of
11–13+6 weeks. The haemodynamic markers (DV, TR and E/A ra-
tio) were measured according to standard techniques [16–18]. All
ultrasound assessments were performed by 1 operator (R.M.). Be-
yond 12 weeks, MCDA twins were managed according to local ob-
stetric policy which included fortnightly ultrasound surveillance.
Discordances between CRL, NT and DV PIV within MCDA
twin pairs were calculated as a percentage of the larger twin. Data
on pregnancy outcome were collated from ultrasound and obstet-
ric electronic medical records, and hard copy notes were reviewed
to check missing/incomplete data. TOPS was defined by Quintero
staging [19]. TAPS was diagnosed when 1 twin had a middle cere-
bral artery peak systolic velocity >1.5 MoM and the co-twin had a
peak systolic velocity <0.8 MoM [20]. sIUGR was either defined on
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 Table 2. Discordance between markers for normal pregnancies and cohort affected by adverse outcome

Normal group TTTS group IUGR group

(n = 31) (n = 9) (n = 24)

Mean difference in CRL, mm 3.3 3.5 3.3

CRL discordance >10% 4/31 (13) 2/9 (22) 0/24 (0)
Mean difference in NT, mm 0.35 1.00 0.46
NT discordance >20% 8/31 (26) 8/9 (89) 7/24 (29)
Mean difference in DV PIV 0.15 0.06 0.1
DV PIV discordance >20% 6/31 (19) 1/9 (11) 6/24 (25)
Tricuspid regurgitation 1/31 (3.2) 1/9 (11) 1/24 (4)
E/A wave ratio >0.7 8/31 (26) 2/9 (22) 4/24 (17)
Monophasic tricuspid wave 0/31 (0) 1/9 (11) 0/24 (0)

Values are n total n (%) unless otherwise indicated. TTTS, twin-twin transfusion syndrome; IUGR, intrauter-
ine growth restriction; CRL, crown-rump length; NT, nuchal translucency; DV, ductus venosus; PIV, pulsatility
index for veins.

the basis of antenatal description of discrepancy in estimated fetal

weight –20% discordance in circumstances where this led to an
antenatal intervention or was defined through a discrepancy in
birthweight with 1 twin <10th centile [21]. Unanticipated deaths
of 1 or both twins beyond 12 weeks’ gestation were also identified.
Statistical Analysis
The associations between discordances in twin pair characteris-
tics (for CRL, NT and DV PIV) and pregnancy outcomes were as-
sessed using non-parametric tests; Wilcoxon test for 2 group com-
parisons and Kruskal-Wallis test for >2 group comparisons. Receiv-
er operating characteristic (ROC) curves were constructed to
document the potential value of these markers in identifying a high-
risk cohort of pregnancies at risk of an adverse pregnancy outcome
using the “rocreg” command in Stata 14 (StataCorp LLC, TX, USA)
to obtain non-parametric estimations with bootstrap resampling of
the area under the ROC curve (AUC). The Mann-Whitney U test
was used to compare medians between the groups (with and without
TOPS), and Fisher’s exact test was used to assess the association be-
tween DV, TR and TOPS. Algorithms combining various ultra-
sound measures were also assessed for screening efficacy.
Results
Seventy MCDA pregnancies were recruited to the
study. Two were subsequently excluded due to later diag-
nosis of congenital malformations (thanatophoric dys-
plasia in both twins at 16 weeks and duodenal atresia in 1
twin at 25 weeks). A further 3 patients were excluded as
they were lost to follow-up. The final analysis is therefore
based on assessment undertaken in 65 MCDA twin pairs.
The CRL, NT, DV waveforms and tricuspid wave-
forms were obtained in all fetuses. Baseline maternal
characteristics, ultrasound findings and details of preg-
nancy outcome are shown in Table 1. The discordance in
markers in pregnancies with normal outcome and co-
horts affected by adverse outcomes are compared in Fig-
ure 1 and Table 2.
A total of 9 (14%) pregnancies were diagnosed with
TTTS at a mean gestation of 17 weeks. Six women with
stage 2–3 TTTS opted for laser dichorionisation of the
placenta, resulting in 4 double survivors and 2 single sur-
vivors. Two with stage 3 TTTS elected selective cord oc-
clusion with survival of both co-twins, and 1 with stage 3
disease at 19 weeks’ gestation chose to terminate her preg-
nancy.
IUGR was identified in 24 (40%) pregnancies, and in
17 (26%) cases, this affected 1 twin and met the defining
criteria for sIUGR. One patient opted for selective termi-
nation by cord occlusion at 18 weeks, with the surviving
twin requiring delivery at 31 weeks as it also had IUGR.
One of the pregnancies had co-twin fetal demise of a
smaller twin at 21 weeks; the co-twin was delivered at 36
weeks with no apparent neurodevelopmental defect at
birth. All remaining pregnancies identified with sIUGR
were delivered before 34 weeks.
Unanticipated sudden fetal demise was diagnosed in 1
(1.5%) twin pair at 19 weeks’ gestation. One patient deliv-
ered prematurely at 23 weeks, and both fetuses died due
to extreme prematurity.
TR was observed in 1 fetus in 3 pregnancies. One patient
had an otherwise uncomplicated pregnancy and delivered
spontaneously at 37 weeks. A second patient satisfied cri-
terion for stage 1 TTTS at 19 weeks’ gestation that resolved
spontaneously but later developed sIUGR prompting de-
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First-Trimester US Prediction in MCDA Fetal Diagn Ther 3

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15
5
4
10
CRL difference
NT difference
3
2
5
1
0 0
No TTTS TTTS
CRL difference
Fig. 1. Discordance between markers in normal pregnancies and cohort affected by TTTS. TTTS, twin-twin trans-
fusion syndrome; CRL, crown-rump length; NT, nuchal translucency; DV, ductus venosus.
livery by emergency Caesarean section at 31 weeks’ gesta-
tion due to abnormal fetal Dopplers. The third patient had
a fetus with severe TR and pulmonary valve stenosis with
right atrial enlargement evident at 13 weeks. This fetus re-
vealed itself to be the recipient in stage 3 TTTS diagnosed
at 15 weeks and treated by laser coagulation of chorioangi-
opagus vessels at 18 weeks. The donor/co-twin died in ute-
ro at 20 weeks and the surviving twin with TR was deliv-
ered at 35 weeks. The antenatal diagnosis of severe valvular
pulmonary stenosis and TR was confirmed in the neonatal
period and required pulmonary valvuloplasty within 6 h of
life. No evidence of diastolic dysfunction was noted on as-
sessment of the tricuspid valve E/A ratio in pregnancies
that later developed TTTS.
We noted that, of the 9 pregnancies that developed
TTTS, haemodynamic changes affecting the DV or tri-
cuspid valve flow were only seen in 1 of the 3 cases where
a formal diagnosis of TTTS was made by 16 weeks’ gesta-
tion. None of those (6) cases diagnosed after 18 weeks had
haemodynamic changes.
The performance of NT, DV and CRL as predictive
markers for TTTS is shown in Figure 2. NT discordance
was the best predictive characteristic for TTTS (ROC
AUC = 0.79; 95% CI 0.58–0.99). Neither DV PIV discor-
dance (AUC = 0.60; 95% CI 0.42–0.78) nor the CRL
(AUC = 0.51; 95% CI 0.30–0.72) were of predictive value.
Combining markers did not improve performance
(AUC = 0.80; 95% CI 0.61–0.99). None of the measured
characteristics were predictive of sIUGR: AUC estimates
were 0.34 (95% CI 0.17–0.51), 0.36 (0.18–0.54) and 0.54
(0.38–0.70) for NT, DV and CRL, respectively (Fig. 3).
4 Fetal Diagn Ther
DOI: 10.1159/000504049
Color version available online
0.4
0.3
DV difference
0.2
0.1
0
No TTTS TTTS No TTTS TTTS
NT difference DV difference
Discussion
The outcomes of this series of 65 MCDA twin pregnan-
cies (14% TTTS; 26% sIUGR) that were prospectively re-
cruited at 11–13+6 weeks’ gestation reinforce previous re-
ports of the high level of morbidity associated with mono-
chorionic placentation. The only characteristic that proved
to be of value in predicting pregnancies at high risk of
TTTS was NT discordance, but this was not useful in pre-
dicting the occurrence of sIUGR and did not, therefore,
predict the majority of pregnancy complications. Adding
other sonographic characteristics (CRL and DV/TR) did
not improve the prediction of an adverse outcome.
The prevalence of increased/discordant NT in MCDA
twins has varied from 8 to 18% in different studies [10–
14]. Sebire et al. [10] were the first to describe this finding
in a retrospective cohort of 287 monochorionic twins and
ascribed a positive likelihood ratio of increased NT
(>95th centile) of 3.5 for the subsequent development of
TTTS. Our findings are similar; 18% (12/65) of fetuses in
our cohort had NT >95th centile and 33% (4/12) of these
developed TTTS. In this prospective cohort, the sensitiv-
ity and specificity of this screening tool were 44% (95%
CI 15–77%) and 86% (95% CI 73–93%), respectively. The
positive and negative predictive values were 33% (95% CI
11–64%) and 90% (95% CI 78–96%), respectively, and the
positive likelihood ratio was 3.0. Neither the sensitivity
nor the negative predictive value was sufficiently strong
to make use of first-trimester increased NT as a discrimi-
nator for assigning MCDA twin pregnancies into a high-
or low-risk model of obstetric care and fetal surveillance.
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 Color version available online

Color version available online

NT, DV or CRL to predict TTTS NT, DV or CRL to predict TTTS
NT 1.00 NT
1.00
CRL CRL
DV DV

0.75
0.75

True-positive rate (ROC)

True-positive rate (ROC)

0.50 0.50

0.25 0.25

0 0

0 0.25 0.50 0.75 1.00 0 0.25 0.50 0.75 1.00

False-positive rate False-positive rate

Fig. 2. NT, DV and CRL to predict TTTS. TTTS, twin-twin trans- Fig. 3. NT, DV and CRL to predict sIUGR. sIUGR, selective intra-
fusion syndrome; CRL, crown-rump length; NT, nuchal translu- uterine growth restriction; CRL, crown-rump length; NT, nuchal
cency; DV, ductus venosus. translucency; DV, ductus venosus.

Kagan et al. [11] found that a >20% discordance in NT with differential growth in twins. However, similar to
was associated with 50% detection of TTTS for a 20% other authors [23], we did not find a meaningful associa-
false-positive rate. In our series, the sensitivity and speci- tion between first-trimester CRL discordance and subse-
ficity of NT discordance (>20%) were 88% (8/9 cases) and quent development of sIUGR in this study.
71% (40/56 cases), respectively. There was evidence that The data did not establish any association between ab-
NT discordance was more marked in those cases with an sence/reversal of the “A” wave of the DV and TTTS; this
early diagnosis (2/3 cases) than in those cases (0/6) that contrasts to previous reports of a 75% sensitivity and 92%
were diagnosed after 18 weeks. If a therapy was developed specificity [13, 14]. We also analysed the DV data in terms
that allowed for chorioangiopagus vessels to be function- of the PIV. Whilst there were more cases (20%) with DV
ally separated in the early part of the second trimester [8, PIV discordance in our series (Table 2), the prevalence
9], then NT discordance >20% would be an effective tool was similar in control and adverse outcome pregnancies.
for defining a cohort who should be offered treatment. An association between TTTS and tricuspid valve flow
However, as 2 out of every 3 pregnancies treated would has not previously been reported. Although the preva-
have been treated on the basis of a false-positive result, lence of TR is slightly higher in the TTTS group, the num-
the intervention would need to carry minimal procedure- bers are too small to draw any conclusions. Importantly,
related risk. in 8/9 pregnancies complicated by TTTS, TR was not ob-
The data attempting to relate CRL discordance in served on assessment at approximately 12 weeks’ gesta-
MCDA twins with subsequent development of TTTS is tion.
conflicting. Similar to the findings of Sebire et al. [22], we Although the Quintero staging system identifies hae-
did not find a meaningful relationship between CRL dis- modynamic changes relatively late in the course of TTTS
cordance and TTTS. This is not surprising given the un- (associated with stage 3 disease), other groups have shown
likely biological link between TTTS (a haemodynamic that significant haemodynamic changes can be demon-
problem) and abnormal CRL. Of greater biological plau- strated from earlier time points – if they are actively
sibility is the possibility that a significant difference in sought during cardiac evaluation. Rychik et al. [24] in a
placenta territory could be anticipated to be associated retrospective review of 150 MCDA twins with TTTS
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found that TR was present in 35% of twins at a mean ges-
tation of 21 weeks. Similarly, Wohlmuth et al. [25] in a
prospective study of 145 MCDA twins found that approx-
imately 23% of TTTS (stage 1 and 2) cases had TR at 21
weeks. Despite this, it appears that these cardiac changes
are not readily apparent as early as 11–13+6 weeks’ gesta-
tion in the majority of cases that go on to develop TTTS.
Transient right ventricular outflow tract obstruction is
more commonly seen later in pregnancies affected by
TTTS and may represent obstruction due to right ven-
tricular myocardial hypertrophy. This typically disap-
pears with the normalization of the myocardium after la-
ser treatment. Semilunar valve maturation is not com-
plete by the early part of the second trimester, and,
therefore, with the early diagnosis of TTTS, the fetal heart
is more susceptible to haemodynamic imbalances leading
to persistent right ventricular outflow tract obstruction.
This was evident in our case of pulmonary stenosis/atre-
sia where laser treatment did not correct the condition
and valvuloplasty was required on the 1st day of neonatal
life [26].
Cardiac dysfunction has been well documented across
the Quintero staging of TTTS. Natural history and pro-
gression to cardiomyopathy are not completely under-
stood. Recent studies have described changes in diastolic
function that precede the development of ventricular hy-
pertrophy and systolic dysfunction [27–30]. Diastolic
dysfunction leads to a reduction in the early passive filling
phase (E wave) and an increase in late active atrial con-
traction (A wave). As diastolic dysfunction increases, the
2 waves of diastole fuse into a single peak. Monophasic
ventricular filling (fusion of E and A wave) is observed in
20–30% of TTTS at 21 weeks [24]. In contrast, in our co-
hort, only 1 patient had a monophasic E/A wave at 13
weeks’ gestation; this pregnancy also had 60% NT discor-
dance and developed TTTS at 18 weeks. We did not find
any evidence of overt diastolic dysfunction in other fe-
tuses who developed TTTS.
Strengths of our study include the prospective nature
of assessment and the availability of almost all outcome
data. Limitations include the small number of pregnan-
cies available for study that were affected by a complica-
tion of monochorionic placentation.
This prospective study has shown that assessment of
NT at 11–13+6 weeks’ gestation is of some value in iden-
tifying MCDA twin pregnancies that will go on to develop
TTTS but not sIUGR. No predictive characteristics for
sIUGR could be identified. Combinations of predictive
tools did not improve screening performance. Currently
suggested strategies for risk prediction are not of suffi-
cient efficacy to alter management of MCDA twin preg-
nancies after the 11- to 13+6-week scan.
Statement of Ethics
The study was approved by the ethics committee (protocol
number X11-0073). Women found to have MCDA twin pregnan-
cies on ultrasound assessment at 11–13+6 weeks’ gestation were
invited to participate and consented for the study.
Disclosure Statement
The authors have no conflicts of interest to declare.
Author Contributions
Ritu Mogra, Jon Hyett and Greg Kesby contributed to the de-
sign and implementation of the research; Ritu Mogra, Rahmah
Saaid and Jane Tooher contributed to the patient recruitment and
data collection; Lars Pedersen did the statistical analysis. All au-
thors contributed to the writing of the manuscript.

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