Human Reproduction Vol.16, No.9 pp. 1999–2004, 2001
Nuchal translucency measurement and pregnancy outcome
after assisted conception versus spontaneously conceived
R.Maymon1,3, E.Jauniaux2, A.Holmes2, Y.M.Wiener1, E.Dreazen1and A.Herman1
1Department of Obstetrics and Gynecology, Assaf Harofe Medical Center, Zerifin 70300 (affiliated with Sackler Faculty of Medicine,
Tel Aviv University, Tel Aviv), Israel, and2Academic Department of Obstetrics and Gynaecology, Royal Free and University
College, UCL campus, London, UK
3To whom correspondence should be addressed. Email: firstname.lastname@example.org
BACKGROUND: Nuchal translucency (NT) measurement for Down’s syndrome screening or detecting various
fetal anomalies is a reliable sonographic marker. This study evaluates the contribution of NT screening in
spontaneously conceived and assisted conception twin pregnancies. METHODS AND RESULTS: Maternal age at
measurement, chorionicity, ultrasound features, karyotype results and pregnancy outcome were recorded prospect-
ively and compared in 83 assisted reproduction treatment and 91 spontaneously conceived twins. Pregnancy outcome
was evaluated according to maternal age, method of conception, NT data and chorionicity. NT measurements (≥95
centiles of the normal range) were considered screen-positive and mid-pregnancy fetal karyotyping was advised.
Complicated pregnancy outcome, which could be signalled by increased NT, was defined as either chromosomal
abnormalities, severe structural defects or fetal demise. Based on NT measurements, 16 fetuses (4.6%) were found
to be screen-positive. Five of them had chromosomal aneuploidy and selective termination was performed. The
parents also opted for this procedure in another five fetuses because of major structural abnormality diagnosed
during NT assessment. No other chromosomal or major fetal abnormality were found post-natally. Although no
difference was found in NT, crown–rump length and maternal age between spontaneous and assisted reproduction
technology twin pregnancies, the former group had a significantly higher rate of screen-positive results (7 versus
2%, P ? 0.047), amniocentesis uptake (33 versus 22%, P ? 0.014), monochorionic twining (32 versus 4%, P ?
0.001) and complicated pregnancy outcome (11 versus 5%, P ? 0.02). CONCLUSION: The present study confirms
that first trimester target scanning can improve outcome by early detection and management of cases with an
anomalous co-twin. It also identifies some differences between spontaneously and artificially conceived twin
pregnancies in relation to this area of testing.
Key words: twins/nuchal translucency/ultrasound/assisted conception/fetal outcome
Over the past decade, both maternal age of primiparas and the
widespread increase in the application of assisted reproduction
technology and ovulation-induction drugs have risen dramatic-
twining rate is related to maternal age, and women ?35 years
of age are three times more likely to spontaneously conceive
twins than are younger women (Spencer, 2000). This trend
has a great impact on perinatal care since twin pregnancies
pose numerous management problems from conception to
delivery. For example, they are at higher risk both for chromo-
somal abnormality (Botting et al., 1987; Cuckle, 1998) and
structural defect for each individual co-twin (Doyle et al.,
1990). Additionally, Down’s syndrome serum screening is of
limited value in twin pregnancies (Wald et al., 1991) because
© European Society of Human Reproduction and Embryology
of the unaffected co-twin’s masking of the abnormal maternal
serum distribution seen in singleton analyses (Cuckle, 1998).
It has also been recently reported that the human chorionic
gonadotrophin (HCG) serum levels are usually higher among
twin pregnancies following assisted reproduction technology
treatment, thus resulting in higher false positive rates for
Down’s syndrome screening (Ra ¨ty et al., 2000).
Women who conceived after assisted reproduction techno-
logy treatment are on average older and, in many cases, their
current pregnancy (which may be their last) was achieved
after long-standing infertility. For this reason, they would be
extremely wary of an invasive fetal karyotyping procedure in
which the miscarriage rate following amniocentesis is doubled
in twins compared with that in matched singletons (Kidd et al.,
1997). It follows that every effort should be made to provide
women who are pregnant with twins with the most accurate
R.Maymon et al.
Down’s syndrome screening tests (Maymon et al., 1999a).
The accumulation of fluid behind the fetal neck, defined as
nuchal translucency (NT) thickness, was found to be a promis-
ing marker alerting for complicated pregnancy outcome. Those
abnormalities include chromosomal aneuploidies, severe struc-
tural defects, a wide range of genetic syndromes and miscar-
riages (Nicolaides et al., 1999). The application of this
sonographic screening method in twin pregnancies is supported
by the observation that NT measurements are similarly accurate
in trisomic twin pregnancies and affected singletons (Pandya
et al., 1995a; Sebire et al., 1996a; Nicolaides et al., 1999).
Furthermore, NT assessment was found to be useful in helping
to choose and perform the appropriate invasive diagnostic
cytogenetic procedure in twin pregnancies (Sebire et al.,
1996b). Finally, in monochorionic twins, a large NT thickness
may alert for early onset of feto-fetal transfusion syndrome
(Sebire et al. 1997a, 2000).
We present herein the results of a twin screening study in
which two centres participated. Specifically, twins conceived
with assisted reproduction technology were compared with
spontaneous twin pregnancies for NT screening results and
throughout their gestation. This subject is not satisfactorily
addressed in the literature.
Materials and Methods
The current study was carried out between June 1998 and November
1999 in two fetal medicine units: Assaf Harofe Medical Center,
Zrifin, Israel and University College London Hospital, London, UK.
All cases were recruited from the same clinics over the same period
of time, and the same diagnostic protocol was used. Each institution
has a tertiary unit known as the ‘twin clinic’ to which pregnant
women with multifetal pregnancies are referred for target scanning.
Data from twins after fetal reduction of high order multiplicity were
not included in the current study. The gestational ages were calculated
from the last menstrual period and thereafter confirmed by the crown–
rump length (CRL) (Robinson and Flemming, 1975). Specifically,
the gestational age was calculated on the basis of the largest CRL
length (Sebire et al., 1997a) and only fetuses with a CRL of 38–84
mm were included. The twin pregnancy group was further subdivided
into twins conceived after assisted reproduction technology treatment
(study group) and spontaneously conceived twins (control group).
A transabdominal and/or transvaginal ultrasound examination
(Aloka 1600, Tokyo, Japan and HDI 3000; Advanced Technology
Laboratories, Seattle, WA, USA) with a variable focus 3.5–5 MHz
curvelinear transducer and a transvaginal 5 or 7 MHz transducer was
performed in all cases. There was no set time limit for generating a
satisfactory image. The ultrasound examination determined the viabil-
ity, size and position of each fetus, as well as the location of the
placenta, placental attachment to the inter-twin membrane and the
relation between the amniotic sac and the cervix. Chorionicity was
determined based on previous sonographic criteria (Sepulveda et al.,
1996, 1997) in which monochorionic twin pregnancies were classified
if there was a single placental mass and the absence of the λ-sign at
the inter-twin membrane–placental junction.
Following the description by Pandya et al. (1995b), precise
measurements of the maximum thickness of the translucent area
between the skin and the soft tissue overlying the cervical spine were
obtained in the sagittal section of the fetus (Pandya et al., 1995b).
Cases with NT ?95 centiles of the normal range for various CRLs
in singletons [2 mm for CRLs ?44 mm, to 2.85 mm for CRLs of
83–84 mm (Herman et al., 2000)], in which the calipers were placed
‘on–on’ the nuchal lines, were considered screen-positive and the
parents were offered the option of invasive prenatal karyotype. Based
on our published model (Herman et al., 1998a), each sonograph NT
image was subject to regular internal audit to check quality control,
standardization and performance. The intra-observer repeatability
coefficients of our team (R.M. and A.H.) were 0.28 mm and
0.34 mm. Intra-observer repeatability of image measurement showed
a significant difference (P ? 0.01), but the mean difference (? SD)
of 0.10 ? 0.18 mm was negligible (Herman et al., 1998b). This
performance corresponds well with other groups (Pandya et al.,
1995c). Prior to examination, the pregnant women were given an
explanation on the nature and implications of the test. Following
the test, they were counselled on the potential risks and specific
recommendations were made. Genetic counselling, fetal karyotyping,
offered in all cases of NT ?95 centiles. Following the sonographic
evaluation, the patients were referred to their obstetrician for further
The method of conception, maternal age at measurement, chorionic-
ity, karyotype results and pregnancy outcome were recorded prospect-
ively on a computer database. For the current study, complicated
pregnancy outcome was defined as aneuploidy, severe structural
defects or miscarriages, since those abnormalities have been reported
to be associated with increased NT (Nicolaides et al., 1999). The
fetal outcome was categorized into miscarriage, intrauterine fetal
death, neonatal death or alive and well. All disorders or abnormalities
were recorded in detail. Karyotype results and pregnancy outcome of
all the twins and their medical history were obtained from the parents
by a telephone interview and, when necessary, their medical records
were requested from the respective departments.
Standardized kurtosis showed that the data derived from a normal
distribution of the twin population, and thus the variables, are
expressed as mean and SD. Frequencies are expressed as a percentage.
Prediction of a complicated pregnancy outcome was classified as
aneuploidy, severe structural defects which justified selective termina-
tion, or fetal demise. Those parameters were assessed based on mode
of conception, maternal age, NT value and CRL. A stepwise logistic
regression model was applied to the data. The cases were further
subdivided according to method of conception (assisted reproduction
technology versus spontaneous) and chorionicity. Differences between
the groups in chorionicity, amniocentesis rate and cases with compli-
cated versus uncomplicated pregnancy outcome were compared using
χ2or Fisher’s exact test, where applicable. The two-sample t-test was
used to assess the difference between CRL, NT and maternal age in
those groups. After excluding all abnormal cases, a linear regression
model for NT and CRL was fitted to the data. P-values ? 0.05 were
considered statistically significant. Statistical analysis was carried out
by the statistical department of the Tel Aviv University, using
This study comprised 91 twins conceived spontaneously and
83 twin pregnancies which followed assisted reproduction
technology treatment, in which complete follow-up was avail-
able. A total of 107 pregnancies were from Assaf Harofe of
which 60 were part of a previous twin study (Maymon et al.,
1999b). Sixty-seven pregnancies were from University College
Twin pregnancy outcome after nuchal translucency assessment
Table I. The distribution and comparison of the 182 spontaneous and 166 assisted reproduction technology
conceived co-twins pregnancies by maternal age, sonographic measurements, amniocentesis rate and
complicated pregnancy outcome*
91 pregnancies (52%)
83 pregnancies (48%)
Maternal age (mean ? SD) (years)
CRL (mean ? SD) (mm)
NT (mean ? SD) (mm)
NT screen-positive ratea
Complicated pregnancy outcomeb
32 ? 4
62 ? 12
1.5 ? 1.3
31 ? 4
62 ? 10
1.5 ? 0.5
dFisher’s exact test.
*Complicated pregnancy outcome: summation of chromosomal aneuploidies, structural anomalies and fetal
NT ? nuchal translucency; CRL ? crown–rump length; ns ? not significant.
London Hospital. Based on first trimester NT screening results,
16 (4.6%) fetuses out of 348 co-twins which had been assessed
were found to be screen-positive and the women were offered
prenatal karyotyping (Table 1). However, the karyotype was
available in another 80 fetuses because of other indications
for testing, including second trimester abnormal sonographic
or biochemistry results and the parents’ request. Thus, the
overall prenatal karyotyping uptake was 28% of the twins
studied. There were five cases with aneuploidy, including three
cases of Turner’s syndrome and two with Down’s syndrome.
The observed prevalence of aneuploidy among fetuses with
abnormal NT (?95 centiles) was 5/16 fetuses (31%), and for
the complete group it was 5/348 (1.4%). Post-natally, no
traits were observed that would have warranted chromosomal
analysis in those neonates in which prenatal karyotyping was
not performed. Overall, 10 fetuses (3%) underwent selective
termination at the request of the parents (nine of them in the
second trimester and one during the third trimester). This was
because of chromosomal aneuploidy in five cases, and major
structural anomalies in the other five (four cases because of
neural tube defect and one bichorionic euploid co-twin because
of hydrops). In one case, the entire pregnancy was lost
following the procedure. A co-twin with increased NT and a
large thoracic cyst which resolved spontaneously and unevent-
ful outcome was reported elsewhere (Jauniaux et al., 2000).
The overall spontaneous miscarriage rate was 5% of the twins
in the current study. There were three cases of monochorionic
twins which developed feto-fetal transfusion syndrome, among
which one co-twin had intrauterine death at 30 weeks and the
other an early neonatal death.
There were no differences between maternal age and method
of conception between the two groups (complicated/uncompli-
cated outcome). Therefore, only CRL and NT (which were
found to be significant after applying the logistic regression
analysis) were included in the model. The probability of a
complicated pregnancy outcome (dependent variable) and the
Figure 1. Linear regression between nuchal translucency (NT, in
mm) and crown-rump length (CRL, in mm) with 95% confidence
limits for unaffected individuals (u ? assisted reproduction
technology; m ? spontaneous conception).
CRL and NT (independent variable) were thus calculated using
a logistic regression model.
Complicated pregnancy outcome was defined as aneuploidy,
major organ anomalies diagnosed prenatally which justified
selective termination and spontaneous miscarriages. The odds
ratio of complicated pregnancy outcome associated with
increasing NT measurement with every 1 mm was 4.36 [95
confidence interval (CI) 2.40–7.93, P ? 0.001] whereas an
increase in the CRL was related to a better pregnancy outcome
with an odds ratio of 0.91 (CI 0.87–0.96, P ? 0.001). The
odds ratios were calculated using continuous variables of NT
R.Maymon et al.
Table II. The distribution of the twins pregnancies, their screen-positive rate (NT ?95thcentile), chorionicity
and complicated pregnancy outcome*
twins (n ? 264)
twins (n ? 64)
Missing data Significance
NT screen-positive ratea
Complicated pregnancy outcomea
P ? nsc
P ? nsc
cFisher’s exact test.
*Complicated pregnancy outcome: summation of chromosomal aneuploidies, structural anomalies and fetal
NT ? nuchal translucency; ns ? not significant.
When an arbitrary cut-off point of P ? 0.5 was used, a
complicated twin pregnancy outcome could be anticipated with
sensitivity, specificity, and positive and negative predictive
values of 33, 100, 100 and 95% respectively.
In the uncomplicated twin pregnancies, a linear regression
model (R2? 0.1227, P ? 0.001) between an individual CRL
and NT was used and showed an increased NT value as
gestation progressed (Figure 1).
Table I presents and compares the data of the assisted
reproduction technology treatment and spontaneous conception
twin pregnancies. The values of the mean maternal age,
CRL and NT thickness were comparable. The spontaneous
conception pregnancies had a significantly higher rate of
screen-positive results, monochorionic twins, amniocentesis
uptake and complicated pregnancy outcome (Table I). The
pregnancies were further subdivided according to their chor-
ionicity (Table II). No significant difference between the
monochorionic and bichorionic twins was found for either the
screen-positive rate or a complicated pregnancy outcome
Preventing the birth of a twin with chromosomal or structural
anomalies whilst minimizing the risk to the normal co-twin
continues topose animportant prenatalchallenge. Thisrequires
early recognition of twin gestation, determination of zygosity
and a target scanning to detect any markers and signs of
The obstetric outcomes of twins are usually analysed by the
method of conception and chorionicity. However, the NT data
from the first trimester emerge as being highly informative for
determining other aspects of pregnancy outcome, such as
chromosomal and structural abnormalities (Nicolaides et al.,
1999). Studies comparing the obstetrical outcome in assisted
and spontaneous conception twin pregnancies have yielded
conflicting results. Moise et al. (1998) found that IVF twins
were at a higher risk of neonatal morbidity and mortality than
spontaneously conceived twins, whereas Olivennes et al.
(1996) and Koudstaal et al. (2000) reported no significant
difference in perinatal outcome, the latter in a matched control
study (Olivennes et al., 1996; Moise et al., 1998; Koudstaal
et al., 2000). We found no significant difference in maternal
age between assisted and spontaneous conception twins. How-
ever, the former group had a significantly higher amniocentesis
uptake and complicated pregnancy outcome rate. Various
theories were proposed to explain this difference: Olivennes
et al. (1996) found fewer obstetric visits among parents with
spontaneous twin pregnancies and argue that this trend may
explain the different outcome (Olivennes et al., 1996). Our
findings did not confirm theirs. A more reasonable explanation
might lie in the higher monozygosity rate found in the
spontaneously-conceived twins. Although it was recently
reported in a series of 303 monochorionic twin pregnancies
that there were 16 (3%) pregnancies in which at least one
fetus was found to be structurally or chromosomally abnormal
(Sebire et al., 2000). Nevertheless, and in agreement with one
of the above studies (Koudstaal et al., 2000), we argue that
this phenomenon implies that the risk for a complicated
outcome in the spontaneous conception twins group is higher
than in the assisted reproduction technology fetuses because
of the difference in the zygosity.
The NT screen-positive rate of 5% is consistent with our
previous twins study (Maymon et al., 1999b) and is lower
than the 7% and 8.6% in dichorionic and uncomplicated
monochorionic twins respectively, reported by others (Sebire
et al., 1996a, 1997a). Additionally, the prevalence of chromo-
somal abnormalities on the basis of maternal age and fetal NT
measurement in the present study was 31% in comparison
with 23% reported by the same group (Sebire et al., 1996b).
However, the median maternal age in their study population
was 35 years and, considering that the maternal background
age-related risk is part of the first trimester NT screen results,
this may contribute to higher false positive rate.
The current finding of a 5% overall spontaneous fetal loss
rate is in agreement with other reports (Sebire et al., 1997b;
Nicolaides et al., 1999), and is more than double the 2% rate
observed in an unselected population at 10–14 weeks gestation
(Pajkrt et al., 1999). These results may extend our understand-
ing of the epidemiological observation of a low Down’s
syndrome prevalence in twin pregnancies. On the basis of
be almost double that in singletons whereas, in fact, the
prevalence in twins and singletons is similar (Cuckle, 1998).
Twin pregnancy outcome after nuchal translucency assessment
The overall fetal loss rate in singleton pregnancies with Down’s
syndrome is about 50% (Macintosh et al., 1995). If the relative
risk of loss in apparently normal twins is the same as that
observed in singletons, then it might also apply to Down’s
syndrome pregnancies, in which case the loss per term preg-
nancy would be much greater in affected than in unaffected
pregnancies. This effect could account for the apparently
similar occurrence in twins and singletons.
An 8.6 and 37.5% incidence of increased NT has been
previously reported in uncomplicated and complicated mono-
chorionic twins respectively. The latter were found to be at
risk for developing feto-fetal transfusion syndrome (Sebire
et al., 1997a, 2000). This finding in 32 sets of monochorionic
twins has not yet been confirmed, and the increased NT rate
being similar to that of our dizygotic twins (4.7 and 4.9%
respectively) may be because of the small size of our series.
The current study sheds more light on those aspects as well
as providing comparative data on the effectiveness of NT
screening in twin pregnancies. Thus, by using the logistic
regression model presented herein, accurate calculations of the
probability for an uncomplicated pregnancy outcome could be
provided as early as 10–14 weeks gestation. The NT values
for both the assisted reproduction technology twins and their
controls were found to increase with advancing gestation
(Figure 1), and an increase in NT was related to a positive
significance odds ratio for complicated pregnancy outcome. In
contrast, an increase in CRL was related to a better pregnancy
outcome. Our data (Figure 1) validate the reference ranges of
NT measurements that had originally been developed for
singletons (Braithwaite et al., 1996).
In twins, NT measurements can be performed either alone
or in combination with first trimester serum biochemistry
(Spencer, 2000). By combining NT measurement and various
serum markers (Cuckle and Shemi, 1999; Wald et al., 1999),
an improvement of the detection of the trisomic co-twins can
be expected, with the benefit of ultrasound being able to
specifically locate the affected one (Spencer, 2000). Hopefully,
those algorithms might counterbalance the increased midgest-
ation HCG maternal serum levels reported in assisted reproduc-
tion technology twins (Ra ¨ty et al., 2000).
In conclusion, our data indicate that assisted reproduction
technology-derived twin pregnancies are not associated with
of this study should be reassuring both for physicians and their
patients who are engaged in assisted reproduction technology
treatment. However, they should not be misguiding: overall,
twin pregnancies still have increased adverse outcome when
compared with singletons. Our experience and that of others
(Nicolaides et al., 1999) shows that first trimester target NT
scan can improve outcome by early detection and management
of cases with an anomalous co-twin. Therefore, the imple-
mentation of NT assessment should be favorably considered
in antenatal twin clinics.
The authors are grateful to the statistical department at the Tel Aviv
University for their assistance. Esther Eshkol is thanked for her
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Received on October 2, 2000; accepted on May 24, 2001