Arch Gynecol Obstet (2012) 285:973–978
DOI 10.1007/s00404-011-2119-z
MATERNAL-FETAL MEDICINE
Selective and non-selective intrauterine growth restriction in twin
pregnancies: high-risk factors and perinatal outcome
Yu Gao • Zhiming He • Yanmin Luo •
Hongyu Sun • Linhuan Huang • Manchao Li •
Yi Zhou • Baojiang Chen • Qun Fang
Received: 17 July 2011 / Accepted: 11 October 2011 / Published online: 25 October 2011
Ó Springer-Verlag 2011
Abstract
Purpose To evaluate the high-risk factors and perinatal
outcome in selective intrauterine growth restriction (sIUGR)
and non-selective IUGR (non-sIUGR) in twins.
Methods In total, 336 pairs of twins were enrolled from
December 2003 to 2009. According to the birth weight,
295 pairs of twins were divided into sIUGR, non-sIUGR
and normal growth groups. Maternal characteristics, com-
plications, chorionicity, zygosity and perinatal outcomes
were analyzed among the three groups.
Results The overall IUGR incidence (including sIUGR
and non-sIUGR) in twin pregnancies was 23.2%. The sI-
UGR incidence was ten times greater than that of non-
sIUGR. Monochorionicity and monozygosity were risk
factors for overall IUGR, especially for the sIUGR
(P \ 0.01). Pre-eclampsia was more common in sIUGR
than in the normal growth group (P \ 0.05). Both the sI-
UGR and non-sIUGR groups had more intrauterine fetal
death and neonatal death than the normal growth group
(P \ 0.01). The sIUGR group had more brain injury than
the normal growth group (P \ 0.01).
Conclusion Monochorionicity, monozygosity, pre-eclampsia
were high-risk factors for IUGR in twins. Perinatal death
Y. Gao
Z. He
Y. Luo
L. Huang
M. Li
Y. Zhou

B. Chen
Q. Fang (&)
Department of Obstetrics and Gynecology, Fetal Medicine
Center, The 1st Affiliated Hospital of Sun Yat-Sen University,
58 Zhong Shan Er Road, Guangzhou 510080,
People’s Republic of China
e-mail: fangqun_sums@hotmail.com
H. Sun
Department of Forensic Medicine, Sun Yat-Sen University,
Guangzhou, People’s Republic of China
was more prevalent in the non-sIUGR group, and neonatal
brain damage was more prevalent in the sIUGR group.
Keywords Twins
Intrauterine growth restriction

Risk factors
Perinatal mortality
Introduction
Intrauterine growth restriction (IUGR) is a serious obstetric
complication that threatens fetal health. With the increas-
ing incidence of twin pregnancy, twin IUGR raises more
and more concern because of its poor prognosis. The IUGR
incidence rate in twins is 15–47% [1], which is higher than
that of singleton (3–10%) [2]. Furthermore, extremely low
fetal birth weight and intrauterine fetal deaths are more
common in twin IUGR than in single pregnancies. To
manage twin growth disorders, it is important to detect the
high-risk factors and prevent the neonatal complications.
Some of the high-risk factors for twin IUGR have already
been identified, such as low maternal weight gain and
tobacco use [3–5], although most of the common risk factors
in single pregnancies are not significant for twin IUGR [1]. It
should be noted that twin pregnancies are far more compli-
cated than single pregnancies, and twin pregnancies present
some unique situations. For example, the fetuses are not
independent, and they have to compete with each other in a
confined intrauterine physical space and nutrient supply.
They interact and affect each other through the placenta,
amniotic fluid and umbilical cord [6, 7]. Chorionicity and
zygosity are the unique characteristics in twin pregnancy
which are closely related to their interactions.
The IUGR phenotype in twins can be separated into two
categories. One category is selective IUGR (sIUGR), in
which just one of the twins meets the criteria for IUGR.
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The other category is non-selective IUGR (non-sIUGR), in
which both of the fetuses are IUGRs. Distinguishing the
discrepancies in twin IUGR can help to figure out the
genetic, epigenetic and pathological etiology, which is very
important for clinical consultation and management [8–10].
However, most of previous twin IUGR epidemiological
reports are focused on the overall IUGR or selective IUGR
only and there are limited studies that compare the dif-
ferent phenotypes of IUGR in twins [1, 5]. The purpose of
our study is to compare the high-risk factors and perinatal
outcomes between sIUGR, non-sIUGR and normal growth
fetuses in twins to provide evidence for clinical treatment
and consultation.
Materials and methods
This was a case control study of 336 twin pregnancies. All
of the twin pregnancy cases were from the 1st Affiliated
Hospital of Sun Yat-Sen University from December 2003
to 2009. All abortions that occurred before 24 gestational
weeks were excluded. All of the patients were informed of
the following sample exam and data collection for
research. Patient consent forms were signed before
enrolling the subject. This study was approved by the
Institutional Review Board.
A first trimester ultrasound was performed to certify the
gestational age. The follow-up ultrasound was performed
every 4 weeks. Twenty-nine cases were diagnosed as twin-
to-twin transfusion syndrome (TTTs) according to the
Quintero’s criteria [11] and excluded from the study
groups. There were 32 twins cases (58 fetuses) underwent
prenatal diagnosis for fetal karyotype analysis due to the
increased risk for fetal abnormality. Twelve cases were
then excluded for abnormal fetal karyotype or neonatal
structural abnormalities.
The remaining 295 cases were managed expectantly.
Cord occlusion or placental laser coagulation were not used
in these cases. The deliveries were determined by sponta-
neously threatened labor or by a specialist and parents
together.
According to the birth weight, the 295 pairs of twins
were divided into three study groups: sIUGR (n = 71),
non-sIUGR (n = 7), and normal growth group (n = 217).
sIUGR was classified as having only one fetus’ birthweight
below the 10th percentile according to the Alexander twin
reference curve [12]. Non-sIUGR was defined as both of
the fetuses meeting the criteria. Discordant twins were
defined as inter-fetal birth weight difference greater than
20%, calculated as the difference between the two fetal
birth weights divided by the larger fetal birth weight.
Chorionicity was diagnosed by 11–14 weeks ultrasound.
T-shaped take-off and lambda sign represented monochorionic
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Arch Gynecol Obstet (2012) 285:973–978
and dichorionic placenta, respectively [13]. After delivery,
placentas were sent to pathological examine to confirm chori-
onic characteristics.
Zygosity was diagnosed as below. Unlike-sex twins
were considered dizygotic twins, and like-sex twins with
monochorionicity were considered monozygotic twins.
Beyond these, there were still 74 pairs of twins that
required identification by short tandem repeat (STR) assay.
During delivery, placental tissues around the individual
umbilical cord insert region were collected for STR assay.
DNA was extracted according to the phenol–chloroform
method and amplified with Power-Plex 16 (Promega,
Madison, USA Cat. DC 6531) to detect 15 autosomal STR
loci plus the gender determination marker, Amelogenin.
Multiplex PCR was performed using 1 ll template DNA in
a 10 ll volume that included 1 ll 10x GeneAmp PCR
Gold-Buffer, 1 ll 10x Primer Pair Mix and 0.3 ll Amp-
liTaq Gold DNA polymerase (1.5 u) (Applied Biosystems,
Carlsbad, USA Cat. 4338856). PCR cycle conditions were
as follows: 95°C for 11 min, 96°C for 2 min; 10 cycles of
94°C for 1 min, 60°C for 1 min, 70°C for 1.5 min; 22
cycles of 90°C for 1 min, 60°C for 1 min, 70°C for
1.5 min; and final extension at 60°C for 30 min. The PCR
products were separated and detected by capillary elec-
trophoresis using an ABI 3100 Genetic Analyzer (Applied
Biosystem, Carlsbad, USA Cat. 4359571) according to the
manufacturer’s instructions. Allele calls were made using
GeneMapper ID v3.2 software (Applied Biosystem,
Carlsbad, USA Cat.4338856). If all genotypes of the 16
loci were identical, the pair was recognized as monozy-
gotic twins. If the genotypes of any loci did not match, the
pair was recognized as dizygotic twins.
Neonates were followed up for regular neurologic
checkup by pediatricians at 1 week and 2 months of age. If
any abnormal sign detected, MRI was prescribed. Neuro-
logical complications were recorded when multicystic
leukencephalomalacia and intraventricular hemorrhage
were diagnosed by MRI.
We summed up the high-risk characteristics, including
the chorionicity, zygosity, maternal age, gestational age at
birth, maternal weight gain during the pregnancy, average
inter-fetal birth weight difference, discordant twin inci-
dence, incidence of preeclampsia and gestational diabetes
mellitus.
The perinatal outcomes, including the rate of intrauter-
ine fetal death, neonatal mortality, and neonatal brain
damage, were also analyzed.
All of the statistical analyses were performed using
SPSS software v19.0 (SPSS Inc., Chicago, USA). Student’s
t test was used for continuous variables. Pearson Chi-squared
and odds ratio tests were used to compare proportions.
P values \0.05 were considered statistically significant for
all tests.
Arch Gynecol Obstet (2012) 285:973–978
Results
There were 78 twins with at least one fetal birth weight
lower than the 10th percentile in a total of 336 pairs.
Among them, 7 pairs were non-sIUGR (2.1%) and 71 pairs
were sIUGR (21.1%). The total IUGR incidence (including
sIUGR and non-sIUGR) in twins was 23.2%. The non-
sIUGR and sIUGR ratio was nearly 1:10.
According to the chorionicity assessment, there were
110 (32.7%) monochorionic twins and 226 (67.3%)
dichorionic twins. Forty-one of the monochorionic twins
were IUGR (38 sIUGR and 3 non-sIUGR), and 37 of the
dichorionic twins were IUGR (33 sIUGR and 4 non-sI-
UGR). The twin IUGR distribution based on chorionicity is
summarized in Table 1. The chorionic distribution in the
sIUGR group compared to the normal growth group was
significantly different (P \ 0.01). The sIUGR group had
more monochorionic twins than the normal group. The
odds ratio (OR) for monochorionicity was 5.602 (95% CI
3.120–10.059). There was no significant difference
between non-sIUGR group and normal growth group
(P [ 0.05). The OR for monochorionicity was 3.649 (95%
CI 0.784–16.989). There was no difference in the chorionic
distribution between the sIUGR and non-sIUGR groups
(P [ 0.05). If taking sIUGR and non-sIUGR groups as a
whole, monochorionicity was also found to be a risk factor
(P \ 0.01). The monochorionicity OR for total IUGR was
3.083 (95% CI 2.148–4.425), while dichorionicity was
showed as preventive factor, whose OR was 0.572 (95% CI
0.449–0.728).
Dichorionic twins comprise monozygotic and dizygotic
twins. To further investigate the overlay effect of zygosity
and chorionicity on IUGR incidence, we compared the
IUGR morbidity in subgroup of dichorionic twins. There
was no significant difference in distribution of sIUGR and
non-sIUGR according to the zygosity in the dichorionic
twins (P [ 0.05) (Table 2).
According to the zygotic identification, there were 101
(30.1%) monozygotic twins and 235 (69.9%) dizygotic
twins. 27 of the monozygotic twins were IUGR (25 sIUGR
and 2 non-sIUGR), and 51 of the dizygotic twins were
IUGR (46 sIUGR and 5 non-sIUGR). The twin IUGR
Table 1 Chorionic characteristic in twin pregnancy
MC (n = 78) DC (n = 217)
sIUGR (n = 71) 38 (53.5%)** 33 (46.5%)
Non-sIUGR (n = 7) 3 (42.9%) 4 (57.1%)
Normal growth (n = 217) 37 (17.1%)*** 180 (82.9%)
MC Monochorionic twins, DC dichorionic twins
* P \ 0.05 versus normal growth twins, ** P \ 0.01 versus normal
growth twins, *** P \ 0.01 versus overall IUGR
975
Table 2 IUGR distribution in dichorionic twin pregnancy
MZDC (n = 14) DZDC (n = 203)
sIUGR (n %) 3 (21.4%) 38 (18.7%)
Non-sIUGR (n %) 1 (7.1%) 3 (1.5%)
Normal growth (n %) 10 (71.4%) 162 (79.8%)
Data was showed as case number (%)
MZDC Monozygotic dichorionic twins, DZDC dizygotic dichorionic
twins
Table 3 Zygotic characteristic in twin pregnancy
MZ (n = 70) DZ (n = 225)
sIUGR (n = 71) 25 (35.2%)** 46 (64.8%)
Non-sIUGR (n = 7) 2 (28.6%) 5 (71.4%)
Normal growth (n = 217) 43 (19.8%)*** 174 (80.2%)
MZ Monozygotic twins, DZ dizygotic twins
* P \ 0.05 versus normal growth twins, ** P \ 0.01 versus normal
growth twins, *** P \ 0.01 versus overall IUGR
distribution based on zygosity is summarized in Table 3.
The monozygotic twins were significantly more prevalent
in the sIUGR group than in the normal growth group
(P \ 0.01) (OR 1.777, 95% CI 1.175–2.688). The dizyg-
osity was showed as preventive factor (OR 0.808, 95% CI
0.672–0.971). There was no difference between the non-
sIUGR group and the other two groups (P [ 0.05). If
taking sIUGR and non-sIUGR groups as a whole, signifi-
cant difference was found between the over-all IUGR
group and the normal growth group (P \ 0.01). The
monozygosity was found to be a risk factor for IUGR (OR
was 1.747, 95% CI 1.164–2.621), and dizygosity was a
preventive factor (OR was 0.815, 95% CI 0.685–0.971).
There was no difference in the maternal age (P [ 0.05)
and gestational age at delivery (P [ 0.05) among the three
groups. There was also no difference in the maternal
weight gain during the entire pregnancy (P [ 0.05).
We calculated the mean fetal birth weights in the three
groups; the weight of the larger fetus in normal group was
2.32 kg, and that of the smaller fetus was 2.19 kg, which
was significantly lighter than the larger fetus (P \ 0.01).
Similarly, the larger fetal birth weight was significantly
heavier than the smaller fetal birth weight in both the
sIUGR and non-sIUGR groups (P \ 0.01).
We found the larger fetal birth weights in both the
sIUGR (2.17 kg) and non-sIUGR groups (1.55 kg) were
lighter than that in the normal group (2.32 kg) (P \ 0.01),
and the smaller fetal birth weights for both the sIUGR
(1.47 kg) and non-sIUGR groups (0.92 kg) were lighter
than that in the normal group (2.19 kg) (P \ 0.01). There
was no difference in the larger fetal birth weight between
the sIUGR and non-sIUGR groups (P [ 0.05). Although
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the average of the smaller fetal birth weight in the non-
sIUGR group (0.92 kg) was lighter than that in the sIUGR
group (1.47 kg), there was no significant difference
between the two groups (P [ 0.05).
The average inter-fetal birth weight difference was the
lowest (10.82%) in the normal growth group. The sIUGR
group had a greater difference (31.54%) than the normal
growth group (P \ 0.01). The non-sIUGR group showed a
moderate difference (20.56%). There was no significant
difference between the non-sIUGR group and the other two
groups (P [ 0.05).
For the discordant twin incidence (difference C20%),
both the sIUGR (54 of 71, 76.1%) and non-sIUGR (4 of 7,
57.1%) groups had more discordant cases than the normal
growth group (14 of 217, 6.5%) (P \ 0.01), but no dif-
ference was found between the sIUGR and non-sIUGR
groups (P [ 0.05).
The sIUGR group showed a greater incidence of
preeclampsia than the normal growth group (15.5% vs.
5.5%, P \ 0.01). The OR for preeclampsia was 3.132
(95% CI 1.316–7.455). There was no preeclampsia in the
non-sIUGR group. Because of the limited case number,
we cannot determine the difference between the non-sI-
UGR group and the other two groups. There was no
difference in the incidence of gestational diabetes melli-
tus among the three groups (P [ 0.05). The pregnancy
characteristics and high-risk factors are summarized in
Table 4.
With 295 pairs of twins, the total number of fetuses was 590.
In comparing the perinatal outcome among the three groups, we
found that the intrauterine fetal death rate in the sIUGR was
7.7%, and much higher in non-sIUGR groups (28.6%)
(P \ 0.05). Both were significantly higher than that in the nor-
mal growth group (1.2%) (P \ 0.01). Similar results were found
in neonatal death rates. The neonatal death rate was 20.0% in
non-sIUGR group, higher than 4.6% of sIUGR group, while both
were higher than that in the normal growth group (P \ 0.01).
The neurological complication was more common in the
sIUGR group than that in the normal growth group (8.0%
vs. 1.4%, P \ 0.01). We could not distinguish between the
non-sIUGR group and the other two groups because of the
limited case number. The perinatal outcomes are summa-
rized in Table 5.
Discussion
Twin pregnancy has a special growth pattern different from
that in single pregnancies. First, the individual fetal weight
during twin pregnancies is often lighter than that in single
fetuses of the same gestational age, especially in the third
trimester [14, 15]. Because lack of race special twin growth
curve, we used the Alexander reference curve in this study.
The overall IUGR incidence in our study was 23.2%,
which was similar to that in previous studies [16].

Table 4 Pregnancy
sIUGR Non-sIUGR Normal growth
characteristics and high-risk
(n = 71) (n = 7) (n = 217)
factors in twin pregnancy
Maternal age (year) 28.65 ± 4.17 29.10 ± 4.82 29.32 ± 4.22
GA at delivery (week) 34.35 ± 4.12 34.96 ± 3.65 34.65 ± 4.51
Maternal weight gain (kg) 14.3 ± 4.3 14.2 ± 4.1 14.5 ± 4.3
Data was showed as the Birth weight (kg)
mean ± standard deviation or Larger fetus 2.17 ± 0.65 ,à 1.55 ± 0.53 ,à 2.32 ± 0.62à
case number (%)    
Smaller fetus 1.47 ± 0.66 0.92 ± 0.40 2.19 ± 0.58
GA Gestational age, GDM
gestational diabetes mellitus Inter-fetal birth weight difference (%) 31.54 ± 18.98  20.56 ± 18.65 10.82 ± 8.27
 
P \ 0.01 versus normal Discordance incidence (n %) 54 (76.1%)  4 (57.1%)  14 (6.5%)
 
growth group, à P \ 0.01 Preeclampsia (n %) 11 (15.5%) 0 (0%) 12 (5.5%)
versus the smaller fetus in the GDM (n %) 4 (5.6%) 1 (14.3%) 10 (4.6%)
same group

Table 5 Perinatal outcomes in twin pregnancy

sIUGR (n = 142) Non-sIUGR (n = 14) Normal growth (n = 434)

IUFD (n %) 11/142 (7.7%)* 4/14 (28.6%)*,  5/434 (1.2%)

Neonatal death (n %) 6/131 (4.6%)* 2/10 (20.0%)*,  3/429 (0.7%)
Neurological complication (n %) 10/125 (8.0%)* 0/8 (0%) 6/426 (1.4%)
Data was showed as positive case number/total number (incidence %)
IUFD Intrauterine fetal death
 
* P \ 0.01 versus normal growth group, P \ 0.05 versus sIUGR group

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Second, fetal birth weight difference is common in twin
pregnancies [17]. The average difference between normal
growth twin fetuses is approximately 10% [18]. Similar
results were found in our study (Table 4). The phenotype
of the growth disorder may also be different between two
fetuses in pair. Then the concept of sIUGR and non-sIUGR
in twins was developed [19].
We investigated the chorionicity in IUGR twins and
found that IUGR were prevalent in monochorionic twins,
especially for sIUGR. This result was similar with other
literature [20, 21]. Ninety-five to ninety-eight percent of
monochorionic twins have inter-fetus vascular connections
[22, 23]. Therefore, Gratacos [10] indicated that the dif-
ference in the sIUGR twin resulted from the influence of
the inter-twin transfusion characteristics. Dichorionicity
was showed as a preventive factor since vascular connec-
tion was nearly extinct in dichorionic placenta.
Zygosity determines the genetic background in twin
pair. There is no information available for zygotic analysis
in twin IUGR. In our study, we identified all of the 336
pairs of twins, and found that monozygosity was a risk
factor for overall IUGR in twins, especially for sIUGR.
The current idea is that the monozygotic twin has the same
genetic background, therefore, the fetal growth will be
similar and manifest as identical normal growth or identical
IUGR (non-sIUGR). However, we saw that 35.7% of
monozygotic twins were sIUGR, which is far more than
non-sIUGR (2.9%). The underlying cause of sIUGR in
monozygotic twins has not been identified. Some people
have thought that it is because of the epigenetic modifi-
cation [24, 25]. There is increasing evidences showing that
various environmental factors can induce the methylation
and acetylation modifications to DNA sequences. These
patterns are widely distributed between twins, and the
influence of epigenetic factors on fetal growth patterns is
unknown. These epigenetic modifications could either be a
meaningful cause of IUGR or just normal variation [26–
30], and these questions need to be further investigated,
especially in phenotypic discrepancy monozygotic twins,
such as sIUGR.
Interestingly as well, dizygosity seemed to be a pre-
ventive factor for IUGR. After all, the gene sequence
makes the most important role to decide the fetal devel-
opment potential. In dizygotic twins, the two fetal geno-
types are similar as siblings’. Although the growth
determining genes remain still unclear, it is relatively less
frequency to inherit the same disease-causing locus at the
same time for both fetuses. Therefore, the non-sIUGR is
seldom occurred in dizygotic twins.
As above mentioned, the genetic, epigenetic, environ-
mental, and vascular causes may act on the fetal growth
simultaneously. The zygosity is closely related with the
genetic and epigenetic factors. The chorionicity is closely
977
related with the vessel communication. We tried to weight
the genetic factors alone and eliminate the effect of vas-
cular anastomosis by comparing the outcome in mono-
zygotic dichorionic twins and dizygotic dichorionic twins.
However, we had not found out the difference. It is still
hard to say if the monozygotic dichorionicity is a pre-
ventive factor depending on our limited case number. The
further investigation is needed to get to a conclusion.
According to our result, we cannot tell which condition,
monochorionicity or monozygosity, will affect fetal growth
more effectively. In clinical practice, the identification of
the chorionicity is sufficiently helpful to detect 52.6% of
IUGR twins. This approach is also more likely to be
antenatally diagnosed from 11 to 14-gestational week scan.
According to Table 4, the fetal weight discordance was
the high-risk factor for sIUGR, which was supported by
average inter-fetal birth weight difference and discordant
twin incidence. We placed 20% weight difference as cut-
off value. The result showed the average inter-fetal birth
weight difference in sIUGR group reached to 30% which
agreed with previous study [31]. Therefore, we should not
only estimate the fetal weight but also pay attention to the
inter-fetal weight difference. Fetal growth is a dynamic
process. The greater the difference between head cir-
cumference, abdominal circumference and femur length,
the stronger the evidence is for an abnormal growth
pattern.
We found that pre-eclampsia was a risk factor for sI-
UGR in twins. Pre-eclampsia has been always associated
with IUGR in single pregnancies. It was difficult to identify
cause-effect relationships between them. Our study showed
that pre-eclampsia occurred in 15.5% of the sIUGR cases
and that there was no pre-eclampsia in the non-sIUGR
group. The data indicated that not all of the IUGR cases
were associated with pre-eclampsia. The vasospasm did not
impact both of the fetuses equally. We assume that there
must be some common pathogenesis behind both condi-
tions that are unevenly distributed between the two fetuses.
For perinatal outcome, the non-sIUGR group had the
highest intrauterine fetal death (IUFD) rate and neonatal
mortality. These data revealed the worst prognosis of non-
sIUGR and corresponded to the lowest fetal birth weight in
the non-sIUGR group. The sIUGR group had more neu-
rological complications than normal growth group. Some
of the reasons can be explained by the presence of large
diameter arterio-arterial communication in the placenta,
which lead to massive blood transfusion [32].
In conclusion, sIUGR occurred more frequently than
non-sIUGR. Monochorionicity, monozygosity, fetal
weight discordance, and pre-eclampsia are high-risk fac-
tors for sIUGR in twins. The non-sIUGR has greater
perinatal death, and the sIUGR has greater neonatal brain
damage.
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Acknowledgments The study was financially supported by
GuangDong province Natural Science Foundation, People’s Republic
of China (# 10151008901000160).
Conflict of interest There is no conflict of interest.
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