Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 265272

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

Prediction of preterm birth in twins

George Makrydimas, PhD, Professor a, *,
Alexandros Sotiriadis, PhD, Assistant Professor b
a
Department of Obstetrics and Gynaecology, University Hospital of Ioannina, Ioannina,
Stavros Niarchos Avenue, 45500 Ioannina, Greece
b
Second Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki,
Ippokrateio General Hospital, Thessaloniki, Greece

Keywords:
About 13% of twins are born before 34 weeks and 7% before 32
twins weeks. The prediction of preterm birth in twins is based on the
preterm birth same tests as in singleton pregnancies. In twin pregnancies, the
ultrasound cut-off for short cervix at the second trimester scan is less than
cervical length 25 mm (compared with 15 mm in singletons); length less than
bronectin 20 mm is associated with 42% risk for birth before 32 weeks and
cervical length less than 25 mm is associated with 28% risk for
birth before 28 weeks. The measurement of cervical length in
pregnancies with symptoms of preterm labour may have limited
accuracy in predicting preterm birth. In asymptomatic women, a
positive fetal bronectin test seems to be associated with 35% risk
for birth before 32 weeks and 40% risk for birth less than 34 weeks,
whereas a negative test decreases the risk to 6% and 17%, respec-
tively. The differences in the predictive value of tests between
twins and singletons reect the diverse pathophysiology of pre-
term birth between the two groups.
2013 Elsevier Ltd. All rights reserved.

Preterm birth in twins

Prematurity is one of the leading causes of perinatal mortality, morbidity, and long-term neuro-
developmental impairment. A child born at 25 weeks has 50% risk for death within the rst few months
of life, [1] and about 50% of the survivors are expected to have moderate-to-severe handicap as infants
[2]. Both survival and neurological prognosis improve with advancing gestational age, and children

* Corresponding author. Tel.: 30 2651099608; Fax: 30 2651070700.

E-mail address: grmak@otenet.gr (G. Makrydimas).

1521-6934/$ see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bpobgyn.2013.11.007
266 G. Makrydimas, A. Sotiriadis / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 265272

born at 32 weeks have a 97% survival rate [3], with only 4.4% risk for cerebral palsy at the age of 2 years
[4] and 8% risk for neurodevelopmental delay [5].
Although up to 12% of children may be born before 37 weeks [6], the rate of birth before 35 weeks in
singleton pregnancies is about 4% [7], and the rates of spontaneous births before 34 and before 32
weeks are 1.1% and 0.6%, respectively [8,9]. The risk of prematurity is much higher in twins. In a
prospective study of 800 dichorionic and 200 monochorionic twin pregnancies, 29% of dichorionic
pregnancies developed a maternal or fetal condition, leading to birth before 36 weeks, whereas 34% of
the monochorionic twins were born before 34 weeks [10]. In a recent meta-analysis, the pooled rates of
birth before 37, 34 and 32 weeks for twins were 41%, 13% and 7%, respectively [11].
During the past 15 years, signicant progress has been achieved in the prediction and prevention of
preterm birth in singleton pregnancies. This process has been slower in twins, apparently reecting the
diverse pathophysiology of preterm birth in multiple pregnancy.

Pathophysiology and demographics

Preterm birth is a syndrome because of its multifactorial aetiology and diverse clinical manifesta-
tions, and this has implications in its understanding, prediction, and prevention. The most widely
accepted contributing factors for prematurity include (1) intrauterine infection or inammation; (2)
uterine ischaemia; (3) uterine overdistension; (4) abnormal allograft reaction; (5) allergy; (6) cervical
insufciency; and (7) hormonal disorders (related to progesterone and corticotrophin-releasing fac-
tors) [12]. Although over-distension would be the obvious candidate mechanism in the case of twins, it
seems that multiple gestations are also a heterogeneous group with different pathophysiological
pathways [12], which is also supported by the decreased effectiveness of interventions that are
commonly successful in singletons. It has been suggested that all mechanisms that participate in the
initiation of term labour and preterm birth in singletons, may be present in a supraphysiological
degree in multiple gestations [13].
In singleton pregnancies, the risk of prematurity is increased in women who had previous late
miscarriages or preterm births, those of AfroCaribbean origin, teenagers, those will low body mass
index, and cigarette smokers [14]. None of these risk factors was found to be signicant in twins [15],
and obstetric history became a signicant predictor only after cervical length was excluded [16].
Moreover, the use of assisted reproduction techniques was found to be associated with preterm birth
only in overweight or obese women [17].

The effect of chorionicity

Chorionicity is a unique factor in twins, which also contributes to the risk of prematurity.
Monochorionic diamniotic (MCDA) twins are at higher risk compared with dichorionic (DCDA)
twins for preterm birth and prenatal complications. In a historical cohort of 1407 twin pregnancies
[18], the rate of birth before 28 weeks was 11% for MCDA compared with 7% for DCDA twins, and
the rates for birth before 32 weeks were 26% compared with 18%, respectively. Monochorionic
diamniotic twins were also at increased risk for fetal death (even at term), necrotising enterocolitis,
and neuromorbidity. A signicant contributor of prematurity and morbidity in MCDA twins is twin-
to-twin transfusion syndrome (TTTS). In a recent multicentre study of about 10,000 twin preg-
nancies [19], the rate of birth before 34 weeks was 24% in the MCDA group compared with 16% in
the DCDA twin group. The rates of preterm premature rupture of membranes and pregnancy-
induced hypertension, however, were similar between the two types of twins, and most of the
difference in the rates of prematurity could be attributed to TTTS in MCDA twins, which was 7.3%
before 37 weeks.
Early markers increasing the risk for development of TTTS later in pregnancy include inter-twin
discrepancy in the nuchal translucency test of 20% or more (30% risk for TTTS) and presence of at
least one abnormal blood ow waveform in the ductus venosus [20,21].
When TTTS is excluded, there seems to be no difference in median cervical length between mon-
ochorionic and dichorionic twins [15], and the risk for early preterm birth does not signicantly differ
between the two groups [9].
 G. Makrydimas, A. Sotiriadis / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 265272 267

Prediction of preterm birth in asymptomatic twin pregnancies

The two most commonly used screening tests for the prediction of preterm birth in singletons are
cervical length measurement and testing for fetal bronectin in the cervicovaginal uid at the time of
the anomaly scan (2124 weeks), and the same tests have been tried in twins.

Cervical length

The rationale for measuring cervical length is that the mechanism of normal human labour requires
cervical remodelling, in which the cervix of the uterus gradually ripens, shortens (effaces), and nally
dilates. Normally, cervical length shows a continuous linear reduction between 10 and 40 weeks. For
example, the median cervical length in singleton pregnancies is 36 mm at 23 weeks, which then de-
creases to 33 mm at 28 weeks, and then to 29 mm at 34 weeks; the corresponding values for the 5th
centile are 20 mm, 17 mm and 10 mm, respectively [22]. In twin pregnancies, the median cervical
length at the time of the anomaly scan (2224 weeks) is similar to that of singletons, but a higher
proportion of twins have cervical length less than 25 mm (12.9% v 8.4% in singletons) and less than
15 mm (4.5% v 1.5%) [15,23,24].
Evidence shows that the initiators of cervical remodelling may differ between preterm and term
birth, with a distinct role for complement activation and macrophages in the former case; however, the
nal steps of the pathway are common, involving release of matrix metalloproteinases, collagen
degradation, and increased cervical distensibility [25].
In singleton pregnancies, screening with cervical length and demographic factors at the time of the
second-trimester scan can predict 69% of cases that will deliver before 32 weeks for a falsepositive
rate of 10% [9]. Cervical length less than 15 mm (which corresponds to the 1.5th centile in singletons)
predicts 58% of the cases who will deliver before 32 weeks, and, conversely, it is associated with 4% risk
for birth before 32 weeks [14].
In contrast to singleton pregnancies, where the risk for preterm birth increases exponentially when
the cervix is less than 15 mm, the cut-off for high risk in twin pregnancies is 25 mm, apparently
because a longer cervix is needed to counteract the increased uterine activity during pregnancy [15,24].
Cervical length of 25 mm or less at 2224 weeks was reported in 100% of women delivering before 28
weeks [26], 80% of those delivering before 30 weeks [26], and about 50% of those delivering before 28
weeks [14,27]. Cervical length less than 25 mm is associated with 10% and cervical length less than
15 mm is associated with 30% risk for birth before 33 weeks [15].
In the largest single study on asymptomatic twins (n 1163) [16], cervical length, previous obstetric
history, cervical surgery, and cigarette smoking were all found to be associated with preterm birth;
however, when the independent contribution of these factors was tested in a multiple logistic
regression model, only cervical length remained a signicant predictor.
A recent meta-analysis summarised data from 16 studies (n 3213) on asymptomatic women with
twin pregnancy at the second trimester [11]. It was found that the most accurate cut-off for the pre-
diction of birth before 28 weeks was cervical length 25 mm or less (area under the curve 0.86), whereas
cervical length 20 mm or less and cervical length 25 mm or less were the most accurate predictors for
birth before 32 weeks (area under curve 0.80 for both), and cervical length 20 mm or less and 35 mm or
less were the best predictors for birth before 34 weeks. In asymptomatic women, a cervical length of
20 mm or less at 2024 weeks was associated with 42% risk for birth before 32 weeks and 62% risk for
birth before 34 weeks. A cervical length of 25 mm or less was associated with 26% risk for birth before
28 weeks; in contrast, a longer cervix was associated with only 1.4% risk for birth before 28 weeks and
about 65% chance for term birth [11].
From a qualitative point of view, the accuracy of cervical length measurement may be slightly better
for birth before 30 weeks than after 30 weeks, and overall accuracy of cervical length measured after 24
weeks may be slightly better than measurements before 24 weeks [28]. The latter result, however, has
not been replicated in the meta-analysis of Conde-Agudelo et al. [11], and it is unlikely that these
differences have actual clinical signicance. Both meta-analyses highlight the profound heterogeneity
of data for many of their analyses. The pooled risk for preterm birth according to mid-trimester cervical
length in asymptomatic women is shown in Table 1.
268 G. Makrydimas, A. Sotiriadis / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 265272

Table 1
Pooled risks for preterm birth (various denitions) according to mid-trimester cervical length (various cut-offs) in asymptomatic
women with twin pregnancy.

Pooled risk % (95% CI)

Birth before 28 weeks Birth before 30 weeks Birth before 32 weeks Birth before 34 weeks
Cervical length less 44.4 (18.9 to 73.3) 50.0 (35.2 to 64.8) 72.5 (57.2 to 83.9) 75.6 (60.7 to 86.2)
than 15 mm [26] [16,26] [16,26] [16,26]
Cervical length less 34.4 (20.4 to 51.7) 24.8 (17.9 to 33.3) 19.9 (16.0 to 24.4) 55.6 (46.5 to 64.4)
than 20 mm [40,50,51] [16,40,51] [16,26,27,40,50,51] [16,40,51]
Cervical length less 12.6 (7.4 to 20.8) 20.7 (15.4 to 27.1) 27.7 (22.8 to 33.3) 51.2 (43.7 to 58.6)
than 25 mm [26,50] [16,26] [16,24,27,50,52] [16,53]
Cervical length less 3.9 (1.5 to 9.7) 10.1 (7.3 to 13.8) 26.5 (21.8 to 31.7) 66.3 (58.6 to 73.1)
than 30 mm [50] [16] [16,27,50] [16]

Fewer studies have assessed the potential value of follow-up cervical length measurements. In a study of
209 asymptomatic women, cervical length shortening by more than 25% over 35 weeks was associated
with an over seven-fold increase in the risk of birth before 32 weeks; in absolute rates, the rate of birth less
than 32 weeks in these women was 29% compared with 4% in women with less shortening [29]. When
examining only women with initially long cervix (>25 mm), another study reported that shortening of over
13% 45 weeks after the initial scan, or cervical length less than 30 mm at the repeat scan, were statistically
signicant predictors of birth at 32 weeks or earlier; however, the actual odds ratios were only about 1.1 [30].

Cervical length in the rst trimester

Recently, attention has shifted towards the potential role of rst-trimester cervical length measure-
ment in the prediction of preterm birth. Studies in singleton pregnancies have shown that the cervix
changes minimally in most women between 11 and 24 weeks, but shortening tends to be more prominent
in women with a history of cervical surgery or preterm delivery, and the median cervical length in the rst
trimester is signicantly lower in those who will deliver preterm [31,32]. The results on the potential
application of rst-trimester cervical screening for the early prediction of preterm birth in an unselected
population of singletons are conicting [3335], and no studies have yet been conducted in twins.

Biochemical markers: fetal bronectin

Fetal bronectin (fFN) is a glycoprotein that is produced by the extravillous trophoblasts, and acts much
like an adhesive substance at the interface between the chorion and the decidua [36]. Although it can
normally test positive during the rst half of pregnancy, its detection in the cervicovaginal uid between 22
and 34 weeks may indicate mechanical separation or inammatory-mediated extracellular matter
distortion at the choriodecidual interface [36,37], and has been associated with increased risk for preterm
birth.
In asymptomatic women with a singleton pregnancy, a positive fFN increases the risk for birth
before 34 weeks by 7.6 times, whereas a negative result decreases this risk by a factor of 0.8 [38].
Cervicovaginal fFN can be measured in twins in the same way as in singletons. In one of the rst
studies on twins, a positive fFN result was found in about 5% of women.
A meta-analysis conducted in 2010 [40] pooled data from 11 studies on asymptomatic twins, in
which fFN was tested (mostly) during the second trimester. In general, fFN showed limited accuracy in
the prediction of preterm birth, as the pooled likelihood ratios did not signicantly alter the pre-test
probabilities, especially for outcomes other than birth less than 32 weeks. The pooled sensitivity for
birth before 32 weeks and before 34 weeks was 35% and 45%, respectively, for 6% and 19% false positive
rates, respectively. On the basis of the data of the particular populations described in this meta-
analysis, a positive fFN test was associated with 34% risk for birth before 32 weeks and 42% risk for
birth before 34 weeks, whereas a negative test decreased the risk to 6% and 17%, respectively. The
investigators, however, highlight the high heterogeneity across studies [39].
Few studies have directly compared cervical length and fFN in twins. In a retrospective study of 155
asymptomatic twin pregnancies in which simultaneous cervical length and fFN screening was offered
 G. Makrydimas, A. Sotiriadis / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 265272 269

between 22 and 32 weeks [40], the combination of cervical length less than 20 mm and positive fFN
had signicantly higher positive predictive value than either of the tests alone, and was associated with
about 55% risk for birth before 32 weeks. The prospective Preterm Prediction Study [24] evaluated
multiple potential risk factors for preterm birth and concluded that, for birth before 32 weeks, cervical
length 25 mm or less was the best predictor at 24 weeks, whereas positive fFN was the best predictor at
28 weeks [23].

Other biochemical markers

Less frequently studied biochemical markers in singleton pregnancies include cervical phosphory-
lated IGFBP-1, cytokines in the cervicovaginal uid, adhesion molecules, PAPP-A, beta-human chorionic
gonadotropin, and proteases. The data on twins are even more limited. A small retrospective study of 70
twin pregnancies reported a ve-fold risk for birth before 32 weeks when rst-trimester free beta-
human chorionic gonadotropin was below the 25th centile [41]. Recently, a secondary analysis of a
randomised-control trial on progesterone for the prevention of preterm birth in twins reported that, in
placebo-treated women, interleukin-8 levels were increased in women who delivered before 34 weeks,
and the risk for preterm birth increased with a large weekly increase in interleukin-8 [42].

Prediction of preterm birth in twin pregnancies with symptoms of preterm labour

Preterm labour is one of the most common reasons for prenatal admission to hospital, accounting
for up to one-third of such cases in some reports [43,44]. The identication of true preterm labour,
however, remains unreliable, resulting in signicant overtreatment, as most of these women (up to 90%
in singleton pregnancies) will not eventually deliver within 1 week or before 35 weeks, irrespective
from treatment [45]. These rates may be higher in twins, but still about 80% of women will not deliver
within 1 week [46], and about 6070% will not deliver before 34 weeks [47,48].
The same methods used for predicting preterm birth in asymptomatic women have also been tried
in women presenting with threatened preterm labour.

Cervical length

In a study of 87 symptomatic women, the rate of delivery within 7 days was inversely correlated
with cervical length, increasing from 0% for cervical length greater than 25 mm, to 35% for cervical
length 20 mm or less, and 55% for cervical length 10 mm or less. The use of tocolytics was a signicant
independent predictor for birth within a week, reducing the risk (OR 0.13). No difference was observed
between MCDA and DCDA twins [46].
Conde-Agudelo et al. [11] summarised the published data in 2010. Their results were limited by the
small size of the included studies and the different cervical length cut-offs and outcomes; it seems,
though, that the measurement of cervical length had only a minimal accuracy in predicting birth before
34 weeks, as the positive and negative likelihood ratios were only 1.2 and 0.67, respectively [11]. A most
recent meta-analysis furthermore highlights the problem that results from the paucity of data on the
predictive performance for birth within 48 h and 7 days from presentation, which would be the most
clinically relevant outcome [49].

Fetal bronectin

Cervicovaginal fFN testing has been extensively used for the prediction of preterm birth in symp-
tomatic women with singleton pregnancies. Its high negative predictive value is its major advantage,
and a negative fFN result is associated with 3% risk for birth within 1 week or 2 weeks from presen-
tation, and 10% risk of birth before 34 weeks (own pooling of published data).
Singer et al. [48] measured fFN in 429 women with singleton and 87 women with twin pregnancies,
presenting with symptoms of threatened preterm labour. The rates of birth within 14 days and before
34 weeks were 8% and 29%, respectively, in twins, compared with 2.5% and 3.5% in singletons. A
positive fFN result was found in 30% of twins compared with 12% of singletons; of those twins with a
270 G. Makrydimas, A. Sotiriadis / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 265272

positive fFN test, the risk of birth (positive predictive value) within 1 week and before 34 weeks was
15% and 42%, respectively. A negative fFN test was associated with 0% risk for birth within 1 week and
23% risk for birth before 34 weeks.
Conde-Agudelo et al. [39] pooled published data on the predictive performance of fFN in asymp-
tomatic and symptomatic twin pregnancies; for the latter group they concluded that fFN was most
accurate for predicting birth within 1 week from presentation, whereas it had minimal accuracy for
birth within 14 days or birth before 34 weeks. The pooled rate of birth within 1 week was 1.6% for
women with a negative fFN test, and increased to 24.5 with a positive fFN test (n 168).

Conclusion

Preterm birth is a major contributor in perinatal morbidity and mortality in twins. During the past
15 years, signicant progress has been achieved in understanding its pathophysiology, developing
screening tests that allow the identication of a signicant proportion of women at risk, and, more
recently, developing interventions that can prevent preterm birth in many women identied as being
at high risk, especially in singleton pregnancies.
The same screening and preventive interventions that have been proved effective in singletons have
been tried in twins. Measuring cervical length at the 2024 weeks in asymptomatic women is still a
valid test for identifying women at risk, whereas the accuracy of fetal bronectin is slightly lower. On
the other hand, cervical length measurement is not sufciently accurate for women presenting with
symptoms of threatened preterm labour, whereas fetal bronectin appears to have signicantly high
negative predictive value.
It is very likely that preterm birth in multiple pregnancies differs in many aspects from that in
singletons, and future research will focus on its prediction and its prevention, where the effectiveness
of interventions is also suboptimal compared with singletons.

Practice points

 Although the gures vary widely among publications, about 15% of twins are born before 34
weeks and 10% are born before 32 weeks. These estimates are higher for monochorionic
twins, mainly because of the contribution of twin-to-twin transfusion syndrome.
 Measuring the cervical length between 20 and 24 weeks in asymptomatic women with twin
pregnancy is a valid screening strategy. The cut-off for short cervix is 25 mm. A cervix longer
than that is associated with 2% risk for birth before 28 weeks and 65% chance for term
pregnancy.
 Cervical length measurement has suboptimal accuracy in women presenting with threatened
preterm labour.
 Cervicovaginal fetal bronectin may be slightly less accurate than cervical length in
asymptomatic women; however it has a high negative predictive value in women presenting
with threatened preterm labour; less than 2% of these women will deliver within 1 week if
the fFN is negative.
 Few or no data have been published on other biochemical markers, as well as on the value of
cervical-length measurement in the rst trimester of pregnancy.

Research agenda

 Value of rst-trimester cervical assessment in the prediction of preterm birth in twins.

 Biochemical markers in both asymptomatic and symptomatic women.
 G. Makrydimas, A. Sotiriadis / Best Practice & Research Clinical Obstetrics and Gynaecology 28 (2014) 265272 271

Conict of interest

None declared.

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