The Journal of Maternal-Fetal & Neonatal Medicine

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Preterm Labor and Birth Management:

Recommendations from the European Association
of Perinatal Medicine

G. C. Di Renzo, L. Cabero Roura, F. Facchinetti, H. Helmer, C. Hubinont, B.

Jacobsson, J. S. Jørgensen, R. F. Lamont, A. Mikhailov, N. Papantoniou, V.
Radzinsky, A. Shennan, Y. Ville, M. Wielgos & G. H. A. Visser

To cite this article: G. C. Di Renzo, L. Cabero Roura, F. Facchinetti, H. Helmer, C. Hubinont,

B. Jacobsson, J. S. Jørgensen, R. F. Lamont, A. Mikhailov, N. Papantoniou, V. Radzinsky, A.
Shennan, Y. Ville, M. Wielgos & G. H. A. Visser (2017) Preterm Labor and Birth Management:
Recommendations from the European Association of Perinatal Medicine, The Journal of Maternal-
Fetal & Neonatal Medicine, 30:17, 2011-2030, DOI: 10.1080/14767058.2017.1323860

To link to this article: http://dx.doi.org/10.1080/14767058.2017.1323860

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 THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE, 2017
VOL. 30, NO. 17, 2011–2030
https://doi.org/10.1080/14767058.2017.1323860

GUIDELINES

Preterm Labor and Birth Management: Recommendations from the

European Association of Perinatal Medicine
G. C. Di Renzoa, L. Cabero Rourab, F. Facchinettic, H. Helmerd, C. Hubinonte, B. Jacobssonf, J. S. Jørgenseng,
R. F. Lamonth,i, A. Mikhailovj, N. Papantoniouk, V. Radzinskyl, A. Shennanm, Y. Villen, M. Wielgosp and
G. H. A. Vissero
a
Department of Obstetrics and Gynecology, University of Perugia, Perugia, Italy; bDepartment of Obstetrics and Gynecology, Hospital
Vall D’Hebron, Barcelona, Spain; cMother–Infant Department, School of Midwifery, University of Modena and Reggio Emilia, Italy;
d
Department of Obstetrics and Gynaecology, General Hospital, University of Vienna, Vienna, Austria; eDepartment of Obstetrics, Saint
Luc University Hospital, Universit
e de Louvain, Brussels, Belgium; fDepartment of Obstetrics and Gynecology, Institute of Clinical
Sciences, University of Gothenburg, Gothenburg, Sweden; gDepartment of Obstetrics and Gynaecology, Odense University Hospital,
Odense, Denmark; hDepartment of Gynaecology and Obstetrics, University of Southern Denmark, Odense University Hospital, Odense,
Downloaded by [Purdue University Libraries] at 03:00 27 September 2017

Denmark; iDivision of Surgery, University College London, Northwick Park Institute of Medical Research Campus, London, UK;
j
Department of Obstetrics and Gynecology, 1st Maternity Hospital, State University of St. Petersburg, Russia; kDepartment of
Obstetrics and Gynaecology, Athens University School of Medicine, Athens, Greece; lDepartment of Medicine, Peoples' Friendship
University of Russia, Moscow, Russia; mSt. Thomas Hospital, Kings College London, UK; nService d'Obst
etrique et de M
edecine Foetale,
H^opital Necker Enfants Malades, Paris, France; oDepartment of Obstetrics, University Medical Center, Utrecht, The Netherlands;
p
Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland

ARTICLE HISTORY: Received 25 January 2017; Revised 23 April 2017; Accepted 24 April 2017

KEYWORDS: Preterm labor; birth management; risk factors

Introduction should be PTD or preterm birth, rather than

These guidelines are based upon most recent and
updated evidence and they are adapted to a European
perspective by an expert view of the problem. These
guidelines are not intended to be a meta-analysis or a
systematic review. They follow the previous guidelines
published in 2006 [1] and 2011 [2].
The syndrome, etiology, risk factors
The syndrome
Preterm delivery (PTD) is one of the most common
and serious complications of pregnancy [3]. In Europe,
preterm delivery is defined as delivery after 22 com-
pleted weeks but before 37 weeks of gestation [4–6].
In most parts of Europe, pregnancies are dated using
first trimester ultrasound, meaning that the practice of
validation of maturity at birth is rare. Practically, this
means that it is adequate to stick to a terminology
that relates to gestational age rather than maturity.
The most relevant terminology for the condition
prematurity.
In Europe, the PTD rate varies between 5–18%, with
only 0.3–0.5% occurring before 28 weeks, obviously
with a worse outcome. Outcome also varies with the
quality of neonatal care. When calculating the fre-
quency of PTD, it is important to note the number of
pregnancies and not the number of children. However,
some nations report the number of babies born pre-
term. Different approaches have been used to cope
with stratifications differences between different popu-
lations [7]. It is not the extremely preterm babies that
create the highest burden for the society as they are
infrequent. It is the children born between 32 and 36
weeks. The “Intergrowth study” has indicated that in a
set of low-risk pregnant women, PTD frequency is
approximately 4.5% [8]. To reduce the European PTD
prevalence to that level, different methods need to be
used in a systematic approach. One single method is
unlikely to have significant impact on a large group of
high-risk women. Such an approach needs to be based
on a determined subset of both clinical and biological
risk factors. Such an approach will be difficult to

CONTACT Gian Carlo Di Renzo giancarlo.direnzo@unipg.it Department of Obstetrics and Gynecology, Centre for Perinatal and Reproductive
Medicine, Santa Maria della Misericordia University Hospital, 06132 San Sisto, Perugia, Italy
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
 2012 G. C. DI RENZO ET AL.
achieve but should be a highly prioritized research
project. The complex nature of PTD as an etiologic
concept might be clearer if the perspective is further
researched.
It is logical to divide PTD into different subcatego-
ries: live-borns vs. intrauterine fetal deaths, singleton
pregnancies vs. multiple pregnancies and spontaneous
PTD vs. iatrogenic PTD. About 80% of all the preterm
infants are live born singletons. The majority of these
deliveries are spontaneous, due to onset of contrac-
tions or to spontaneously ruptured membranes.
Conversely, iatrogenic preterm deliveries are due to
the physician's decision to induce labor for maternal
or fetal medical reasons. However, since the termin-
ology varies, it is crucial to use clear definitions in all
circumstances where the different phenotypical terms
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are used [9].
Etiology
The main hypothesis of the etiology of spontaneous
PTD is ascending infection from the lower genital tract
up in the sterile uterus invading the decidua, cho-
rioamniotic membranes, amniotic fluid and, in some
cases, the fetus. This is responsible for an inflammatory
condition that might trigger myometrial contractions,
rupture of the membranes and cervical maturation
leading to PTD [4–6,10]. Investigations have shown
that the amount of bacteria present in the amniotic
fluid is correlated to the level of intrauterine inflamma-
tion [12–14]. Inflammation is also related to the pres-
ence of bacteria in the amniotic fluid and to
histological chorioamnionitis [15]. Recently, “sterile”
intrauterine inflammation has been described,
although it seems to be quite rare in women with pre-
term prelabor rupture of the membranes [16]. The
term “preterm parturition syndrome” has been
launched to separate women with spontaneous pre-
term labor onset of delivery who are considered to
have a pathological activation of the delivery process,
from those with spontaneous onset of delivery at
term, which is considered to be a normal activation
[10,11].
The dogma of the “sterile womb” has recently been
challenged in a groundbreaking study published in
Science in 2014. Kjersti Aagaard et al. suggested that
placenta is not sterile and has a bacterial flora more
similar to the oral cavity than to the vagina [17].
During the last couple of years there have been stud-
ies suggesting that women using oral probiotic prod-
ucts had reduced risk of PTD [18] and preeclampsia
[19]. This supports the hypothesis that oral consump-
tion of potentially immune-modulating bacteria can,
through unknown mechanisms, affect gestation.
Interestingly, the supernatant of the probiotic organ-
ism Lactobacillus rhamnosus has been found to reduce
the lipopolysaccharide (LPS) inflammatory response in
placental trophoblast cells [20].
Another approach for a better understanding of the
etiology of PTB is to study the relation between genet-
ics and gestational age at birth [21–23]. The heritability
of both PTD and gestational age is estimated to be
around 30%, however, only a very small fraction of
variability in gestational age could be explained by
currently known PTD-risk-increasing genetic polymor-
phisms [24, 25].
Risk factors
The risk of spontaneous PTD correlates to intrinsic
characteristics of the mother; in fact it is different
between racial and ethnic groups and it is related to
advanced maternal age. In order to identify potential
women at risk it is also important to assess maternal
life style, level of education and adequacy of prenatal
care, as well as employment-related psychological and
physical stress. Furthermore, maternal BMI, nutritional
status, chronic diseases (as hypertension, diabetes mel-
litus), intrauterine malformation or infections, and
endocrinological diseases have been linked with an
increased risk of PTD.
Numerous studies have published risk factors for
spontaneous PTD, either from population or hospital-
based datasets. One of the main risk factors for PTD is
multiple pregnancy. Another is a previous PTD. Many
behaviors influence the risk of PTD such as tobacco
use, alcohol and illicit drug use. Other factors are
those related to nutritional factors such as high intake
of sugar sweetened drinks [26] and modern Western
diet [27] which increases the risk of PTD, whereas
other nutritional factors are associated with a
decreased risk such as fish liver oil, probiotic milk, gar-
lic and other leek products. Other factors that are
related to an increased risk of PTD are unemployment,
chronic stress, catastrophic event, life events and phys-
ical inactivity. Also several sociodemographic and com-
munity factors contribute to PTD such as: low or high
maternal age, material status, race and ethnicity. Many
medical conditions also increase the risk of PTD: differ-
ent types of diabetes, rheumatologic conditions and
heart disease. Several population-based and regis-
tered-based studies have sought to create risk-based
approaches trying to predict PTD but there has only
been limited success [28,29]. The most common clin-
ical used risk factor is that the women have had a pre-
vious PTD.

Identification of the preterm laboring women
with or without symptoms
Before undertaking any therapeutic strategy, careful
identification of women at risk for preterm labor and
delivery is needed, so as to detect manageable condi-
tions and fetal and/or maternal contraindications.
Methods to identify symptomatic women at risk
for preterm delivery
Symptoms reported by patients with suspected pre-
term labor are: pelvic pain, vaginal discharge, back
pain, and menstrual-like cramps.
In most countries the identification of preterm labor
is based only on clinical subjective data. This increases
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the risk of hospitalization and of costs and of unneces-
sary and potentially harmful interventions such as the
use of tocolysis and of prenatal corticosteroids
administration.
To improve the accuracy of the diagnosis of threat-
ened PTD in symptomatic women, two methods have
been proposed:

Transvaginal ultrasound cervical length
measurement;

Measurement of fetal fibronectin (fFN)/PAMG1/IGF-
BP 1 in cervical-vaginal secretions.
Transvaginal ultrasound cervical length
measurement
Cervical length is predictive of preterm birth in all
populations, including asymptomatic women with
prior cone biopsy, mullerian anomalies, or multiple
dilation and evacuations. Cervical length remains the
most predictive measurement, but funneling may add
to its predictive value in some populations. In terms of
interventions aimed at preventing preterm birth once
a short cervical length has been identified in asymp-
tomatic women, recent data from a meta-analysis
of all trials published so far point to the benefit of
ultrasound-indicated cerclage in women with both a
prior preterm birth and a cervical length less than
25 mm [30].
Because the presence of certain biomarkers or of a
short cervix have been independently associated with
PTD, the utility of biomarker testing in combination
with cervical length measurement using transvaginal
ultrasound has been examined to improve the clinical
ability to diagnose preterm labor and predict immi-
nent spontaneous PTD in symptomatic women
[31,32].
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 2013
In symptomatic women, both qualitative and quan-
titative fetal fibronectin in cervico-vaginal secretions
have been separately shown not to improve the pre-
diction of delivery within 7 days compared to the
sonographic measurement of cervical length. However,
quantitative fFN testing has been shown to add lim-
ited value across the risk range [33].
Several observational studies have suggested that
knowledge of fetal fibronectin status or cervical length
may help health care providers to reduce the use of
unnecessary resources; however, these findings have
not been confirmed by randomized trials [34,35]. The
positive predictive value of most biomarker test results
or a short cervix alone are poor and it has been rec-
ommended that neither should be used exclusively to
direct management in the setting of acute symptoms
[36,37].
Fetal fibronectin (fFN)
Qualitative fFN detection. Fetal fibronectin (fFN) is an
isoform of fibronectin with a unique III-CS region, and
a component of the extracellular matrix of the mem-
branes making up the amniotic sac, confined to the
interface between the maternal and fetal units. fFN is
found in amniotic fluid, placental tissue, and the extra-
cellular component of the decidua basalis adjacent to
the placental intervillous space. The test is available in
two primary formats (Hologic, Marlborough, MA). In
both, a cervicovaginal specimen is collected via a
speculum examination and is then mixed with a liquid
buffer in a collection tube. In the case of Rapid fFN (or
Full Term) a portion of this sample is pipetted to the
lateral-flow, rapid fFN cassette in the TLi IQ analyser.
The assay takes approximately 30 min to process the
sample and deliver the results. The TLi automatically
prints and displays positive or negative results along
with patient details. In the case of QuikCheck, a dip-
stick test is directly inserted into the tube for 10 min,
after which it is removed and the results are read as
either negative or positive depending on the presence
one or two lines, respectively. For both tests, an fFN
level of 50 ng/ml is a positive result and an fFN level
of <50 ng/ml is a negative result.
In a recent systematic review of the accuracy of the
fFN test to predict PTD in women with symptoms of
preterm labor, Deshpande et al. reported a pooled
sensitivity and specificity from 27 studies for predicting
PTB 7 to 10 days after testing of 76.7% (95%CI: 70.4 to
82.0%) and 82.7% (95%CI: 79.4 to 85.5%), respectively.
In line with several previous systematic reviews, the
authors suggested that the sensitivity of fFN testing
 2014 G. C. DI RENZO ET AL.
may be highest for predicting PTB within 7–10 days of
testing [38].
While Joffe et al. demonstrated that the introduc-
tion of fFN testing into clinical practice led to signifi-
cant cost savings for the hospital system by reducing
preterm labor hospital admissions, length of stay and
prescriptions of tocolytic agents by approximately
40%, the American College of Obstetricians and
Gynecologists (ACOG) concluded that although the
results of observational studies have suggested that
knowledge of fFN or cervical length may help health
care providers to reduce the use of unnecessary
resources [34,35], these findings have not been con-
firmed by randomized trials [39–41].
Quantitative fFN detection. Most recently, a quantita-
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tive bedside fetal fibronectin test has been devel-
oped, and while one study has demonstrated
enhanced clinical utility compared with the traditional
qualitative test another has concluded that quantita-
tive fFN testing does not improve the prediction of
PTB within 7 days compared with qualitative fFN test-
ing in combination with CL measurement in terms of
reclassification from high to low (<5%) risk [33]. The
value of the test relies on the use of alternative
thresholds of fFN detection (10, 50, 200, and 500 ng/
mL, respectively) that may allow optimal selection of
higher PPV for sPTB (an improved “rule in” test)
within 14 days and before <34 weeks’, whilst the NPV
remains reasonable as a rule out throughout all
thresholds. Clinicians can therefore more accurately
stratify individual patient risk and management. A
threshold of 10 ng/ml has high sensitivity and nega-
tive predictive value to determine those women
unlikely to deliver prematurely. The higher the qfFN
CVF concentration, the greater the need for surveil-
lance, and intervention.
Phosphorylated insulin-like growth factor binding
protein (phIGFBP-1). Phosphorylated insulin-like
growth factor binding protein (phIGFBP-1) is produced
by the placental decidual cells and thought to be
released into the cervical vaginal fluid after tissue
damage to the choriodecidual interface [42]. A qualita-
tive test, either positive or negative, is measured from
a vaginal swab taken with a speculum between 22
and 36 weeks of gestation. An immunochromatogra-
phy-based dipstick test (Actim Partus, Medix
Biochemica, Kauniainen, Finland) is used to obtain the
result within 5 min.
Conde-Agudelo and Romero have reported pooled
sensitivity and specificity from 18 studies for predicting
PTB 7 days after testing symptomatic women of 67%
(62% to 72%) and 77% (75% to 79%), respectively [43].
A negative test result had a low to moderate accuracy
to identify women who were not at risk for delivering
within the next 48 h (summary negative likelihood
ratio of 0.28 in all women and 0.23 in women with
singleton gestations), which would decrease its pretest
probability from 6.6% to 1.6–1.9%. Among women
with a singleton gestation and a cervical length
30 mm, a positive cervical phIGFBP-1 test (summary
likelihood ratio of 5.5) increased the pretest probability
of delivery within 7 days of testing from 17.8% to
54.4%, whereas a negative test result (summary likeli-
hood ratio of 0.3) decreased the risk to 6.1%. One
advantage is this test maybe less prone to influence
with sexual intercourse, known to increase the false
positive rate with fFN [44].
Placental alpha microglobulin 1 (PAMG-1). Placental
alpha microglobulin 1 (PAMG-1) is another glycopro-
tein synthesized by the decidua. It is present in the
amniotic fluid in high concentrations but few data are
available on the cervicovaginal fluid content [45]. A
vaginal swab can be inserted directly into the vagina,
removing the need for a speculum in patients
between 20 and 37 weeks of gestation. An immuno-
assay bedside “dipstick test” (PartoSure Test, Parsagen
Diagnostics, Inc., USA) is used to obtain the result
within 5 min. Lee et al. explained the presence of
PAMG-1 in cases of threatened preterm labor by a
transudation of PAMG-1 through chorioamniotic pores
in fetal membranes during uterine contractions, or by
the degradation of extracellular matrix of fetal mem-
branes due to inflammatory process of labor and/or
infection.
While several articles have been published on the
accuracy of PAMG-1 detection for the prediction of
sPTB within 7 or 14 days of testing in symptomatic
women, a systematic review or meta-analysis has not
been conducted, as has been the case for both fFN
and phIGFBP-1. In one of the original investigations of
PAMG-1, Lee et al. noted all preterm patients who had
clinically intact membranes but a positive PAMG-1 test
who also showed signs and symptoms of labor, deliv-
ered within 7 days [46]. In 2012, the clinical value of a
positive PAMG-1 test in patients presenting with signs
and symptoms of PTL without membrane rupture was
investigated and the results demonstrated that PAMG-
1 detection was highly predictive of delivery of these
patients within 48 h, 7 days and 14 days, providing
both a high negative predictive value (NPV) and posi-
tive predictive value (PPV), which was found to be
higher than fFN testing [47]. Several additional early
studies have corroborated these findings [48,49]. More

recent studies have used a more sensitive PAMG-1 test
(PartoSure). In the first multicenter, multinational clin-
ical study evaluating this test in 101 pts, the PAMG-1
test provided a 97.4% and 93.6% NPV, 78.3% and
87.0% PPV, 90.0% and 80.0% sensitivity and 93.8% and
96.1% specificity at 7 and 14 days, respectively [50].
In a subsequent trial by the same group that com-
pared PAMG-1 detection to fFN detection for predict-
ing sPTD in 7 days in 203 consecutively recruited
patients, the authors reported sensitivities of 80% and
50%, specificities of 95% and 72%, NPVs of 96%, and
87%, and PPVs of 76% and 29%, for PAMG-1 and fFN,
respectively [51]. Another study in 49 patients reported
that the PAMG-1 test predicted sPTB within 14 days
with 100% SN, 98% SP, 75% PPV and 100% NPV [52].
Werlen et al. confirmed a high specificity (97.5% [CI
Downloaded by [Purdue University Libraries] at 03:00 27 September 2017
95%; 86.8–99.9]) and NPV (97.5% [CI 95%; 86.8–99.9])
of the test and suggested that test results may not be
affected by vaginal examination, thus possibly provid-
ing an advantage over other methods in that the
PAMG-1 test can be used shortly after vaginal examin-
ation whereas others cannot [53]. Like fetal fibronectin,
PAMG-1 is found in maternal blood. Thus, in cases of
moderate to gross vaginal bleeding, neither test
should be used. In the presence of trace amounts of
blood, however, either test can be used.
Methods to identify asymptomatic women at risk
for preterm delivery
In case of asymptomatic pregnancies, cervicometry can
be applied as screening and has been proposed as a
universal screening in singleton gestations without a
previous preterm birth [55]. It is recommended to be
performed in the second trimester at 18–23 weeks of
gestation. The finding of a cervical length (CL) < 2.5 cm
is associated with an increased risk of subsequent PTB
with a sensitivity between 30 and 60%.
The PAMG-1 biomarker has shown it to be useful in
diagnosing cases where CL is between 15 and 30 mm
where the predictive value of CL is lowest. Because
the predictive accuracy of CL measurement declines
with increasing cervical length, the high PPV of PAMG-
1 (75% for CL < 25 mm and 76% for CL  25 mm) is of
particular interest. This may indicate that when results
are acted upon consistently, the use of the PAMG-1
biomarker in conjunction with cervical length meas-
urement, could provide both clinical and economic
benefits [51].
Main points
1. The use of cervical length measurements and of
biochemical markers, especially if combined,
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 2015
improves identification of patients at risk for immi-
nent spontaneous PTD as compared to clinical
symptoms alone (i.e. vaginal bleeding, contraction
frequency/duration, cervical dilation, etc.). A cer-
vical length equal or inferior of 25 mm in single-
ton pregnancy is the cutoff value mostly utilized
to identify patients at high risk of delivery
preterm.
2. Of the available biochemical tests, that based on
fetal fibronectin (fFN) has been the best character-
ized. However, the value of this test, like that of
phosphorylated insulin-like growth factor protein-
1 (phIGFBP-1) and cervical length (CL) measure-
ment alone, may be limited only to its negative
predictive value (NPV), given its poor positive pre-
dictive value (PPV).
3. As is the case with CL ranges, quantification of
fFN may provide additional value in stratifying the
risk of spontaneous PTD in women with symp-
toms of preterm labor. However, as is the case
with patients with CL less than 1.5 cm, the preva-
lence of women with an elevated concentration of
fFN (500 ng/ml) who would be at the greatest
risk of imminent spontaneous delivery may be too
low to provide practical value to clinicians, given
the cost of the test and the difficulty of assessing
the risk level at lower concentrations.
4. While CL less than 1.5 cm and above 3.0 cm has
high predictive value, to identify patients at risk
or to exclude the risk, the majority of patients
presenting with symptoms of preterm labor have
CL within these limits. Thus, we recommend the
use of transvaginal ultrasound to measure cervical
length (CL) in patients presenting with symptoms
of preterm labor in order to assess their risk of
imminent spontaneous PTD. In patients where the
CL is between 1.5 and 3.0 cm, we recommend the
use of a biomarker test with the highest combin-
ation of NPV and PPV that can be run shortly
after a vaginal examination. According to recent
literature, this test seems to be that based on pla-
cental alpha-microglobulin-1 (PAMG-1 Partosure)
(Table 1).
Prevention in asymptomatic women
Risk assessment
Short cervix
A sonographic short cervix measured by transvaginal
ultrasonography is the most powerful predictor of PTD
[56]. Prediction of preterm birth varies widely depend-
ing on several factors: number of fetuses, obstetric
 2016 G. C. DI RENZO ET AL.

Table 1. Biochemical marker tests to predict spontaneous PTD within 7 days of testing in women with symptoms of preterm
labor.
Biomarker Name of test Test cutoff N SN (%) SP (%) PPV (%) NPV (%)
fFN (qualitative) [54] Rapid fFN/QuikCheck 50 ng/mL 4285 76% 83% 25% 98%
fFN (quantitative) [33] Rapid fFN 10Q Analyser 10 ng/mL 350 96% 42% 29% 98%
50 ng/mL 350 91% 65% 39% 97%
200 ng/mL 350 71% 84% 52% 92%
500 ng/mL 350 42% 96% 71% 87%
phIGFBP-1 [43] Actim Partus 10 ng/mL 2159 67% 79% 35% 93%
PAMG-1 [50–52] PartoSure 1 ng/mL 353 84% 95% 77% 97%
fFN: fetal fibronectin; phIGFBP-1: phosphorylated insulin-like growth factor binding protein-1 (IGFBP-1); PAMG-1: placental alpha microglobulin-1.

history, symptoms of threatened preterm labor and
gestational age at screening. The most accepted cer-
vical length cutoff is <25 mm (the lower 10th percent-
ile in low-risk women at 14–30 weeks of gestation)
[56].
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was significantly reduced by weekly intramuscular
injections of 17-OHP-C [64]. A recent meta-analysis
suggest that daily vaginal progesterone started at
about 16 weeks (either suppository or gel) is a reason-
able, if not better, alternative to weekly 17-OHPC for

prevention of SPTB in women with singleton gesta-

Recommendation. Sonographic cervical length meas-
urement in all the pregnant patients regardless of
obstetrical history at 19–23 6/7 weeks of gestation
using transvaginal ultrasound should be encouraged
where skills, equipment and funding permit [57].
Preventive tools
Progesterone and progestogens
Progesterone has been suggested to promote myome-
trial relaxation by regulating and maintaining high lev-
els of cyclic adenosine mono-phosphate and nitric
oxide synthetase, low levels of oxytocin that enhance
the activity of b-agonists and intracellular calcium and
by inhibiting formation of myometrial gap junctions
(channels made of connexin 43) [58,59]. Progesterone
also inhibits prostaglandins production by amnio-chor-
ion-decidua (via cyclooxygenase). It has been shown
that the decreased fetal membranes progesterone
binding is responsible at term of the predominant
estrogen effect in promoting prostaglandin production
and triggering labor.
High dosage progesterone has been advocated as a
possible tocolytic agent.
However, the half-life of progesterone in the myo-
metrium is very short [60], so it may be only useful in
conjunction with other tocolytic agents [61, 62]. For
example, the combination of natural micronized pro-
gesterone and ritodrine has shown synergistic effects
by decreasing the need for high concentrations of the
b-agonist, which have potentially troublesome side
effects [63]. Progesterone (P4) and related synthetic
compounds such as 17-a-hydroxy progesterone capro-
ate (17-OHP-C) have been tested in clinical trials to
prevent preterm birth. In women with prior history of
preterm birth, the incidence of recurrent preterm birth
tions and prior SPTB. However, the quality level of the
summary estimates was low [65].
Randomized clinical trials and an individual patient
data meta-analysis have shown that vaginal P4
reduces significantly the rate of PTD and neonatal
morbidity and mortality in asymptomatic women with
a sonographically short cervix, with or without a his-
tory of preterm birth [66–70]. However, there is no
evidence that 17 OHP-C can decrease the risk of pre-
term birth in similar women with a short cervix [71].
In a recent randomized placebo controlled prag-
matic study (the OPPTIMUM study), it was shown that
vaginal progesterone was not associated with reduced
risk of preterm birth or composite neonatal adverse
outcomes, and had no long-term benefit or harm on
children outcomes at two years of age in a heteroge-
neous population of singleton pregnant women at risk
for preterm birth [72].
However, in a updated aggregate meta-analysis
including data from the above study the preventive
effect of vaginal P was reconfirmed with a decreased
risk of preterm birth 34 weeks of gestation or fetal
death compared to placebo (18.1% vs. 27.5%; RR, 0.66
(95% CI, 0.52–0.8 [73].
The effect of progesterone in the short cervix sub-
groups was similar to those reported in two previous
studies (by E. Fonseca and by S. Hassan) [70] included
in a meta-analysis by J. Dodd in the Cochrane Reviews
and Romero’s in a IPD Meta-analysis, the OR for pre-
term birth prevention was 0.69 in women with a short
cervix in the OPPTIMUM study, compared with a RR of
0.64 [before 34 weeks] in one systematic review by
J. Dodd, a RR of 0.58 [before 33 weeks] in the individ-
ual patient data meta-analysis by Romero [73] and a
RR of 0.66 in a updated aggregate meta-analysis
including data from the OPPTIMUM Study. The study

was underpowered to determine real the effect of pro-
gesterone in the prevention of preterm birth in
women with a short cervix. The interaction term
approached statistical significance (p ¼ .051) for the
neonatal outcome in the subgroup with a history of a
previous spontaneous preterm birth, where the OR
(95% CI) for the neonatal outcome was lower in the
progesterone group (0.49, 0.30, 0.80); compared with
1.20 (0.56, 2.59) in the complementary group with no
previous spontaneous preterm birth.
In the most recent NICE guidelines (November
2015) it is recommended to offer prophylactic vaginal
P4 to women with no history of spontaneous preterm
birth or mid-trimester loss in whom a transvaginal
ultrasound scan has been carried out between 16 þ 0
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and 24 þ 0 weeks of pregnancy that reveals a cervical
length of less than 25 mm. It is also recommended to
offer a choice of either prophylactic vaginal P4 (or
prophylactic cervical cerclage) to women with a history
of spontaneous preterm birth or mid-trimester loss
between 16 þ 0 and 34 þ 0 weeks of pregnancy and in
whom a transvaginal ultrasound scan has been carried
out between 16 þ 0 and 24 þ 0 weeks of pregnancy
that reveals a cervical length of less than 25 mm. The
benefits and risks of prophylactic P4 and cervical cerc-
lage need to be discussed with the woman taking her
preferences into account.
Still controversial, however, is the efficacy of either
progestogens in single pregnant symptomatic women
with a short cervix for the so-called secondary or
maintenance tocolysis. Areja et al. in 2013 [74] and
Martinez de Tejada [75] did not find vaginal P effica-
cious in the above condition, while a recent meta-
analysis, which included studies where the cervix was
not objectively measured, reached opposite conclu-
sions [76]. Another meta-analysis comparing 17 P to
placebo/no intervention did not show efficacy of pro-
gestogen in reducing PTB [77]. Even in this last study
inclusion criteria did not require an objective cervical
length measurement.
As far as twin gestation is concerned, a meta-analysis
based on individual participant data from 13 random-
ized clinical trials demonstrated that treatment with
progestogens (either intramuscular 17-OHP-C or vaginal
natural P4) does not prevent preterm birth, nor improve
perinatal outcome in unselected women with an
uncomplicated twin gestation [78]. However, vaginal
progesterone may be effective in the reduction of
adverse perinatal outcome of twins in women with a
cervical length of 25 mm. Also the results of individual
participant data analysis from randomized trials demon-
strated the increased incidence of adverse perinatal
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 2017
outcomes in a subgroup of women with a cervical
length >25 mm treated with intramuscular 17OHP-C
[79].
Recommendations. Women with prior history of PTB
or late second trimester abortion should be offered 17
OHP-C weekly injection starting early in the 2nd tri-
mester or vaginal progesterone based on individual
benefits/risks evaluation with the patient. It should be
noted that intramuscular 17 OHP-C has been found to
increase by three times the incidence of gestational
diabetes in the treated population of pregnant
women.
Asymptomatic women with a sonographically short
cervix (25 mm) regardless of their obstetrical history
should be offered vaginal progesterone treatment for
the prevention of preterm birth and neonatal morbid-
ity. Two forms of vaginal micronized progesterone can
be used daily: 200 mg vaginal soft capsules or 90 mg
vaginal gel [57].
In symptomatic women undelivered after an epi-
sode of PTL the efficacy of progestagens remain to be
clarified.
Based on current evidence, the use of vaginal P4 in
twin pregnancies is recommended when the cervix is
found shorter than 25 mm. There is now evidence of a
clear benefit on the neonatal outcome. 17-OHP-C
treatment should not be used in twin pregnancies.
Cervical cerclage
Cervical cerclage aims to reinforce cervical integrity
and keep it closed, to prevent or treat cervical insuffi-
ciency and reduce the rate of late miscarriage and
PTB.
A meta-analysis of randomized trials has demon-
strated that cerclage does not prevent preterm birth
in all women with short cervical length on transvaginal
ultrasonography. However, in the subgroup of single-
ton gestations with a previous spontaneous PTB the
placement of a cervical cerclage showed a significant
reduction in the risk of PTB and a decrease in the risk
of perinatal morbidity and mortality [80]. In cases with
a history of three or more late abortions, or PTD, inde-
pendently from cervical length, cerclage performed in
the first half of pregnancy was associated with a lower
rate of PTD, although there were no differences in
fetal or neonatal outcome [81].
An individual patient data meta-analysis of random-
ized trials of twin pregnancies where women with a
short cervix were randomized to cerclage vs. no-cerc-
lage showed no significant differences in the rate of
preterm birth <34 weeks. However, the rates of very
 2018 G. C. DI RENZO ET AL.
low birthweight and of respiratory distress syndrome
were significantly higher in the cerclage than in the
control group [82]. Similar data of a previous meta-ana-
lysis demonstrated that in twins, cerclage was associ-
ated with a higher incidence of preterm birth [80].
Women with prior ultrasound-indicated cerclage have
similar outcomes if they receive either transvaginal
ultrasound cervical length screening with ultrasound-
indicated cerclage for cervical length 25 mm or less or
planned history-indicated cerclage in the subsequent
pregnancy. Less than 50% of the transvaginal ultra-
sound cervical length screening group required a
repeat ultrasound-indicated cerclage in the subsequent
pregnancy [83,84]. Singleton gestations in women with
prior preterm birth may be monitored safely with a pol-
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icy of transvaginal ultrasound cervical length screening
as compared with a policy of routine history-indicated
cerclage. Cerclage can be reserved for the minority of
women who develop a short cervical length. An indirect
meta-analysis of randomized controlled trials showed
that cervical cerclage and vaginal P are equally effica-
cious in the prevention of preterm birth, in women
with a sonographically short cervix and previous pre-
term birth [85]. However, taking into consideration
adverse events the trials revealed that cervical cerclage
was associated with a higher rate of maternal side
effects (pyrexia, vaginal discharge and bleeding) and
larger number of cesarean deliveries [86].
Recommendation. Women with prior spontaneous pre-
term birth, singleton gestation, and transvaginal ultra-
sound cervical length of less than 25 mm before 24
weeks, should be offered the placement of cervical cerc-
lage or vaginal P4 for the prevention of preterm birth
and neonatal morbidity. Both can be offered after dis-
cussing the benefits/risks ratio and taking patient pref-
erence into consideration. Based on current evidence,
cervical cerclage should not be used in twin gestations.
Cervical pessary
The transvaginal placement of a pessary around the
cervix is used to change cervix direction toward the
sacrum and to relieve direct pressure on the internal
cervical os by distributing the weight of the pregnant
uterus onto the vaginal floor, retrosymphyseal osteo-
muscular structures, and Douglas cavity.
Recently performed randomized studies investigat-
ing the preventive effect on PTD of placing a cervical
pessary in non-symptomatic patients, in singleton
pregnancies with a short cervix, have provided contra-
dictory results. In one randomized clinical trial the cer-
vical pessary reduced the rate of preterm labor from
27% to 6% [87] while in the second study PTD
occurred more frequently in the pessary (9.4%) in
respect with the control group (5.5%) [88].
Two multicenter RCTs performed in almost 2000
unselected twin pregnancies reported that cervical
pessary did not significantly reduce the rate of
preterm birth [89,90]. A recently published RCT con-
ducted on 137 women with a sonographic cervical
length 25 mm showed that the insertion of a cervical
pessary was associated with a significant reduction in
spontaneous preterm birth in twin gestation [91].
These data, however, are in contrast with a subgroup
analysis of 214 patients with short cervix from one of
the previous study in which no benefit of cervical pes-
sary was reported [90]. Some of these differences in
results may be attributed to the lack of proper training
in placing the pessary in some protocols.
Recommendation. Although promising and with a
potentially favorable cost-benefit ratio, current evi-
dence is conflicting regarding the usefulness of cer-
vical pessary in women with a short cervix, in either
singleton or twin gestation. There is a need for further
RCTs to clarify this point. Proper training to apply the
pessary should be homogenised and encouraged in
further investigations.
Tocolysis
Women who present with signs and symptoms of
labor frequently will not deliver in the short term and
many will continue to full term, even in the absence
of interventions. Women with risk factors will usually
not deliver preterm. Conversely, even women who
receive prophylactic interventions may still deliver
early. Improved prediction in all these groups would
be clinically beneficial, to target preventative interven-
tions, to select those women who should be admitted
to a hospital with neonatal care facilities, and there-
fore, triage the need for prenatal transfers as well as
that for in utero therapies to improve outcomes (e.g.
steroids and magnesium sulfate).
Objective of tocolysis
Although tocolytics have not shown to improve peri-
natal outcome, their use can rely on achieving two
goals:

To gain time for antenatal corticosteroids to
become effective;

To gain time, to allow in utero transfer to a hospital
with intensive care and newborn intensive care
units [92–97].

Indications

Onset of labor: Regular contractions (not less than
4 per 20 min) at a gestational age of 22 to 33
weeks þ6 days;

Dynamic changes in the cervix (shortening and
effacement, increasing speed of dilatation) [98].
Tocolytic drugs
Currently licensed drugs for tocolysis include beta-
agonist, oxytocin receptor antagonists. Prostaglandin
synthetase inhibitors have restrictions in usage. There
is no evidence for the effectiveness of magnesium
sulfate.
There is no evidence about advantage of one toco-
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lytic drug in comparison with others in prolongation
of pregnancy.
Drugs combination is used in exceptional cases as it
increases the risk of side effects [92,97,99–102].
Licensed tocolytic agents
Beta-agonists
The effects of beta-agonists (ritodrine, fenoterol) on
the mother, fetus and newborn are the most studied
[96,98,100]. The search for the new form of beta-agon-
ist is due to frequent side effects: tachycardia, dys-
pnea, pulmonary edema, mother’s heart attack, fetal
tachycardia and acute hypoxia, etc. Administration of
beta-agonists causes myometrium relaxation by their
binding to 2-b adrenergic receptors and increasing
level of intracellular cyclic adenosine monophosphate,
which in turn activates protein kinase, blocks myosin
light-chain kinase and inhibits the contractile activity
of the myometrium.
These tocolytic drugs penetrate trough placenta
barrier and can cause fetal tachycardia and hypogly-
cemia, in some cases hyperinsulinemia after birth.
They are not indicated for prolonged treatment due to
significant cardiotoxic effect.
Beta-agonists are administered as intravenous infu-
sion for tocolysis: starting from 6 to 8 doses per minute,
gradually increasing the introduction rate to 15–20 dose
per minute. Hexoprenaline sulfate administration is rec-
ommended in two stages: 10 mcg intravenous bolus
administration and 10 mcg in 500 ml isotonic solution
intravenously (one or two courses). When using infusion
pump 75 mcg of infusion concentrate (3 vials) is diluted
in 50 ml of sodium chloride isotonic solution; the rate of
administration should be 0.075 g/min. Fenoterol is
administrated intravenously (solution is prepared ex
tempore, diluting in 5% dextrose, xylitol, 0.9% sodium
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 2019
chloride solution or Ringer's solution) at initial dose of
50 mg/min, the maximum injection rate is 300 g/min.
Administration of beta-agonists requires:

Mother’s heart rate control every 15 min;

Mother’s bp monitoring every 15 min;

Glycemia control every 4 hours;

Control of the volume of injected fluid and diuresis;

Lungs auscultation every 4 hours;

Control of the fetal condition and uterine contract-
ile activity [98,100].
Contraindications for beta-agonist administration
Mother cardio-vascular disorders, thyrotoxicosis,
closed-angle glaucoma, diabetes mellitus, blood dis-
charge in case of placenta praevia, premature placenta
abruption, fetal heart rate disorders, fetal anomalies,
suspected rupture of the uterine scar.
Supporting therapy (extension of drug administra-
tion per os) for prevention of preterm labor is ineffect-
ive (A-1a) and has numerous side effects [1].
Oxytocin receptor antagonists
The principal activity of these drugs is their capacity to
block oxytocin receptors, which decreases myometrial
tonus and reduces contractility of the uterus with no
dangerous side effects: dyspnea, mother’s tachycardia
and fetal heart rate disorders. Tocolytics of this group
– Tractocile (AtosibanV) – inhibit vasopressin effects by
R
binding to its receptors but have no effect on the car-
diovascular system [95,96,103–105].
Tocolysis with atosiban should start immediately at
diagnosis of “the onset of preterm labor”. The therapy
is carried out in three stages:
1. First intravenous administration of 1 vial (0.9 ml) of
the drug without dilution (initial dose – 6.75 mg for
1 min)
2. Immediately thereafter infusion of atosiban is
carried out for 3 h at dose 300 lg/min (rate of
administration – 24 ml/h, the dose of atosiban –
18 mg/h);
3. Atosiban then infused at a dose of 100 lg/min
(rate of administration – 8 mg/h) up to 45 h.
An absence of systemic effect on the mother and
fetus, as well as the dangerous side effects for the
mother and premature neonate distinguishes antago-
nists of oxytocin receptors from other tocolytic drugs
[98,99,105,106]. This fact determines its advantage
 2020 G. C. DI RENZO ET AL.
over other tocolytic agents and suggests its use as a
first-line drug [103–105]. Safety for mother and fetus
makes it possible to use this type of tocolytics at
outpatient stage and during transfer to obstetrical
units able to carry out intensive care of newborns
[92,95,96].
Calcium channel blockers
Nifedipine, a calcium channel blocker, is used as toco-
lytic drug. Nifedipine and beta-agonists have compar-
able effectiveness. Lower level of side effects is an
advantage of the nifedipine therapy (ff-1a). Nifedipine
is administrated in the dosage regimen: 3 doses of
20 mg every 30 min per os, followed by sublingual
intake 20–40 mg every 4 h until 48 h after beginning of
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the therapy.
Recommended nifedipine tocolysis: monitoring

Continuous monitoring of fetal heart rate while
uterine contractions;

Mother’s heart rate and blood pressure control
every 30 min during the first hour, then every hour
for the first 24 h and then every 4 h [101,107].
Maternal contraindications: hypotension, heart diseases
(e.g. aortic valve insufficiency).
Fetal contraindications: disorders of uteroplacental
blood flow, fetal distress (tachycardia).
Limited application tocolytic agents
Prostaglandin synthetase inhibitors
The mechanism of tocolytic action of prostaglandin
synthetase inhibitors (aspirin, indomethacin, diclofe-
nac) is based on blocking the synthesis of prostaglan-
dins [108].
Indomethacin or diclofenac is used as 100 mg rectal
suppositories. The same dose should be repeated in
one hour, then – 50 mg every 4–6 h during 48 h. The
total dose should not exceed 500 mg and the treat-
ment duration should be no more than 5 days.
Indomethacin is recommended only for pregnancies
between 22 and 32 weeks.
The advantages of prostaglandin synthetase inhibi-
tors for tocolysis:
1. Indomethacin or diclofenac should be prescribed
only if the amniotic fluid index is normal.
2. Before starting tocolysis, amniotic fluid volume
should be measured and controlled in 48–72 h. In
case of oligohydramnios, the therapy should be
discontinued or, in certain cases, the dose should
be reduced.
If necessary, the treatment may be repeated after a
5-day break. The therapy should be discontinued if
uneffective to stop labor.
Maternal contraindications: blood-clotting disorders,
compromised liver function, asthma, and aspirin
allergy.
Fetal contraindications: growth restriction, kidney
anomalies, chorioamnionitis, oligohydramnios, heart
defects involving the pulmonary trunk and twin–twin
transfusion syndrome.
The effects of indomethacin and of other medical
products of this class on a human fetus in the 3rd tri-
mester of pregnancy include: intrauterine premature
closure of the ductus arteriosus, insufficiency of the tri-
cuspid valve and pulmonary hypertension, non-closure
of the ductus arterious in the postnatal period, resist-
ant to drug correction, degenerative myocardial
changes, platelet disorders that cause bleeding, intra-
cranial bleeding, renal dysfunction or failure, kidney
damage/developmental defect which can lead to renal
failure, oligohydramnion, gastrointestinal bleeding or
perforation, increased risk of necrotizing enterocolitis.
FDA pregnancy risk category: . During the indometh-
acin therapy, the pulmonary trunk blood flow should
be checked and the severity of regurgitation at the
level of the tricuspid valve should be assessed. At least
once a week, the study should be repeated and the
therapy should be discontinued when the shunting
reduces. The volume of amniotic fluid should be meas-
ured 2 times a week [95,96,109].
Tocolytic agents of unproven efficacy
Magnesium sulfate
Magnesium sulfate is not registered anymore as a
tocolytic agent, because its efficacy is not proven.
Magnesium sulfate may be prescribed for the purpose
of neuroprotection to prevent ICP in neonates after a
patient is taken to hospital [110,111].
Contraindications to tocolysis
A pregnancy of <22 or >34 full weeks; preterm rup-
ture of fetal membranes and a pregnancy of >32
weeks; fetal growth restriction and/or signs of fetal dis-
tress; chorioamnionitis; premature detachment of pla-
centa; cases where it is not reasonable to prolong
pregnancy (eclampsia, preeclampsia, serious extrageni-
tal diseases of the mother); fatal fetal developmental
defects; intrauterine infection or suspected intrauterine

infection; antenatal fetal death; suspected incompetent
uterine scar; dilatation of the orifice of the uterus for
4 cm or more.
Recommendations.

Use tocolysis mainly for corticosteroid administra-
tion and/or in utero transfer

Use the safest tocolytic therapy available in well
selected cases and for the shortest time

Be aware that no-responding to tocolysis may
imply presence of infection/inflammation (cho-
rioamnionitis and fetal inflammatory syndrome)

Maintenance tocolysis has no efficiency and no place.
Antenatal corticosteroids1
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Antenatal corticosteroids given to mothers with antici-
pated PTD will improve survival, reduce the risk of
respiratory distress syndrome (RDS), necrotizing
enterocolitis and intraventricular hemorrhage and a
single course does not appear to be associated with
any significant maternal or short-term fetal adverse
effects. The beneficial effects of antenatal steroids
were similar in studies conducted in the 1970 s as in
those conducted more recently implying that they
remain beneficial in the presence of modern neonatal
care [113]. Prenatal corticosteroid therapy is recom-
mended in all pregnancies with threatened preterm
labor below 34 weeks’ gestation where active care of
the newborn is anticipated. Although there are limited
randomized controlled trial (RCT) data in babies <26
weeks’ gestation or very immature twins, observational
studies support the concept that antenatal corticoste-
roids also reduce mortality in these infants [114,115].
In pregnancies delivering between 34 and 36 weeks’
gestation prenatal steroids will also reduce the risk of
short term respiratory morbidity, although there is a
paucity of data on longer-term follow-up [116]. When
given before elective cesarean section (CS) at term
they reduce the risk of admission to NICU, although
the number needed to treat is >20 [117]. Follow-up
data on term babies exposed to antenatal steroids is
limited.
The optimal treatment to delivery interval is more
than 24 h and less than 7 days after the start of steroid
treatment; beyond 14 days the benefits are diminished.
There is a continuing debate as to whether steroids
should be repeated one or two weeks after the first
course for women with threatened preterm labor.
Such repeat courses do not reduce the risk of neonatal
1
The section on antenatal corticosteroids is largely based on the recent
European Consensus Guidelines on the Management of Neonatal
Respiratory Distress Syndrome – 2016 update [112].
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 2021
death nor of long-term morbidity, but reduce RDS and
other short-term health problems, although birth
weight is reduced and long-term beneficial effects are
lacking [118]. The WHO recommend that a single
repeat course of steroids may be considered if preterm
birth does not occur within 7 days after the initial
course and subsequent assessment demonstrates that
there is a high risk of preterm birth in the next 7 days
[119]. It is unlikely that repeat courses given after 32
weeks’ gestation improve outcome and recent long-
term follow-up studies show no benefit by school age
in terms of reduction in death or disability if repeat
courses are used [120].
Betamethasone is likely to be more effective than
dexamethasone, but it also has more side-effects. It
reduces fetal body and breathing movements and fetal
heart rate variation for about 1–3 days, without evi-
dence for an impaired fetal condition [121]. Due
account for this phenomenon has to be given when
monitoring the fetal condition. Betamethasone does
not induce heart rate decelerations, nor does it affect
fetal Dopplers [122].
A cautionary note – a recent RCT from low to
medium income countries showed a higher neonatal
mortality and maternal infection rate in women given
prenatal steroids [123,123]. The majority of babies
were >2 kg at birth and these data emphasize the
importance of adequate dating of duration of preg-
nancy and of assessment of risk of preterm birth
before considering use of antenatal steroids [121].
Steroids are potent drugs with many potential side-
effects. When given appropriately they improve out-
come. If not, then side-effects, such as impaired fetal
and placental growth, apoptosis in the brain and
increased infection risks may prevail [e.g. 125–127].
The use of steroids should be reduced by adequate
preterm birth risk assessment and by avoidance of
early elective CS. Cervical length measurement, in
combination with PAMG-1 testing can help to deter-
mine which women are at low risk of delivery within
7 days, and perhaps allow more judicious use of ante-
natal treatments [128]. In some cases when an early
CS is needed establishment of fetal lung maturity may
be better than giving steroids to all women [129].
Recommendations
Clinicians should offer a single course of prenatal corti-
costeroids to all women at risk of PTD, from when
pregnancy is considered potentially viable up to 34
completed weeks’ gestation
A single repeated course of antenatal steroids may
be appropriate if the first course was administered
 2022 G. C. DI RENZO ET AL.
more than 1–2 weeks prior and the duration of preg-
nancy is <32–34 weeks’ gestation when another
obstetric indication arises.
Antenatal steroids can also be considered for cesar-
ean section (CS) not in labor up to term. However,
there should be a clear medical reason to do an early
CS and elective CS should not be performed <39
weeks’ gestation.
In late preterm pregnancy at risk of early birth, a
course of antenatal steroids may also be considered
provided there is no evidence of chorioamnionitis.
In women with symptoms of preterm labor cervical
length and fibronectin/PAMG1 measurements should
be considered to prevent unnecessary hospitalization
and use of tocolytic drugs and/or antenatal steroids.
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Clinicians should be aware, that betamethasone
gives a transient reduction in fetal movements and
heart rate variation.
Short-term use of tocolytic drugs should be consid-
ered in very preterm pregnancies to allow completion
of a course of prenatal corticosteroids and/or in utero
transfer to a perinatal center (B).
Magnesium sulphate (MgSO4)
MgSO4 is not an effective tocolytic drug, but it has
been shown to reduce the incidence of cerebral palsy
in preterm infants. The mechanism of action might be
that it blocks calcium influx into the cell in case of
asphyxia. In five RCTs, in which neuro-prevention of
was the primary aim the four of them, the RR of cere-
bral palsy was 0.69 (95% CI 0.54–0.87) and of motor
dysfunction 0.61 (CI 0.44–0.85) with no effects on mor-
tality or on other neurological impairments or disabil-
ities during the first years of life [111]. The number
needed to treat to prevent one case of moderate to
severe CP when given <28 weeks is 30 and when
given before 30 week it is 52. MgSO4 may have severe
maternal side-effects when an inappropriately high
dose is given (vaso-dilatation, neuro-muscular block-
ing); therefore, most guidelines advise to use the drug
only before 32 weeks. Several Societies have incorpo-
rated MgSO4 into their guidelines, although recent
longer term follow-up of an Australian cohort showed
no differences by school age [130]. MgSO4 should be
administered when women are in preterm labor
before 30 or 32 weeks of gestation. An i.v. loading
dose of 4 g is given, followed by a maintenance dose
of 1–2 g/h for max.12 h. It is uncertain – but likely –
that such a treatment should be repeated if labor
stops and starts again later at a gestational age before
32 weeks. The dose is similar to that given in case of
maternal preeclampsia and it uncertain if this is the
right dose for neuro-prevention.
Recommendation
In case of preterm labor before 32 weeks it should be
considered to give MgSO4 to reduce the risk of cere-
bral palsy in the newborn.
Prophylactic antibiotics for the prevention of
infection-related preterm birth
Infection and inflammation is an important cause of
PTB, particularly at early gestations, and detection of
vaginal dysbiosis in the form of bacterial vaginosis
(BV) at 13–16 weeks gestation is associated with a 5–7
fold increased risk of late miscarriage and early PTB
[131,132]. While individual antibiotic prophylaxis stud-
ies have found benefit for the prevention of PTB, the
heterogeneity of methodologies and results is confus-
ing. For antibiotics to be effective, they should be
active against BV or BV-related organisms, (currently
only clindamycin or metronidazole), they should be
used in women with objective evidence of vaginal dys-
biosis in the form of BV (not previous PTB of unknown
etiology) and they should be used early in pregnancy
before infection and inflammatory damage can occur
[133]. However, until recently, no systematic review
and meta-analysis carried out to address this confu-
sion, has simultaneously addressed the optimal choice
of antibiotic agent, patient and timing of administra-
tion [133]. In a recent systematic review of clindamycin
used before 22 weeks gestation in women with BV,
the rate of late miscarriage, and PTB before 37 weeks
gestation was statistically significantly reduced by 80%
and 40%, respectively [134].
Clindamycin may be more effective for treating BV
than metronidazole. Accordingly, even in well-con-
ducted meta-analyses, positive effects may have been
negated by the inclusion of large studies with nega-
tive results that used metronidazole. New information
from molecular-based culture-independent techniques
has demonstrated that BV is not a single entity but a
syndrome of vaginal dysbioses of different microbial
community subtypes, which may respond differently
to different antimicrobial agents [135]. It has been
suggested that metronidazole, through an effect on
microbial synergism (eradication of anaerobes result-
ing in decreased nutrients for the growth of BV-
related organisms such as Gardnerella vaginalis and
Atopobium vaginae which are resistant to metronida-
zole in vitro) may be effective in a subtype of vaginal
dysbiosis that is anaerobe dominated, whereas

clindamycin may be more beneficial across a wider
range of subtypes of BV [133]. In addition, rescreen-
ing and retreating with clindamycin may be beneficial
and clindamycin is anti-inflammatory as well as anti-
microbial. The presence or absence of lactobacillus
phage viruses may also affect the efficacy of clinda-
mycin or metronidazole [133].
Finally, in an antenatal screen-and-treat program of
over 20,000 women between 10 and 16 weeks to pre-
vent preterm birth, vaginal candidiasis, and trichomon-
iasis treated appropriately, and BV treated with
clindamycin vaginal cream reduced the rate of PTB
and low birth weight from 22.3% and 20% in controls
to 9.7% and 8.4% in the intervention group respect-
ively (p ¼ .001) [136].
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Recommendations

Pregnant women symptomatic for vaginal candidia-
sis, trichomoniasis or BV should be treated.

The case for routine screening of all pregnant women
is not yet established but there is sufficient equipoise
for this to be addressed in a research context.

Before 20 weeks gestation, high-risk women with a
previous PTB of infectious etiology before 34 com-
pleted weeks, should be counseled and either
screened for vaginal dysbiosis or offered antibiotic
prophylaxis.

Women with recurrent vaginal bleeding in 2nd tri-
mester before 20 weeks gestation should be coun-
seled about the risks of PPROM and PTB and the
risks versus benefits of antibiotic prophylaxis.

There is increasing evidence to support the use of
clindamycin over metronidazole for prophylaxis,
but whether this should be intravaginal or oral clin-
damycin (or both) remains unanswered.

Future systematic reviews and meta-analyses of
treatment of BV in pregnancy should exclude trials
where antibiotics other than metronidazole or clin-
damycin were used and metronidazole and clinda-
mycin studies should be analyzed separately.
Treatment at early gestations should be included
and care should be taken that arbitrary gestational
age cutoff points do not exclude important studies.

Future studies should use neonatal outcomes as
the primary endpoints rather than the surrogate of
a specific preterm gestational age.

In future studies, when calculating a priori sample
size, it should be remembered that BV in early preg-
nancy, whether this resolves spontaneously or fol-
lowing antibiotic treatment, is still associated with
an adverse outcome rate above that in women who
did not have BV at baseline. An assumption that
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 2023
resolution of BV will result in an outcome rate the
same as women without BV at baseline will result in
an overestimate of the benefit of treating BV and an
underestimate in sample size required.
Mode of delivery of preterm infants
The mode of delivery of preterm infants has been con-
troversial for decades as neonatal outcome depends
on many factors including perinatal management but
also gestational age, corticosteroid administration,
presence of chorioamnionitis, and multiple
pregnancies.
In order to reduce the incidence of intrapartum
hypoxia associated with prematurity and a possible
long labor, a policy of elective cesarean section (CS)
has been recommended in the eighties even if there
was no medical evidence to support it [137].
Vaginal delivery in preterm labor
In low and extremely low birth weight with vertex
presentation, there is no clear correlation between the
delivery mode and neonatal complications incidence.
Survival rate and neonatal outcome of singletons with
a birth weight lower than 1500 g are either not differ-
ent after CS and vaginal delivery (VD) [138–140] or are
better after a VD [141,142].
A Cochrane review on the mode of delivery in pre-
term singletons confirms a similar rate of birth injury,
asphyxia and perinatal mortality rates after CS and VD
[143].
Moreover, VD-associated maternal morbidity in pre-
term deliveries is significantly decreased compared to
CS (OR 6.2; 95% CI 1.3–30.1) confirming that in the
absence of fetal and obstetrical indications, vaginal
delivery in preterm labor should be chosen [143,144].
Caesarean section in preterm labor
The presence of intrauterine growth restriction in pre-
term vertex neonates between 26 and 36 weeks is
associated with a higher rate of cesarean sections. This
mode of delivery increases the survival rate of the
small – for-gestational age (SGA) neonates below 31
weeks but not that of SGA >33 weeks [145]. In vertex
singletons with a birth weight lower than 1500 g, CS
delivery decreases the neonatal mortality rate of the
growth restricted newborns [139,141].
In previable infants between 22 and 25 weeks of
gestation, independently of the risk cofactors, CS could
be associated with a better neonatal outcome
[146,147].
 2024 G. C. DI RENZO ET AL.
In breech preterm deliveries, data are conflicting:
one retrospective study done on preterm breech
between 24 and 37 weeks reports a lower arterial pH
after VD but no difference for transfer rate in neonatal
intensive care [148]. A multicenter randomized con-
trolled trial comparing different modes of delivery for
patients with preterm breech labor showed non-con-
clusive results because of low recruitment [149]. A
recent systematic review based on 7 studies concluded
that neonatal mortality rate is lower in the CS group
(3.8%) than in the VD group (11.5%) [150].
In very low birth weight twins, the protective effect
of CS is unclear: in one study, regardless the presenta-
tion, CS significantly reduces the rate of intraventricu-
lar hemorrhage but does not affect adverse neonatal
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outcome and mortality [151]. In a multicenter retro-
spective study, there is no significant difference in the
neonatal mortality and morbidity rate after VD or CS
[152]. Then, vaginal delivery could be safely considered
in preterm vertex twins. For a non-vertex presenting
twin, most guidelines recommend elective CS.
Instrumental delivery in preterm labor
Vacuum delivery in preterm fetuses is associated with
an increased risk of intracranial hemorrhage due to
venous sinuses fragility [153]. However, a retrospective
study comparing the outcomes of preterm infants
(between 1500 and 2.499 g) delivered by vacuum
extraction compared to normal vaginal delivery did not
show any significant difference in neonatal morbidity
[154]. In a retrospective study comparing the outcome
of late preterm infants (31 to 34 weeks þ4) delivered
by forceps and vacuum delivery, there was no differ-
ence between the two groups suggesting that both
instruments are safe options in the hands of experi-
enced obstetricians [155]. A Swedish population-based
cohort study reported increased rates of cerebral hem-
orrhages and Erb’s palsy following vacuum delivery in
preterm infants compared with CS or normal VD deliv-
eries [156]. Guidelines issued from the Royal College of
Obstetrics and Gynecology do not recommend the use
of vacuum extraction below 34 weeks and consider
that the safety has not clearly ben established between
34 þ 0 and 36 þ 0 weeks [157].
Recommendations
Preterm gestational age alone is not a valid indication
for CS, unless if there are specific obstetrical
indications.
Vaginal delivery appears to be safe and the gold
standard for singleton and twins in vertex position.
Despite an increased risk of IVH in previable infants,
the neonatal outcome is similar to that found after CS.
Caesarean section should be recommended in pre-
term labor in the presence of intrauterine growth
restriction, breech presentation and in twins with a
non-vertex presenting fetus. CS delivery is not recom-
mended but might be an option for previable infants.
CS delivery does not prevent the occurrence of neuro-
logical sequelae. Short- and long-term maternal risks
are clearly increased in case of CS.
Instrumental delivery is not recommended in pre-
term infants. However, if necessary, a low forceps
delivery should be preferred to vacuum extraction
below 34 weeks.
Delayed cord clamping
Delayed umbilical cord clamping in neonates born pre-
term is associated with less need for red blood cell
transfusions, increase in hemoglobin and hematocrit
levels and decrease in risk of intraventricular hemor-
rhage and necrotizing enterocolitis. No maternal or
neonatal risks have been demonstrated. Data on long-
term outcomes are lacking. The optimal time to delay
cord clamping and potential risks are poorly studied
[158]. One recent study in infants born before 32
weeks has shown that delaying clamping of the cord
for slightly more than 30 s after the birth of the infant,
resulted in a three-fold reduction of a low Bayley score
at the age of 2 years [159]. Delayed cord clamping is a
simple procedure. It should therefore be applied,
unless there are strong contra-indications.
Recommendation
Delaying of clamping of the cord after the birth of a
preterm infant should strongly be considered.
Summary of recommendations

Proper identification of patients at risk or in true
preterm labor is essential

Take into consideration new risk factors (age, PMA,
fetal sex, psychosocial stress, previous cesarean sec-
tion, etc.)

Sonographic cervical length measurement is recom-
mended in all pregnant patients regardless of
obstetrical history at 18–23 6/7 weeks of gestation
using transvaginal ultrasound

Cervical US measurement and PAMG1/Quantitative
Ffn are best tests for identifying the true preterm
laboring patient or excluding preterm labor

Asymptomatic women with a sonographically short
cervix (25 mm) at mid gestation, either with
singleton or twin pregnancy and regardless of

their obstetrical history should be offered vaginal
progesterone treatment for the prevention of pre-
term birth and neonatal morbidity.

Detection of vaginal-cervical colonization by tricho-
monas vaginalis and candida albicans treated
appropriately reduce the risks of preterm labor

Vaginal dysbiosis in the form of bacterial vaginosis
detected early in pregnancy should be treated pref-
erably with clyndamicin and may reduce the associ-
ated risk of preterm delivery

Tocolytic drugs have never shown to improve
perinatal outcome, although they are capable of
stopping contractions. If these drugs are being
used, use them with a clear aim (corticosteroid
administration and/or in utero transfer). Moreover,
use a tocolytic drugs with a low incidence of
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maternal side-effects (Atosiban, maybe prostaglan-
din inhibitor) in well-selected cases and for the
shortest time

Be aware that no-responding to tocolysis may
imply presence of infection/inflammation (cho-
rioamnionitis and fetal inflammatory syndrome)

Use steroids (betamethasone or dexamethasone)
only when strictly needed (short cervix and/or posi-
tive fibronectin or early elective cesarean delivery).
Steroids may be repeated once, but only before
32–34 weeks

Use magnesium sulfate as a neuro-protective medi-
cation in imminent preterm birth before 32 weeks

Preterm gestational age alone is not a valid indica-
tion for CS unless if there are obstetrical
indications.

Vaginal delivery appears to be safe and the gold
standard mode of delivery for singleton and twin
vertex preterm fetuses

Caesarean section should be recommended in pre-
term labor in the presence of intrauterine growth
restriction, breech presentation and in twins with a
non-vertex presenting fetus. CS delivery is not rec-
ommended but could be discussed for previable
infants

Instrumental delivery is not recommended in pre-
term infants. However, if necessary, a low forceps
delivery should be preferred to vacuum extraction
below 34 weeks

Delaying of clamping of the cord after the birth of
a preterm infant should be strongly considered
Acknowledgements
We would like to thank Prof. Dorota Agata Bomba-Opon,
from the Medical University of Warsaw, Poland, for her valu-
able contribution in the writing of these Guidelines.
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 2025
Disclosure statement
No potential conflict of interest was reported by the authors.
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