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The Journal of Maternal-Fetal & Neonatal Medicine
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Preterm Labor and Birth Management:Recommendations from the
European Associationof 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
Accepted author version posted online: 08May 2017.Published
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GUIDELINES
Preterm Labor and Birth Management: Recommendations from
theEuropean 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 andG. H. A. Vissero
aDepartment of Obstetrics and Gynecology, University of Perugia,
Perugia, Italy; bDepartment of Obstetrics and Gynecology,
HospitalVall D’Hebron, Barcelona, Spain; cMother–Infant Department,
School of Midwifery, University of Modena and Reggio Emilia,
Italy;dDepartment of Obstetrics and Gynaecology, General Hospital,
University of Vienna, Vienna, Austria; eDepartment of Obstetrics,
SaintLuc University Hospital, Universit�e de Louvain, Brussels,
Belgium; fDepartment of Obstetrics and Gynecology, Institute of
ClinicalSciences, 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,Denmark; iDivision of Surgery, University College
London, Northwick Park Institute of Medical Research Campus,
London, UK;jDepartment of Obstetrics and Gynecology, 1st Maternity
Hospital, State University of St. Petersburg, Russia; kDepartment
ofObstetrics and Gynaecology, Athens University School of Medicine,
Athens, Greece; lDepartment of Medicine, Peoples'
FriendshipUniversity of Russia, Moscow, Russia; mSt. Thomas
Hospital, Kings College London, UK; nService d'Obst�etrique et de
M�edecine Foetale,Hôpital Necker Enfants Malades, Paris, France;
oDepartment of Obstetrics, University Medical Center, Utrecht, The
Netherlands;pDepartment 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
These guidelines are based upon most recent andupdated evidence
and they are adapted to a Europeanperspective by an expert view of
the problem. Theseguidelines are not intended to be a meta-analysis
or asystematic review. They follow the previous guidelinespublished
in 2006 [1] and 2011 [2].
The syndrome, etiology, risk factors
The syndrome
Preterm delivery (PTD) is one of the most commonand 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
usingfirst trimester ultrasound, meaning that the practice
ofvalidation of maturity at birth is rare. Practically, thismeans
that it is adequate to stick to a terminologythat relates to
gestational age rather than maturity.The most relevant terminology
for the condition
should be PTD or preterm birth, rather thanprematurity.
In Europe, the PTD rate varies between 5–18%, withonly 0.3–0.5%
occurring before 28 weeks, obviouslywith a worse outcome. Outcome
also varies with thequality of neonatal care. When calculating the
fre-quency of PTD, it is important to note the number ofpregnancies
and not the number of children. However,some nations report the
number of babies born pre-term. Different approaches have been used
to copewith stratifications differences between different
popu-lations [7]. It is not the extremely preterm babies thatcreate
the highest burden for the society as they areinfrequent. It is the
children born between 32 and 36weeks. The “Intergrowth study” has
indicated that in aset of low-risk pregnant women, PTD frequency
isapproximately 4.5% [8]. To reduce the European PTDprevalence to
that level, different methods need to beused in a systematic
approach. One single method isunlikely to have significant impact
on a large group ofhigh-risk women. Such an approach needs to be
basedon a determined subset of both clinical and biologicalrisk
factors. Such an approach will be difficult to
CONTACT Gian Carlo Di Renzo [email protected]
Department of Obstetrics and Gynecology, Centre for Perinatal and
ReproductiveMedicine, Santa Maria della Misericordia University
Hospital, 06132 San Sisto, Perugia, Italy� 2017 Informa UK Limited,
trading as Taylor & Francis Group
THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE, 2017VOL.
30, NO. 17,
2011–2030https://doi.org/10.1080/14767058.2017.1323860
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achieve but should be a highly prioritized researchproject. The
complex nature of PTD as an etiologicconcept might be clearer if
the perspective is furtherresearched.
It is logical to divide PTD into different subcatego-ries:
live-borns vs. intrauterine fetal deaths, singletonpregnancies vs.
multiple pregnancies and spontaneousPTD vs. iatrogenic PTD. About
80% of all the preterminfants are live born singletons. The
majority of thesedeliveries are spontaneous, due to onset of
contrac-tions or to spontaneously ruptured membranes.Conversely,
iatrogenic preterm deliveries are due tothe physician's decision to
induce labor for maternalor fetal medical reasons. However, since
the termin-ology varies, it is crucial to use clear definitions in
allcircumstances where the different phenotypical termsare used
[9].
Etiology
The main hypothesis of the etiology of spontaneousPTD is
ascending infection from the lower genital tractup in the sterile
uterus invading the decidua, cho-rioamniotic membranes, amniotic
fluid and, in somecases, the fetus. This is responsible for an
inflammatorycondition that might trigger myometrial
contractions,rupture of the membranes and cervical
maturationleading to PTD [4–6,10]. Investigations have shownthat
the amount of bacteria present in the amnioticfluid 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
tohistological 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]. Theterm “preterm parturition syndrome” has
beenlaunched to separate women with spontaneous pre-term labor
onset of delivery who are considered tohave a pathological
activation of the delivery process,from those with spontaneous
onset of delivery atterm, which is considered to be a normal
activation[10,11].
The dogma of the “sterile womb” has recently beenchallenged in a
groundbreaking study published inScience in 2014. Kjersti Aagaard
et al. suggested thatplacenta is not sterile and has a bacterial
flora moresimilar 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 reducethe lipopolysaccharide (LPS) inflammatory
response inplacental trophoblast cells [20].
Another approach for a better understanding of theetiology of
PTB is to study the relation between genet-ics and gestational age
at birth [21–23]. The heritabilityof both PTD and gestational age
is estimated to bearound 30%, however, only a very small fraction
ofvariability in gestational age could be explained bycurrently
known PTD-risk-increasing genetic polymor-phisms [24, 25].
Risk factors
The risk of spontaneous PTD correlates to
intrinsiccharacteristics of the mother; in fact it is
differentbetween racial and ethnic groups and it is related
toadvanced maternal age. In order to identify potentialwomen at
risk it is also important to assess maternallife style, level of
education and adequacy of prenatalcare, as well as
employment-related psychological andphysical stress. Furthermore,
maternal BMI, nutritionalstatus, chronic diseases (as hypertension,
diabetes mel-litus), intrauterine malformation or infections,
andendocrinological diseases have been linked with anincreased risk
of PTD.
Numerous studies have published risk factors forspontaneous PTD,
either from population or hospital-based datasets. One of the main
risk factors for PTD ismultiple pregnancy. Another is a previous
PTD. Manybehaviors influence the risk of PTD such as tobaccouse,
alcohol and illicit drug use. Other factors arethose related to
nutritional factors such as high intakeof sugar sweetened drinks
[26] and modern Westerndiet [27] which increases the risk of PTD,
whereasother nutritional factors are associated with adecreased
risk such as fish liver oil, probiotic milk, gar-lic and other leek
products. Other factors that arerelated 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 highmaternal
age, material status, race and ethnicity. Manymedical conditions
also increase the risk of PTD: differ-ent types of diabetes,
rheumatologic conditions andheart disease. Several population-based
and regis-tered-based studies have sought to create
risk-basedapproaches trying to predict PTD but there has onlybeen
limited success [28,29]. The most common clin-ical used risk factor
is that the women have had a pre-vious PTD.
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Identification of the preterm laboring womenwith or without
symptoms
Before undertaking any therapeutic strategy,
carefulidentification of women at risk for preterm labor
anddelivery is needed, so as to detect manageable condi-tions and
fetal and/or maternal contraindications.
Methods to identify symptomatic women at riskfor preterm
delivery
Symptoms reported by patients with suspected pre-term labor are:
pelvic pain, vaginal discharge, backpain, and menstrual-like
cramps.
In most countries the identification of preterm laboris based
only on clinical subjective data. This increasesthe risk of
hospitalization and of costs and of unneces-sary and potentially
harmful interventions such as theuse of tocolysis and of prenatal
corticosteroidsadministration.
To improve the accuracy of the diagnosis of threat-ened PTD in
symptomatic women, two methods havebeen proposed:
� Transvaginal ultrasound cervical lengthmeasurement;
� Measurement of fetal fibronectin (fFN)/PAMG1/IGF-BP 1 in
cervical-vaginal secretions.
Transvaginal ultrasound cervical lengthmeasurement
Cervical length is predictive of preterm birth in
allpopulations, including asymptomatic women withprior cone biopsy,
mullerian anomalies, or multipledilation and evacuations. Cervical
length remains themost predictive measurement, but funneling may
addto its predictive value in some populations. In terms
ofinterventions aimed at preventing preterm birth oncea short
cervical length has been identified in asymp-tomatic women, recent
data from a meta-analysisof all trials published so far point to
the benefit ofultrasound-indicated cerclage in women with both
aprior preterm birth and a cervical length less than25mm [30].
Because the presence of certain biomarkers or of ashort cervix
have been independently associated withPTD, the utility of
biomarker testing in combinationwith cervical length measurement
using transvaginalultrasound has been examined to improve the
clinicalability to diagnose preterm labor and predict immi-nent
spontaneous PTD in symptomatic women[31,32].
In symptomatic women, both qualitative and quan-titative fetal
fibronectin in cervico-vaginal secretionshave been separately shown
not to improve the pre-diction of delivery within 7 days compared
to thesonographic 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 thatknowledge of
fetal fibronectin status or cervical lengthmay help health care
providers to reduce the use ofunnecessary resources; however, these
findings havenot been confirmed by randomized trials [34,35].
Thepositive predictive value of most biomarker test resultsor a
short cervix alone are poor and it has been rec-ommended that
neither should be used exclusively todirect management in the
setting of acute symptoms[36,37].
Fetal fibronectin (fFN)
Qualitative fFN detection. Fetal fibronectin (fFN) is anisoform
of fibronectin with a unique III-CS region, anda component of the
extracellular matrix of the mem-branes making up the amniotic sac,
confined to theinterface between the maternal and fetal units. fFN
isfound in amniotic fluid, placental tissue, and the extra-cellular
component of the decidua basalis adjacent tothe placental
intervillous space. The test is available intwo primary formats
(Hologic, Marlborough, MA). Inboth, a cervicovaginal specimen is
collected via aspeculum examination and is then mixed with a
liquidbuffer in a collection tube. In the case of Rapid fFN (orFull
Term) a portion of this sample is pipetted to thelateral-flow,
rapid fFN cassette in the TLi IQ analyser.The assay takes
approximately 30min to process thesample and deliver the results.
The TLi automaticallyprints and displays positive or negative
results alongwith patient details. In the case of QuikCheck, a
dip-stick test is directly inserted into the tube for 10min,after
which it is removed and the results are read aseither negative or
positive depending on the presenceone or two lines, respectively.
For both tests, an fFNlevel of �50 ng/ml is a positive result and
an fFN levelof
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may be highest for predicting PTB within 7–10 days oftesting
[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 reducingpreterm labor hospital admissions,
length of stay andprescriptions of tocolytic agents by
approximately40%, the American College of Obstetricians
andGynecologists (ACOG) concluded that although theresults of
observational studies have suggested thatknowledge of fFN or
cervical length may help healthcare providers to reduce the use of
unnecessaryresources [34,35], these findings have not been
con-firmed by randomized trials [39–41].
Quantitative fFN detection. Most recently, a quantita-tive
bedside fetal fibronectin test has been devel-oped, and while one
study has demonstratedenhanced clinical utility compared with the
traditionalqualitative test another has concluded that
quantita-tive fFN testing does not improve the prediction ofPTB
within 7 days compared with qualitative fFN test-ing in combination
with CL measurement in terms ofreclassification from high to low
(
-
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-1test provided a
97.4% and 93.6% NPV, 78.3% and87.0% PPV, 90.0% and 80.0%
sensitivity and 93.8% and96.1% 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 recruitedpatients, the authors reported
sensitivities of 80% and50%, specificities of 95% and 72%, NPVs of
96%, and87%, and PPVs of 76% and 29%, for PAMG-1 and
fFN,respectively [51]. Another study in 49 patients reportedthat
the PAMG-1 test predicted sPTB within 14 dayswith 100% SN, 98% SP,
75% PPV and 100% NPV [52].Werlen et al. confirmed a high
specificity (97.5% [CI95%; 86.8–99.9]) and NPV (97.5% [CI 95%;
86.8–99.9])of the test and suggested that test results may not
beaffected by vaginal examination, thus possibly provid-ing an
advantage over other methods in that thePAMG-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
ofmoderate to gross vaginal bleeding, neither testshould be used.
In the presence of trace amounts ofblood, however, either test can
be used.
Methods to identify asymptomatic women at riskfor preterm
delivery
In case of asymptomatic pregnancies, cervicometry canbe applied
as screening and has been proposed as auniversal screening in
singleton gestations without aprevious preterm birth [55]. It is
recommended to beperformed in the second trimester at 18–23 weeks
ofgestation. The finding of a cervical length (CL)< 2.5 cmis
associated with an increased risk of subsequent PTBwith a
sensitivity between 30 and 60%.
The PAMG-1 biomarker has shown it to be useful indiagnosing
cases where CL is between 15 and 30mmwhere the predictive value of
CL is lowest. Becausethe predictive accuracy of CL measurement
declineswith increasing cervical length, the high PPV of PAMG-1
(75% for CL< 25mm and 76% for CL � 25mm) is ofparticular
interest. This may indicate that when resultsare acted upon
consistently, the use of the PAMG-1biomarker in conjunction with
cervical length meas-urement, could provide both clinical and
economicbenefits [51].
Main points
1. The use of cervical length measurements and ofbiochemical
markers, especially if combined,
improves identification of patients at risk for immi-nent
spontaneous PTD as compared to clinicalsymptoms alone (i.e. vaginal
bleeding, contractionfrequency/duration, cervical dilation, etc.).
A cer-vical length equal or inferior of 25mm in single-ton
pregnancy is the cutoff value mostly utilizedto identify patients
at high risk of deliverypreterm.
2. Of the available biochemical tests, that based onfetal
fibronectin (fFN) has been the best character-ized. However, the
value of this test, like that ofphosphorylated insulin-like growth
factor protein-1 (phIGFBP-1) and cervical length (CL) measure-ment
alone, may be limited only to its negativepredictive value (NPV),
given its poor positive pre-dictive value (PPV).
3. As is the case with CL ranges, quantification offFN may
provide additional value in stratifying therisk of spontaneous PTD
in women with symp-toms of preterm labor. However, as is the
casewith patients with CL less than 1.5 cm, the preva-lence of
women with an elevated concentration offFN (�500 ng/ml) who would
be at the greatestrisk of imminent spontaneous delivery may be
toolow to provide practical value to clinicians, giventhe cost of
the test and the difficulty of assessingthe risk level at lower
concentrations.
4. While CL less than 1.5 cm and above 3.0 cm hashigh predictive
value, to identify patients at riskor to exclude the risk, the
majority of patientspresenting with symptoms of preterm labor
haveCL within these limits. Thus, we recommend theuse of
transvaginal ultrasound to measure cervicallength (CL) in patients
presenting with symptomsof preterm labor in order to assess their
risk ofimminent spontaneous PTD. In patients where theCL is between
1.5 and 3.0 cm, we recommend theuse of a biomarker test with the
highest combin-ation of NPV and PPV that can be run shortlyafter a
vaginal examination. According to recentliterature, 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
transvaginalultrasonography is the most powerful predictor of
PTD[56]. Prediction of preterm birth varies widely depend-ing on
several factors: number of fetuses, obstetric
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history, symptoms of threatened preterm labor andgestational age
at screening. The most accepted cer-vical length cutoff is
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was underpowered to determine real the effect of pro-gesterone
in the prevention of preterm birth inwomen with a short cervix. The
interaction termapproached statistical significance (p¼ .051) for
theneonatal outcome in the subgroup with a history of aprevious
spontaneous preterm birth, where the OR(95% CI) for the neonatal
outcome was lower in theprogesterone group (0.49, 0.30, 0.80);
compared with1.20 (0.56, 2.59) in the complementary group with
noprevious spontaneous preterm birth.
In the most recent NICE guidelines (November2015) it is
recommended to offer prophylactic vaginalP4 to women with no
history of spontaneous pretermbirth or mid-trimester loss in whom a
transvaginalultrasound scan has been carried out between 16þ 0and
24þ 0 weeks of pregnancy that reveals a cervicallength of less than
25mm. It is also recommended tooffer a choice of either
prophylactic vaginal P4 (orprophylactic cervical cerclage) to women
with a historyof spontaneous preterm birth or mid-trimester
lossbetween 16þ 0 and 34þ 0 weeks of pregnancy and inwhom a
transvaginal ultrasound scan has been carriedout between 16þ 0 and
24þ 0 weeks of pregnancythat reveals a cervical length of less than
25mm. Thebenefits and risks of prophylactic P4 and cervical
cerc-lage need to be discussed with the woman taking herpreferences
into account.
Still controversial, however, is the efficacy of
eitherprogestogens in single pregnant symptomatic womenwith a short
cervix for the so-called secondary ormaintenance tocolysis. Areja
et al. in 2013 [74] andMartinez 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 wasnot
objectively measured, reached opposite conclu-sions [76]. Another
meta-analysis comparing 17 P toplacebo/no intervention did not show
efficacy of pro-gestogen in reducing PTB [77]. Even in this last
studyinclusion criteria did not require an objective cervicallength
measurement.
As far as twin gestation is concerned, a meta-analysisbased on
individual participant data from 13 random-ized clinical trials
demonstrated that treatment withprogestogens (either intramuscular
17-OHP-C or vaginalnatural P4) does not prevent preterm birth, nor
improveperinatal outcome in unselected women with anuncomplicated
twin gestation [78]. However, vaginalprogesterone may be effective
in the reduction ofadverse perinatal outcome of twins in women with
acervical length of �25mm. Also the results of
individualparticipant data analysis from randomized trials
demon-strated the increased incidence of adverse perinatal
outcomes in a subgroup of women with a cervicallength >25mm
treated with intramuscular 17OHP-C[79].
Recommendations. Women with prior history of PTBor late second
trimester abortion should be offered 17OHP-C weekly injection
starting early in the 2nd tri-mester or vaginal progesterone based
on individualbenefits/risks evaluation with the patient. It should
benoted that intramuscular 17 OHP-C has been found toincrease by
three times the incidence of gestationaldiabetes in the treated
population of pregnantwomen.
Asymptomatic women with a sonographically shortcervix (�25mm)
regardless of their obstetrical historyshould be offered vaginal
progesterone treatment forthe prevention of preterm birth and
neonatal morbid-ity. Two forms of vaginal micronized progesterone
canbe used daily: 200mg vaginal soft capsules or 90mgvaginal gel
[57].
In symptomatic women undelivered after an epi-sode of PTL the
efficacy of progestagens remain to beclarified.
Based on current evidence, the use of vaginal P4 intwin
pregnancies is recommended when the cervix isfound shorter than
25mm. There is now evidence of aclear benefit on the neonatal
outcome. 17-OHP-Ctreatment should not be used in twin
pregnancies.
Cervical cerclage
Cervical cerclage aims to reinforce cervical integrityand keep
it closed, to prevent or treat cervical insuffi-ciency and reduce
the rate of late miscarriage andPTB.
A meta-analysis of randomized trials has demon-strated that
cerclage does not prevent preterm birthin all women with short
cervical length on transvaginalultrasonography. However, in the
subgroup of single-ton gestations with a previous spontaneous PTB
theplacement of a cervical cerclage showed a significantreduction
in the risk of PTB and a decrease in the riskof perinatal morbidity
and mortality [80]. In cases witha history of three or more late
abortions, or PTD, inde-pendently from cervical length, cerclage
performed inthe first half of pregnancy was associated with a
lowerrate of PTD, although there were no differences infetal or
neonatal outcome [81].
An individual patient data meta-analysis of random-ized trials
of twin pregnancies where women with ashort cervix were randomized
to cerclage vs. no-cerc-lage showed no significant differences in
the rate ofpreterm birth
-
low birthweight and of respiratory distress syndromewere
significantly higher in the cerclage than in thecontrol 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
havesimilar outcomes if they receive either transvaginalultrasound
cervical length screening with ultrasound-indicated cerclage for
cervical length 25mm or less orplanned history-indicated cerclage
in the subsequentpregnancy. Less than 50% of the transvaginal
ultra-sound cervical length screening group required arepeat
ultrasound-indicated cerclage in the subsequentpregnancy [83,84].
Singleton gestations in women withprior preterm birth may be
monitored safely with a pol-icy of transvaginal ultrasound cervical
length screeningas compared with a policy of routine
history-indicatedcerclage. Cerclage can be reserved for the
minority ofwomen who develop a short cervical length. An
indirectmeta-analysis of randomized controlled trials showedthat
cervical cerclage and vaginal P are equally effica-cious in the
prevention of preterm birth, in womenwith a sonographically short
cervix and previous pre-term birth [85]. However, taking into
considerationadverse events the trials revealed that cervical
cerclagewas associated with a higher rate of maternal sideeffects
(pyrexia, vaginal discharge and bleeding) andlarger number of
cesarean deliveries [86].
Recommendation. Women with prior spontaneous pre-term birth,
singleton gestation, and transvaginal ultra-sound cervical length
of less than 25mm before 24weeks, should be offered the placement
of cervical cerc-lage or vaginal P4 for the prevention of preterm
birthand 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 thecervix is used
to change cervix direction toward thesacrum and to relieve direct
pressure on the internalcervical os by distributing the weight of
the pregnantuterus 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 cervicalpessary in
non-symptomatic patients, in singletonpregnancies 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 PTDoccurred more
frequently in the pessary (9.4%) inrespect with the control group
(5.5%) [88].
Two multicenter RCTs performed in almost 2000unselected twin
pregnancies reported that cervicalpessary did not significantly
reduce the rate ofpreterm birth [89,90]. A recently published RCT
con-ducted on 137 women with a sonographic cervicallength�25mm
showed that the insertion of a cervicalpessary was associated with
a significant reduction inspontaneous preterm birth in twin
gestation [91].These data, however, are in contrast with a
subgroupanalysis of 214 patients with short cervix from one ofthe
previous study in which no benefit of cervical pes-sary was
reported [90]. Some of these differences inresults may be
attributed to the lack of proper trainingin placing the pessary in
some protocols.
Recommendation. Although promising and with apotentially
favorable cost-benefit ratio, current evi-dence is conflicting
regarding the usefulness of cer-vical pessary in women with a short
cervix, in eithersingleton or twin gestation. There is a need for
furtherRCTs to clarify this point. Proper training to apply
thepessary should be homogenised and encouraged infurther
investigations.
Tocolysis
Women who present with signs and symptoms oflabor frequently
will not deliver in the short term andmany will continue to full
term, even in the absenceof interventions. Women with risk factors
will usuallynot deliver preterm. Conversely, even women whoreceive
prophylactic interventions may still deliverearly. Improved
prediction in all these groups wouldbe clinically beneficial, to
target preventative interven-tions, to select those women who
should be admittedto a hospital with neonatal care facilities, and
there-fore, triage the need for prenatal transfers as well asthat
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 twogoals:
� To gain time for antenatal corticosteroids tobecome
effective;
� To gain time, to allow in utero transfer to a hospitalwith
intensive care and newborn intensive careunits [92–97].
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Indications
� Onset of labor: Regular contractions (not less than4 per
20min) at a gestational age of 22 to 33weeks þ6 days;
� Dynamic changes in the cervix (shortening andeffacement,
increasing speed of dilatation) [98].
Tocolytic drugs
Currently licensed drugs for tocolysis include beta-agonist,
oxytocin receptor antagonists. Prostaglandinsynthetase inhibitors
have restrictions in usage. Thereis no evidence for the
effectiveness of magnesiumsulfate.
There is no evidence about advantage of one toco-lytic drug in
comparison with others in prolongationof pregnancy.
Drugs combination is used in exceptional cases as itincreases
the risk of side effects [92,97,99–102].
Licensed tocolytic agents
Beta-agonists
The effects of beta-agonists (ritodrine, fenoterol) onthe
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, fetaltachycardia and acute hypoxia, etc. Administration
ofbeta-agonists causes myometrium relaxation by theirbinding to 2-b
adrenergic receptors and increasinglevel of intracellular cyclic
adenosine monophosphate,which in turn activates protein kinase,
blocks myosinlight-chain kinase and inhibits the contractile
activityof the myometrium.
These tocolytic drugs penetrate trough placentabarrier and can
cause fetal tachycardia and hypogly-cemia, in some cases
hyperinsulinemia after birth.They are not indicated for prolonged
treatment due tosignificant 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 doseper minute.
Hexoprenaline sulfate administration is rec-ommended in two stages:
10mcg intravenous bolusadministration and 10mcg in 500ml isotonic
solutionintravenously (one or two courses). When using infusionpump
75mcg of infusion concentrate (3 vials) is dilutedin 50ml of sodium
chloride isotonic solution; the rate ofadministration should be
0.075 g/min. Fenoterol isadministrated intravenously (solution is
prepared extempore, diluting in 5% dextrose, xylitol, 0.9%
sodium
chloride solution or Ringer's solution) at initial dose
of50mg/min, the maximum injection rate is 300 g/min.
Administration of beta-agonists requires:
� Mother’s heart rate control every 15min;� Mother’s bp
monitoring every 15min;� 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 placentaabruption, 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 toblock
oxytocin receptors, which decreases myometrialtonus and reduces
contractility of the uterus with nodangerous side effects: dyspnea,
mother’s tachycardiaand fetal heart rate disorders. Tocolytics of
this group– Tractocile (AtosibanVR ) – inhibit vasopressin effects
bybinding to its receptors but have no effect on the
car-diovascular system [95,96,103–105].
Tocolysis with atosiban should start immediately atdiagnosis of
“the onset of preterm labor”. The therapyis carried out in three
stages:
1. First intravenous administration of 1 vial (0.9ml) ofthe drug
without dilution (initial dose – 6.75mg for1 min)
2. Immediately thereafter infusion of atosiban iscarried out for
3 h at dose 300 lg/min (rate ofadministration – 24ml/h, the dose of
atosiban –18mg/h);
3. Atosiban then infused at a dose of 100 lg/min(rate of
administration – 8mg/h) up to 45 h.
An absence of systemic effect on the mother andfetus, as well as
the dangerous side effects for themother and premature neonate
distinguishes antago-nists of oxytocin receptors from other
tocolytic drugs[98,99,105,106]. This fact determines its
advantage
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over other tocolytic agents and suggests its use as afirst-line
drug [103–105]. Safety for mother and fetusmakes it possible to use
this type of tocolytics atoutpatient stage and during transfer to
obstetricalunits 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 anadvantage of the nifedipine
therapy (ff-1a). Nifedipineis administrated in the dosage regimen:
3 doses of20mg every 30min per os, followed by sublingualintake
20–40mg every 4 h until 48 h after beginning ofthe therapy.
Recommended nifedipine tocolysis: monitoring
� Continuous monitoring of fetal heart rate whileuterine
contractions;
� Mother’s heart rate and blood pressure controlevery 30min
during the first hour, then every hourfor 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 uteroplacentalblood flow,
fetal distress (tachycardia).
Limited application tocolytic agents
Prostaglandin synthetase inhibitors
The mechanism of tocolytic action of prostaglandinsynthetase
inhibitors (aspirin, indomethacin, diclofe-nac) is based on
blocking the synthesis of prostaglan-dins [108].
Indomethacin or diclofenac is used as 100mg rectalsuppositories.
The same dose should be repeated inone hour, then – 50mg every 4–6
h during 48 h. Thetotal dose should not exceed 500mg and the
treat-ment duration should be no more than 5 days.Indomethacin is
recommended only for pregnanciesbetween 22 and 32 weeks.
The advantages of prostaglandin synthetase inhibi-tors for
tocolysis:
1. Indomethacin or diclofenac should be prescribedonly if the
amniotic fluid index is normal.
2. Before starting tocolysis, amniotic fluid volumeshould be
measured and controlled in 48–72 h. Incase of oligohydramnios, the
therapy should be
discontinued or, in certain cases, the dose shouldbe
reduced.
If necessary, the treatment may be repeated after a5-day break.
The therapy should be discontinued ifuneffective to stop labor.
Maternal contraindications: blood-clotting disorders,compromised
liver function, asthma, and aspirinallergy.
Fetal contraindications: growth restriction, kidneyanomalies,
chorioamnionitis, oligohydramnios, heartdefects involving the
pulmonary trunk and twin–twintransfusion syndrome.
The effects of indomethacin and of other medicalproducts of this
class on a human fetus in the 3rd tri-mester of pregnancy include:
intrauterine prematureclosure of the ductus arteriosus,
insufficiency of the tri-cuspid valve and pulmonary hypertension,
non-closureof the ductus arterious in the postnatal period,
resist-ant to drug correction, degenerative myocardialchanges,
platelet disorders that cause bleeding, intra-cranial bleeding,
renal dysfunction or failure, kidneydamage/developmental defect
which can lead to renalfailure, oligohydramnion, gastrointestinal
bleeding orperforation, increased risk of necrotizing
enterocolitis.FDA pregnancy risk category: �. During the
indometh-acin therapy, the pulmonary trunk blood flow shouldbe
checked and the severity of regurgitation at thelevel of the
tricuspid valve should be assessed. At leastonce a week, the study
should be repeated and thetherapy should be discontinued when the
shuntingreduces. 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 atocolytic agent,
because its efficacy is not proven.Magnesium sulfate may be
prescribed for the purposeof neuroprotection to prevent ICP in
neonates after apatient is taken to hospital [110,111].
Contraindications to tocolysis
A pregnancy of 34 full weeks; preterm rup-ture of fetal
membranes and a pregnancy of >32weeks; fetal growth restriction
and/or signs of fetal dis-tress; chorioamnionitis; premature
detachment of pla-centa; cases where it is not reasonable to
prolongpregnancy (eclampsia, preeclampsia, serious extrageni-tal
diseases of the mother); fatal fetal developmentaldefects;
intrauterine infection or suspected intrauterine
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infection; antenatal fetal death; suspected incompetentuterine
scar; dilatation of the orifice of the uterus for4 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
Antenatal corticosteroids given to mothers with antici-pated PTD
will improve survival, reduce the risk ofrespiratory distress
syndrome (RDS), necrotizingenterocolitis and intraventricular
hemorrhage and asingle course does not appear to be associated
withany significant maternal or short-term fetal adverseeffects.
The beneficial effects of antenatal steroidswere similar in studies
conducted in the 1970 s as inthose conducted more recently implying
that theyremain beneficial in the presence of modern neonatalcare
[113]. Prenatal corticosteroid therapy is recom-mended in all
pregnancies with threatened pretermlabor below 34 weeks’ gestation
where active care ofthe newborn is anticipated. Although there are
limitedrandomized controlled trial (RCT) data in babies 20 [117].
Follow-updata on term babies exposed to antenatal steroids
islimited.
The optimal treatment to delivery interval is morethan 24 h and
less than 7 days after the start of steroidtreatment; beyond 14
days the benefits are diminished.There is a continuing debate as to
whether steroidsshould be repeated one or two weeks after the
firstcourse for women with threatened preterm labor.Such repeat
courses do not reduce the risk of neonatal
death nor of long-term morbidity, but reduce RDS andother
short-term health problems, although birthweight is reduced and
long-term beneficial effects arelacking [118]. The WHO recommend
that a singlerepeat course of steroids may be considered if
pretermbirth does not occur within 7 days after the initialcourse
and subsequent assessment demonstrates thatthere is a high risk of
preterm birth in the next 7 days[119]. It is unlikely that repeat
courses given after 32weeks’ gestation improve outcome and recent
long-term follow-up studies show no benefit by school agein terms
of reduction in death or disability if repeatcourses are used
[120].
Betamethasone is likely to be more effective thandexamethasone,
but it also has more side-effects. Itreduces fetal body and
breathing movements and fetalheart rate variation for about 1–3
days, without evi-dence for an impaired fetal condition [121].
Dueaccount for this phenomenon has to be given whenmonitoring the
fetal condition. Betamethasone doesnot induce heart rate
decelerations, nor does it affectfetal Dopplers [122].
A cautionary note – a recent RCT from low tomedium income
countries showed a higher neonatalmortality and maternal infection
rate in women givenprenatal steroids [123,123]. The majority of
babieswere >2 kg at birth and these data emphasize theimportance
of adequate dating of duration of preg-nancy and of assessment of
risk of preterm birthbefore 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 fetaland placental growth, apoptosis
in the brain andincreased infection risks may prevail [e.g.
125–127].The use of steroids should be reduced by adequatepreterm
birth risk assessment and by avoidance ofearly elective CS.
Cervical length measurement, incombination with PAMG-1 testing can
help to deter-mine which women are at low risk of delivery within7
days, and perhaps allow more judicious use of ante-natal treatments
[128]. In some cases when an earlyCS is needed establishment of
fetal lung maturity maybe 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 whenpregnancy is
considered potentially viable up to 34completed weeks’
gestation
A single repeated course of antenatal steroids maybe appropriate
if the first course was administered
1The section on antenatal corticosteroids is largely based on
the recentEuropean Consensus Guidelines on the Management of
NeonatalRespiratory Distress Syndrome – 2016 update [112].
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more than 1–2 weeks prior and the duration of preg-nancy is
-
clindamycin may be more beneficial across a widerrange of
subtypes of BV [133]. In addition, rescreen-ing and retreating with
clindamycin may be beneficialand clindamycin is anti-inflammatory
as well as anti-microbial. The presence or absence of
lactobacillusphage viruses may also affect the efficacy of
clinda-mycin or metronidazole [133].
Finally, in an antenatal screen-and-treat program ofover 20,000
women between 10 and 16 weeks to pre-vent preterm birth, vaginal
candidiasis, and trichomon-iasis treated appropriately, and BV
treated withclindamycin vaginal cream reduced the rate of PTBand
low birth weight from 22.3% and 20% in controlsto 9.7% and 8.4% in
the intervention group respect-ively (p¼ .001) [136].
Recommendations
� Pregnant women symptomatic for vaginal candidia-sis,
trichomoniasis or BV should be treated.
� The case for routine screening of all pregnant womenis not yet
established but there is sufficient equipoisefor this to be
addressed in a research context.
� Before 20 weeks gestation, high-risk women with aprevious PTB
of infectious etiology before 34 com-pleted weeks, should be
counseled and eitherscreened for vaginal dysbiosis or offered
antibioticprophylaxis.
� 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 therisks versus benefits of antibiotic prophylaxis.
� There is increasing evidence to support the use ofclindamycin
over metronidazole for prophylaxis,but whether this should be
intravaginal or oral clin-damycin (or both) remains unanswered.
� Future systematic reviews and meta-analyses oftreatment of BV
in pregnancy should exclude trialswhere 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 includedand care should be taken that
arbitrary gestationalage cutoff points do not exclude important
studies.
� Future studies should use neonatal outcomes asthe primary
endpoints rather than the surrogate ofa specific preterm
gestational age.
� In future studies, when calculating a priori samplesize, it
should be remembered that BV in early preg-nancy, whether this
resolves spontaneously or fol-lowing antibiotic treatment, is still
associated withan adverse outcome rate above that in women whodid
not have BV at baseline. An assumption that
resolution of BV will result in an outcome rate thesame as women
without BV at baseline will result inan overestimate of the benefit
of treating BV and anunderestimate 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 dependson many factors including
perinatal management butalso gestational age, corticosteroid
administration,presence of chorioamnionitis, and
multiplepregnancies.
In order to reduce the incidence of intrapartumhypoxia
associated with prematurity and a possiblelong labor, a policy of
elective cesarean section (CS)has been recommended in the eighties
even if therewas no medical evidence to support it [137].
Vaginal delivery in preterm labor
In low and extremely low birth weight with vertexpresentation,
there is no clear correlation between thedelivery mode and neonatal
complications incidence.Survival rate and neonatal outcome of
singletons witha birth weight lower than 1500 g are either not
differ-ent after CS and vaginal delivery (VD) [138–140] or
arebetter 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 toCS (OR 6.2; 95% CI
1.3–30.1) confirming that in theabsence of fetal and obstetrical
indications, vaginaldelivery 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 isassociated with a higher
rate of cesarean sections. Thismode of delivery increases the
survival rate of thesmall – for-gestational age (SGA) neonates
below 31weeks but not that of SGA >33 weeks [145]. In
vertexsingletons with a birth weight lower than 1500 g, CSdelivery
decreases the neonatal mortality rate of thegrowth restricted
newborns [139,141].
In previable infants between 22 and 25 weeks ofgestation,
independently of the risk cofactors, CS couldbe associated with a
better neonatal outcome[146,147].
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In breech preterm deliveries, data are conflicting:one
retrospective study done on preterm breechbetween 24 and 37 weeks
reports a lower arterial pHafter VD but no difference for transfer
rate in neonatalintensive care [148]. A multicenter randomized
con-trolled trial comparing different modes of delivery forpatients
with preterm breech labor showed non-con-clusive results because of
low recruitment [149]. Arecent systematic review based on 7 studies
concludedthat 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 effectof CS is
unclear: in one study, regardless the presenta-tion, CS
significantly reduces the rate of intraventricu-lar hemorrhage but
does not affect adverse neonataloutcome and mortality [151]. In a
multicenter retro-spective study, there is no significant
difference in theneonatal mortality and morbidity rate after VD or
CS[152]. Then, vaginal delivery could be safely consideredin
preterm vertex twins. For a non-vertex presentingtwin, most
guidelines recommend elective CS.
Instrumental delivery in preterm labor
Vacuum delivery in preterm fetuses is associated withan
increased risk of intracranial hemorrhage due tovenous sinuses
fragility [153]. However, a retrospectivestudy comparing the
outcomes of preterm infants(between 1500 and 2.499 g) delivered by
vacuumextraction compared to normal vaginal delivery did notshow
any significant difference in neonatal morbidity[154]. In a
retrospective study comparing the outcomeof late preterm infants
(31 to 34 weeksþ4) deliveredby forceps and vacuum delivery, there
was no differ-ence between the two groups suggesting that
bothinstruments are safe options in the hands of experi-enced
obstetricians [155]. A Swedish population-basedcohort study
reported increased rates of cerebral hem-orrhages and Erb’s palsy
following vacuum delivery inpreterm infants compared with CS or
normal VD deliv-eries [156]. Guidelines issued from the Royal
College ofObstetrics and Gynecology do not recommend the useof
vacuum extraction below 34 weeks and considerthat the safety has
not clearly ben established between34þ 0 and 36þ 0 weeks [157].
Recommendations
Preterm gestational age alone is not a valid indicationfor CS,
unless if there are specific obstetricalindications.
Vaginal delivery appears to be safe and the goldstandard 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 growthrestriction, breech presentation and
in twins with anon-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 risksare clearly increased in case of
CS.
Instrumental delivery is not recommended in pre-term infants.
However, if necessary, a low forcepsdelivery should be preferred to
vacuum extractionbelow 34 weeks.
Delayed cord clamping
Delayed umbilical cord clamping in neonates born pre-term is
associated with less need for red blood celltransfusions, increase
in hemoglobin and hematocritlevels and decrease in risk of
intraventricular hemor-rhage and necrotizing enterocolitis. No
maternal orneonatal risks have been demonstrated. Data on long-term
outcomes are lacking. The optimal time to delaycord clamping and
potential risks are poorly studied[158]. One recent study in
infants born before 32weeks has shown that delaying clamping of the
cordfor slightly more than 30 s after the birth of the
infant,resulted in a three-fold reduction of a low Bayley scoreat
the age of 2 years [159]. Delayed cord clamping is asimple
procedure. It should therefore be applied,unless there are strong
contra-indications.
Recommendation
Delaying of clamping of the cord after the birth of apreterm
infant should strongly be considered.
Summary of recommendations
� Proper identification of patients at risk or in truepreterm
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 ofobstetrical history at 18–23 6/7
weeks of gestationusing transvaginal ultrasound
� Cervical US measurement and PAMG1/QuantitativeFfn are best
tests for identifying the true pretermlaboring patient or excluding
preterm labor
� Asymptomatic women with a sonographically shortcervix (�25mm)
at mid gestation, either withsingleton or twin pregnancy and
regardless of
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their obstetrical history should be offered vaginalprogesterone
treatment for the prevention of pre-term birth and neonatal
morbidity.
� Detection of vaginal-cervical colonization by tricho-monas
vaginalis and candida albicans treatedappropriately reduce the
risks of preterm labor
� Vaginal dysbiosis in the form of bacterial vaginosisdetected
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 improveperinatal outcome,
although they are capable ofstopping contractions. If these drugs
are beingused, use them with a clear aim
(corticosteroidadministration and/or in utero transfer).
Moreover,use a tocolytic drugs with a low incidence ofmaternal
side-effects (Atosiban, maybe prostaglan-din inhibitor) in
well-selected cases and for theshortest time
� Be aware that no-responding to tocolysis mayimply 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
before32–34 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 obstetricalindications.
� Vaginal delivery appears to be safe and the goldstandard mode
of delivery for singleton and twinvertex preterm fetuses
� Caesarean section should be recommended in pre-term labor in
the presence of intrauterine growthrestriction, breech presentation
and in twins with anon-vertex presenting fetus. CS delivery is not
rec-ommended but could be discussed for previableinfants
� Instrumental delivery is not recommended in pre-term infants.
However, if necessary, a low forcepsdelivery should be preferred to
vacuum extractionbelow 34 weeks
� Delaying of clamping of the cord after the birth ofa 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.
Disclosure statement
No potential conflict of interest was reported by the
authors.
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