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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 online: 06 Jul 2017.

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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 giancarlo.direnzo@unipg.it 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

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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

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

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.

References

[1] Di Renzo GC, Cabero Roura L. European Associationof Perinatal Medicine-Study Group on Preterm Birth.Guidelines for the management of spontaneous pre-term labor. J Perinat Med. 2006;34:359–366.

[2] Di Renzo GC, Roura LC, Facchinetti F, et al.Guidelines for the management of spontaneous pre-term labor: identification of spontaneous pretermlabor, diagnosis of preterm premature rupture ofmembranes, and preventive tools for preterm birth.J Matern Fetal Neonatal Med. 2011;24:659–667.

[3] Group E, Fellman V, Hellstrom-Westas L, et al. One-year survival of extremely preterm infants afteractive perinatal care in Sweden. JAMA. 2009;301:2225–2233.

[4] Romero R, Dey SK, Fisher SJ. Preterm labor: one syn-drome, many causes. Science. 2014;345:760–765.

[5] Rubens CE, Sadovsky Y, Muglia L, et al. Prevention ofpreterm birth: harnessing science to address the glo-bal epidemic. Sci Transl Med. 2014;6:262sr5.

[6] Muglia LJ, Katz M. The enigma of spontaneous pre-term birth. N Engl J Med. 2010;362:529–535.

[7] Morken NH, Vogel I, Kallen K, et al. Reference popu-lation for international comparisons and time trendsurveillance of PTD proportions in three countries.BMC Womens Health. 2008;8:16.

[8] Barros FC, Papageorghiou AT, Victora CG, et al. Thedistribution of clinical phenotypes of preterm birthsyndrome: implications for prevention. JAMA Pediatr.2015;169:220–229.

[9] Morken NH, Kallen K, Hagberg H, et al. Preterm birthin Sweden 1973–2001: rate, subgroups, and effect ofchanging patterns in multiple births, maternal age,and smoking. Acta Obstet Gynecol Scand.2005;84:558–565.

[10] Romero R, Espinoza J, Kusanovic JP, et al. The pre-term parturition syndrome. BJOG. 2006;113:17–42.

[11] Romero R, Espinoza J, Mazor M, et al. The pretermparturition syndrome. In: Critchely H, Bennett P,Thornton S, editors. Preterm birth. London: RCOGPress; 2004. p. 28–60.

[12] Jacobsson B, Aaltonen R, Rantakokko-Jalava K, et al.Quantification of Ureaplasma urealyticum DNA in theamniotic fluid from patients in PTL and pPROM andits relation to inflammatory cytokine levels. ActaObstet Gynecol Scand. 2009;88:63–70.

[13] Kacerovsky M, Pliskova L, Bolehovska R, et al. Themicrobial load with genital mycoplasmas correlateswith the degree of histologic chorioamnionitis inpreterm PROM. Am J Obstet Gynecol. 2011;205:213e1–217.

[14] Kacerovsky M, Musilova I, Khatibi A, et al.Intraamniotic inflammatory response to bacteria:analysis of multiple amniotic fluid proteins in womenwith preterm prelabor rupture of membranes.J Matern Fetal Neonatal Med. 2012;25:2014–2019.

THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 2025

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Purd

ue U

nive

rsity

Lib

rari

es]

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3:00

27

Sept

embe

r 20

17

[15] Cobo T, Kacerovsky M, Andrys C, et al. Umbilicalcord blood IL-6 as predictor of early-onset neonatalsepsis in women with preterm prelabour rupture ofmembranes. PLoS One. 2013;8:e69341.

[16] Musilova I, Kutova R, Pliskova L, et al. IntraamnioticInflammation in Women with Preterm PrelaborRupture of Membranes. PLoS One. 2015;10:e0133929.

[17] Aagaard K, Ma J, Antony KM, et al. The placenta har-bors a unique microbiome. Sci Transl Med. 2014;6:237ra65.

[18] Myhre R, Brantsaeter AL, Myking S, et al. Intake ofprobiotic food and risk of spontaneous pretermdelivery. Am J Clin Nutr. 2011;93:151–157.

[19] Brantsaeter AL, Myhre R, Haugen M, et al. Intake ofprobiotic food and risk of preeclampsia in primipar-ous women: the Norwegian Mother and ChildCohort Study. Am J Epidemiol. 2011;174:807–815.

[20] Yeganegi M, Watson CS, Martins A, et al. Effect ofLactobacillus rhamnosus GR-1 supernatant and fetalsex on lipopolysaccharide-induced cytokine andprostaglandin-regulating enzymes in human placen-tal trophoblast cells: implications for treatment ofbacterial vaginosis and prevention of preterm labor.Am J Obstet Gynecol. 2009;200:532 e1–538.

[21] Plunkett J, Muglia LJ. Genetic contributions to pre-term birth: implications from epidemiological andgenetic association studies. Ann Med. 2008;40:167–195.

[22] Plunkett J, Feitosa MF, Trusgnich M, et al. Mother'sgenome or maternally-inherited genes acting in thefetus influence gestational age in familial pretermbirth. Hum Hered. 2009;68:209–219.

[23] Pennell CE, Jacobsson B, Williams SM, et al. Geneticepidemiologic studies of preterm birth: guidelinesfor research. Am J Obstet Gynecol. 2007;196:107–118.

[24] Myking S, Boyd HA, Myhre R, et al. X-chromosomalmaternal and fetal SNPs and the risk of spontaneouspreterm delivery in a Danish/Norwegian genome-wide association study. PLoS One. 2013;8:e61781.

[25] Alleman BW, Myking S, Ryckman KK, et al. Noobserved association for mitochondrial SNPs withpreterm delivery and related outcomes. Pediatr Res.2012;72:539–544.

[26] Englund-Ogge L, Brantsaeter AL, Haugen M, et al.Association between intake of artificially sweetenedand sugar-sweetened beverages and preterm deliv-ery: a large prospective cohort study. Am J Clin Nutr.2012;96:552–559.

[27] Englund-Ogge L, Brantsaeter AL, Sengpiel V, et al.Maternal dietary patterns and preterm delivery:results from large prospective cohort study. BMJ.2014;348:g1446.

[28] Morken NH, Kallen K, Jacobsson B. Predicting risk ofspontaneous preterm delivery in women with asingleton pregnancy. Paediatr Perinat Epidemiol.2014;28:11–22.

[29] Di Renzo GC, Giardina I, Rosati A, et al. Maternal riskfactors for preterm birth: a country-based populationanalysis. Eur J Obstet Gynecol Reprod Biol. 2011;159:342–346.

[30] Grimes-Dennis J, Berghella V. Cervical length andprediction of preterm delivery. Curr Opin ObstetGynecol. 2007;19:191–195.

[31] Peaceman AM, Andrews WW, Thorp JM, et al. Fetalfibronectin as a predictor of preterm birth in patientswith symptoms: a multicenter trial. Am J ObstetGynecol. 1997;177:13–18.

[32] Skoll A, St Louis P, Amiri N, et al. The evaluation ofthe fetal fibronectin test for prediction of pretermdelivery in symptomatic patients. J Obstet GynaecolCan. 2006;28:206–213.

[33] Bruijn M, Vis JY, Wilms FF, et al. Quantitative fetalfibronectin testing in combination with cervicallength measurement in the prediction of spontan-eous preterm delivery in symptomatic women. BJOG.2016;123:1965–1971.

[34] Joffe GM, Jacques D, Bemis-Heys R, et al. Impact ofthe fetal fibronectin assay on admissions for pretermlabor. Am J Obstet Gynecol. 1999;180:581–586.

[35] Giles W, Bisits A, Knox M, et al. The effect of fetalfibronectin testing on admissions to a tertiary mater-nal-fetal medicine unit and cost savings. Am JObstet Gynecol. 2000;182:439–442.

[36] Berghella V, Hayes E, Visintine J, et al. Fetal fibronec-tin testing for reducing the risk of preterm birth.Cochrane Database Syst Rev. 2008;CD006843. doi:10.1002/14651858.CD006843.pub2.

[37] American College of Obstetricians and Gynecologists;Committee on Practice Bulletins—Obstetrics. ACOGpractice bulletin no. 127: Management of pretermlabor. Obstet Gynecol. 2012;119:1308–1317.

[38] Deshpande SN, van Asselt AD, Tomini F, et al. Rapidfetal fibronectin testing to predict preterm birth inwomen with symptoms of premature labour: a sys-tematic review and cost analysis. Health TechnolAssess. 2013;17:1–138.

[39] Plaut MM, Smith W, Kennedy K. Fetal fibronectin: theimpact of a rapid test on the treatment of womenwith preterm labor symptoms. Am J Obstet Gynecol.2003;188:1588–1593. discussion 1593-5.

[40] Grobman WA, Welshman EE, Calhoun EA. Does fetalfibronectin use in the diagnosis of preterm laboraffect physician behavior and health care costs? Arandomized trial. Am J Obstet Gynecol.2004;191:235–240.

[41] Ness A, Visintine J, Ricci E, et al. Does knowledge ofcervical length and fetal fibronectin affect manage-ment of women with threatened preterm labor? Arandomized trial. Am J Obstet Gynecol. 2007;197:426.e1–427.

[42] Akercan F, Kazandi M, Sendag F, et al. Value of cer-vical phosphorylated insulinlike growth factor bind-ing protein-1 in the prediction of preterm labor.J Reprod Med. 2004;49:368–372.

[43] Conde-Agudelo A, Romero R. Cervical phosphory-lated insulin-like growth factor binding protein-1 testfor the prediction of preterm birth: a systematicreview and metaanalysis. Am J Obstet Gynecol.2016;214:57–73.

[44] McLaren JS, Hezelgrave NL, Ayubi H, et al. Predictionof spontaneous preterm birth using quantitative fetal

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https://doi.org/10.1002/14651858.CD006843.pub2

fibronectin after recent sexual intercourse. Am JObstet Gynecol. 2015;212:89.e1–85.

[45] Petrunin DD, Griaznova IM, Petrunina IUA, et al.Immunochemical identification of organ specifichuman placental al-globulin and its concentration inamniotic fluid. Akush Ginekol. 1977;1:62–64.

[46] Lee SM, Lee J, Seong HS, et al. The clinical signifi-cance of a positive Amnisure test in women withterm labor with intact membranes. J Matern FetalNeonatal Med. 2009;22:305–310.

[47] Lee SM, Romero R, Park JW, et al. The clinical signifi-cance of a positive Amnisure test in women withpreterm labor and intact membranes. J Matern FetalNeonatal Med. 2012;25:1690–1698.

[48] Sukchaya K, Phupong V. A comparative study ofpositive rate of placental a-microglobulin-1 test inpre-term pregnant women with and without uterinecontraction. J Obstet Gynaecol. 2013;33:566–568.

[49] Ehsanipoor RM, Swank ML, Jwa SC, et al. Placentala-Microglobulin-1 in Vaginal Secretions of Womenwith Evidence of Preterm Labor. Am J Perinatol.2016;33:208–213.

[50] Nikolova T, Bayev O, Nikolova N, et al. Evaluation ofa novel placental alpha microglobulin-1 (PAMG-1)test to predict spontaneous preterm delivery.J Perinat Med. 2014;42:473–477.

[51] Nikolova T, Bayev O, Nikolova N, et al. Comparisonof a novel test for placental alpha microglobulin-1with fetal fibronectin and cervical length measure-ment for the prediction of imminent spontaneouspreterm delivery in patients with threatened pretermlabor. J Perinat Med. 2015;43:395–402.

[52] Bolotskikh VM, Borisova VY. Role of biochemical testsand cervicometry in the diagnosis of threatened pre-term birth. Akusherstvo i Ginekologiya/Obstetricsand Gynecology 2015;2:(in Russian). 127:384–389.

[53] Werlen S, Raia T, Di Bartolomeo A, et al. [Pretermlabor: Reproducibility of detection test of PAMG-1before and after digital examination, and transvagi-nal ultrasound cervical length]. Gynecol Obstet Fertil.2015;43:640–645. French.

[54] Revah A, Hannah ME, Sue-A-Quan AK. Fetal fibronec-tin as a predictor of preterm birth: an overview. AmJ Perinatol. 1998;15:613–621.

[55] Khalifeh A, Quist-Nelson J, Berghella V. Universal cer-vical length screening for preterm birth preventionin the United States. J Matern Fetal Neonatal Med.2017;30:1500–1503

[56] Mella MT, Berghella V. Prediction of preterm birth: cer-vical sonography. Semin Perinatol. 2009;33:317–324.

[57] FIGO Working Group On Best Practice In Maternal-Fetal Medicine; International Federation ofGynecology and Obstetrics. Best practice in mater-nal-fetal medicine. Int J Gynaecol Obstet. 2015;128:80–82.

[58] Simhan HN, Caritis SN. Prevention of preterm deliv-ery. N Engl J Med. 2007;357:477–487.

[59] Smith R, Walker MC, Ohlsson A, et al. Randomizeddouble-blind placebo-controlled trial of transdermalnitroglycerin for preterm labor. N Engl J Med. 2007;356:2066–2074.

[60] Ferre F, Uzan M, Janssens Y, et al. Oral administra-tion of micronized natural progesterone in latehuman pregnancy. Effects on progesterone andestrogen concentrations in the plasma, placenta, andmyometrium. Am J Obstet Gynecol. 1984;148:26–34.

[61] Baumbach J, Shi S-Q, Shi L, et al. Inhibition of uter-ine contractility with various tocolytics with andwithout progesterone: in vitro studies. Am J ObstetGynecol. 2012;206:254.e1–255.

[62] Chanrachakul B, Broughton Pipkin F, Warren AY,et al. Progesterone enhances the tocolytic effect ofritodrine in isolated pregnant human myometrium.Am J Obstet Gynecol. 2005;192:458–463.

[63] Noblot G, Audra P, Dargent D, et al. The use ofmicronized progesterone in the treatment of menaceof preterm delivery. Eur J Obstet Gynecol ReprodBiol. 1991;40:203–209.

[64] Meis PJ, Klebanoff M, Thom E, National Institute ofChild Health and Human Development Maternal-FetalMedicine Units Network, et al. Prevention of recurrentpreterm delivery by 17 alpha-hydroxyprogesteronecaproate. N Engl J Med. 2003;348:2379–2385.

[65] Saccone G, Khalifeh A, Elimian A, et al. Vaginal pro-gesterone compared to intramuscular 17-alpha-hydroxyprogesterone caproate for prevention ofrecurrent spontaneous preterm birth in singletongestations: a systematic review and meta-analysis ofrandomized controlled trials. Ultrasound ObstetGynecol. 2017;49:315–321.

[66] Fonseca EB, Bittar RE, Carvalho MH, et al.Prophylactic administration of progesterone by vagi-nal suppository to reduce the incidence of spontan-eous preterm birth in women at increased risk: arandomized placebo-controlled double-blind study.Am J Obstet Gynecol. 2003;188:419–424.

[67] Fonseca EB, Celik E, Parra M, Fetal MedicineFoundation Second Trimester Screening Group, et al.Progesterone and the risk of preterm birth amongwomen with a short cervix. N Engl J Med.2007;357:462–469.

[68] DeFranco EA, O'Brien JM, Adair CD, et al. Vaginalprogesterone is associated with a decrease in risk forearly preterm birth and improved neonatal outcomein women with a short cervix: a secondary analysisfrom a randomized, double-blind, placebo-controlledtrial. Ultrasound Obstet Gynecol. 2007;30:697–705.

[69] Hassan SS, Romero R, Vidyadhari D, PREGNANT Trial,et al. Vaginal progesterone reduces the rate of pre-term birth in women with a sonographic short cer-vix: a multicenter, randomized, double-blind,placebo-controlled trial. Ultrasound Obstet Gynecol.2011;38:18–31.

[70] Romero R, Nicolaides K, Conde-Agudelo A, et al.Vaginal progesterone in women with an asymptom-atic sonographic short cervix in the midtrimesterdecreases preterm delivery and neonatal morbidity:a systematic review and metaanalysis of individualpatient data. Am J Obstet Gynecol. 2012;206:124.e1–119.

[71] Grobman WA, Thom EA, Spong CY, Eunice KennedyShriver National Institute of Child Health and HumanDevelopment Maternal-Fetal Medicine Units (MFMU)

THE JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE 2027

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3:00

27

Sept

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17

Network, et al. 17 alpha-hydroxyprogesterone capro-ate to prevent prematurity in nulliparas with cervicallength less than 30mm. Am J Obstet Gynecol.2012;207:390.e1–398.

[72] Norman JE, Marlow N, Messow C-M, et al. Vaginalprogesterone prophylaxis for preterm birth (theOPPTIMUM study): a multicentre, randomised, dou-ble-blind trial. Lancet. 2016;387:2106–2116.Published Online February 23, 2016. http://dx.doi.org/10.1016/S0140-6736(16)00350-0.

[73] Romero R, Nicolaides KH, Conde-Agudelo A, et al.Vaginal progesterone decreases preterm birth �34weeks of gestation in women with singleton gesta-tion and a short cervix: an updated meta-analysisincluding data from the Opptimum Study.Ultrasound Obstet Gynecol. 2016;48:308–317.

[74] Areia A, Fonseca E, Moura P. Progesterone use aftersuccessful treatment of threatened pre-term delivery.J Obstet Gynaecol. 2013;33:678–681.

[75] Sentilhes L, S�enat MV, Ancel PY, et al. Prevention ofspontaneous preterm birth (excluding preterm pre-mature rupture of membranes): guidelines for clinicalpractice. J Gynecol Obstet Biol Reprod (Paris).2016;45:1446–1456.

[76] Suhag A, Saccone G, Berghella V. Vaginal progester-one for maintenance tocolysis: a systematic reviewand metaanalysis of randomized trials. Am J ObstetGynecol. 2015;213:479–487.

[77] Saccone G, Suhag A, Berghella V. 17-alpha-hydroxy-progesterone caproate for maintenance tocolysis: asystematic review and metaanalysis of randomizedtrials. Am J Obstet Gynecol. 2015;213:16–22.

[78] Schuit E, Stock S, Rode L, Global Obstetrics Network(GONet) collaboration, et al. Effectiveness of proges-togens to improve perinatal outcome in twin preg-nancies: an individual participant data meta-analysis.BJOG. 2015;122:27–37.

[79] Caritis SN, Simhan HN, Zhao Y, Eunice KennedyShriver National Institute of Child Health and HumanDevelopment Maternal-Fetal Medicine UnitsNetwork, et al. Relationship between 17-hydroxypro-gesterone caproate concentrations and gestationalage at delivery in twin gestation. Am J ObstetGynecol. 2012;207:396.e1–398.

[80] Berghella V, Odibo AO, To MS, et al. Cerclage forshort cervix on ultrasonography: meta-analysis of tri-als using individual patient-level data. ObstetGynecol. 2005;106:181–189.

[81] Story L, Shennan A. Cervical cerclage: an establishedintervention with neglected potential? Eur J ObstetGynecol Reprod Biol. 2014;176:17–19.

[82] Saccone G, Rust O, Althuisius S, et al. Cerclage forshort cervix in twin pregnancies: systematic reviewand meta-analysis of randomized trials using individ-ual patient-level data. Acta Obstet Gynecol Scand.2015;94:352–358.

[83] Suhag A, Reina J, Sanapo L, et al. Prior ultrasound-indicated cerclage: comparison of cervical lengthscreening or history-indicated cerclage in the nextpregnancy. Obstet Gynecol. 2015;126:962–968.

[84] Berghella V, Mackeen AD. Cervical length screeningwith ultrasound-indicated cerclage compared with

history-indicated cerclage for prevention of pretermbirth: a meta-analysis. Obstet Gynecol. 2011;118:148–155.

[85] Conde-Agudelo A, Romero R, Nicolaides K, et al.Vaginal progesterone vs cervical cerclage for the pre-vention of preterm birth in women with a sono-graphic short cervix, previous preterm birth, andsingleton gestation: a systematic review and indirectcomparison metaanalysis. Am J Obstet Gynecol.2013;208:42.e1–18.

[86] Alfirevic Z, Stampalija T, Roberts D, et al. Cervicalstitch (cerclage) for preventing preterm birth insingleton pregnancy. Cochrane Database Syst Rev.2012;4:CD008991.

[87] Goya M, Pratcorona L, Merced C, et al. Cervical pes-sary in pregnant women with a short cervix (PECEP):an open-label randomised controlled trial. Lancet.2012;379:1800–1806.

[88] Hui SY, Chor CM, Lau TK, et al. Cerclage pessary forpreventing preterm birth in women with a singletonpregnancy and a short cervix at 20 to 24 weeks: arandomized controlled trial. Am J Perinatol.2013;30:283–288.

[89] Liem S, Schuit E, Hegeman M, et al. Cervical pessa-ries for prevention of preterm birth in women with amultiple pregnancy (ProTWIN): a multicentre, open-label randomized controlled trial. Lancet. 2013;382:1341–1349.

[90] Nicolaides KH, Syngelaki A, Poon LC, et al. Cervicalpessary placement for prevention of preterm birth inunselected twin pregnancies: a randomized con-trolled trial. Am J Obstet Gynecol. 2016;214:3.e1–9.

[91] Goya M, de la Calle M, Pratcorona L, et al. PECEP-Twins Trial Group.Cervical pessary to preventpreterm birth in women with twin gestation andsonographic short cervix: a multicenter randomizedcontrolled trial (PECEP-Twins). Am J Obstet Gynecol.2016;214:145–152.

[92] Menon R. Preterm birth: a global burden on mater-nal and child health. Pathog Glob Health.2012;106:139–140.

[93] Nour NM. Premature delivery and the millenniumdevelopment goal. Rev Obstet Gynecol. 2012;5:100–105.

[94] Blencowe H, Cousens S, Oestergaard MZ, et al.National, regional, and worldwide estimates of pre-term birth rates in the year 2010 with time trendssince 1990 for selected countries: a systematic ana-lysis and implications. Lancet (London, England).2012;379:2162–2172.

[95] Radzinsky VE. Obstetric aggression. M. Publishinghouse of the Status. Praesens J. 2011;688:178–186.

[96] Radzinsky VE. Reproductive Health: Student Book. M.RPFU; 2011;727:281–291.

[97] Lee HC, Lyndon A, Blumenfeld YJ, et al. Antenatalsteroid administration for premature neonates inCalifornia. Obstet Gynecol. 2011;117603–609.

[98] Royal College of Obstetricians and Gynaecologists(RCOG). Tocolysis for women in preterm labour:Green-top Guideline N� 18. London (UK): RoyalCollege of Obstetricians and Gynaecologists (RCOG).London (UK), 2011.

2028 G. C. DI RENZO ET AL.

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http://dx.doi.org/10.1016/S0140-6736 (16)00350-0http://dx.doi.org/10.1016/S0140-6736 (16)00350-0

[99] Haram K, Mortensen JHS, Morrison JC. Tocolysis foracute preterm labor: does anything? J Maternal-FetalNeonatal Med. 2015;28:371–378.

[100] Serov VN, Tyutyunnik VL. Treatment of threateningpreterm birth. Reprod Endocrinol. 2012;445:22–24.

[101] Salim R, Garmi G, Nachum Z, et al. Nifedipine com-pared with atosiban for treating preterm labor: arandomized controlled trial. Obstetrics andGynecology. 2012;120:1323–1331.

[102] Vogel JP, Nardin JM, Dowswell T, et al. Combinationof tocolytic agents for inhibiting preterm labour.Cochrane Database Syst Rev. 2014;7:CD00616.

[103] Driul L, Londero AP, Adorati-Menegato A, et al.Therapy side-effects and predictive factors for pre-term delivery in patients undergoing tocolysis withatosiban or ritodrine for threatened preterm labour.J Obstet Gynaecol. 2014;34:684–689.

[104] Flenady V, Wojcieszek AM, Papatsonis DNM, et al.Calcium channel blockers for inhibiting pretermlabour and birth. Cochrane Database of SystematicReviews Ed. The Cochrane Collaboration. Chichester,UK: John Wiley & Sons, Ltd; 2014.

[105] Flenady V, Reinebrant HE, Liley HG, et al. Oxytocinreceptor antagonists for inhibiting preterm labour.V.Cochrane Database of Systematic Reviews. TheCochrane Collaboration. Chichester, UK: John Wiley &Sons, Ltd; 2014.

[106] Beck S, Wojdyla D, Say L, et al. The worldwide inci-dence of preterm birth: a systematic review ofmaternal mortality and morbidity. Bull World HealthOrg. 2010;88:31–38.

[107] Lyell DJ, Pullen KM, Mannan J, et al. Maintenancenifedipine tocolysis compared with placebo: arandomized controlled trial. Obstet Gynecol.2008;112:1221–1226.

[108] Reinebrant HE, Flenady V, Cole S, et al. Cyclo-oxy-genase (COX) inhibitors for treating preterm labour.Cochrane Database Syst Rev. 2015;6:CD001992.

[109] Loe SM, Sanchez-Ramos L, Kaunitz AM. Assessing theneonatal safety of indomethacin tocolysis: a system-atic review with meta-analysis. Obstet Gynecol.2005;106:173–179.

[110] American College of Obstetricians and GynecologistsCommittee on Obstetric Practice; Society forMaternal-Fetal Medicine. Committee Opinion No. 455:Magnesium sulfate before anticipated pretermbirth for neuroprotection. Obstet Gynecol.2010;115:669–671.

[111] Doyle LW, Crowther CA, Middleton P, et al.Magnesium sulphate for women at risk of preterm birthfor neuroprotection of the fetus. Cochrane DatabaseSyst Rev. 2009;(1):CD004661.

[112] Sweet DG, Carnielli V, Greisen G, et al. EuropeanConsensus Guidelines on the management of neo-natal respiratory distress syndrome: 2016 update.Neonatology. 2016;111:107–125.

[113] Roberts D, Dalziel S. Antenatal corticosteroids foraccelerating fetal lung maturation for women at riskof preterm birth. Cochrane Database Syst Rev.2017;(3):CD004454.

[114] Manktelow BN, Lal MK, Field DJ, et al. Antenatal cor-ticosteroids and neonatal outcomes according to

gestational age: a cohort study. Arch Dis Child FetalNeonatal Ed. 2010;95:F95–F98.

[115] Boghossian NS, McDonald SA, Bell EF, et al. EuniceKennedy Shriver National Institute of Child Healthand Human Development Neonatal ResearchNetwork: Association of antenatal corticosteroidswith mortality, morbidity, and neurodevelopmentaloutcomes in extremely preterm multiple gestationinfants. JAMA Pediatr. 2016;170:593–601.

[116] Gyamfi-Bannerman C, Thom EA, Blackwell SC, et al.Antenatal betamethasone for women at risk for latepreterm delivery. N Engl J Med. 2016;374:1311–1320.

[117] Sotiriadis A, Makrydimas G, Papatheodorou S, et al.Corticosteroids for preventing neonatal respiratorymorbidity after elective caesarean section at term.Cochrane Database Syst Rev. 2009;(4):CD006614.

[118] Crowther CA, McKinlay CJD, Middleton P, et al.Repeat doses of prenatal corticosteroids for womenat risk of preterm birth for improving neonatalhealth outcomes. Cochrane Database Syst Rev. 2015;CD003935. doi: 10.1002/14651858.CD003935.pub4.

[119] WHO recommendations on interventions to improvepreterm birth outcomes. WHO 2015. WHO/RHR/15.16- WHO/MCA 15.02.

[120] Asztalos EV, Murphy KE, Willan AR, et al. Multiplecourses of antenatal corticosteroids for preterm birthstudy: outcomes in children at 5 years of age(MACS-5). JAMA Pediatr. 2013;167:1102–1110.

[121] Mulder EJH, Derks JB, Visser GHA. Antenatal cortico-steroid therapy and fetal behaviour: a randomisedstudy of the effects of betamethasone and dexa-methasone. Br J Obstet Gynaecol. 1997;104:1239–1247.

[122] Cohlen BJ, Stigter RH, Derks JB, et al. Absence of sig-nificant hemodynamic changes in the fetus followingmaternal betamethasone administration. UltrasoundObstet Gynecol. 1996;8:252–255.

[123] Althabe F, Beliz�an JM, McClure EM, et al. A popula-tion-based, multifaceted strategy to implement ante-natal corticosteroid treatment versus standard carefor the reduction of neonatal mortality due to pre-term birth in low-income and middle-income coun-tries: the ACT cluster-randomised trial. Lancet. 2015;385:629–639.

[124] Visser GHA, Di Renzo GC. Antenatal corticosteroidsfor preterm births in resource-limited settings; cor-respondence. Lancet. 2015;385:1943–1944. doi:10.1016/S0140-6736(15)60953-9.

[125] Murphy KE, Hannah ME, Willan AR, MACSCollaborative Group, et al. Multiple courses of ante-natal corticosteroids for preterm birth (MACS): arandomised controlled trial. Lancet. 2008;372:2143–2151.

[126] Tijsseling D, Wijnberger LD, Derks JB, et al. Effects ofantenatal glucocorticoid therapy on hippocampalhistology of preterm infants. PLoS One. 2012;7:e33369.

[127] Sawady J, Mercer BM, Wapner RJ, National Instituteof Child Health and Human Development MaternalFetal Medicine Units Network. The National Instituteof Child Health and Human Development Maternal-Fetal Medicine Units Network, et al. Beneficial Effects

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https://doi.org/10.1002/14651858.CD003935.pub4https://doi.org/10.1016/S0140-6736(15)60953-9

of Antenatal Repeated Steroids study: impact ofrepeated doses of antenatal corticosteroids on pla-cental growth and histologic findings. Am J ObstetGynecol. 2007;197:281.e1–288.

[128] Van Baaren GJ, Vis JY, Wilms FF, et al. Predictivevalue of cervical length measurement and fibronec-tin testing in threatened preterm labor. ObstetGynecol. 2014;123:1185–1192.

[129] American College of Obstetricians and GynecologistsACOG committee opinion no. 559: Cesarean deliveryon maternal request. Obstet Gynecol. 2013;121:904–907.

[130] Darlow B, Austin N, French N, et al. School-age out-comes of very preterm infants after antenatal treat-ment with magnesium sulfate vs placebo. JAMA.2014;312:1105–1113.

[131] Hay PE, Lamont RF, Taylor-Robinson D, et al.Abnormal bacterial colonisation of the genital tractand subsequent preterm delivery and late miscar-riage. BMJ (Clinical Research Ed). 1994;308:295–298.

[132] Kurki T, Sivonen A, Renkonen OV, et al. Bacterialvaginosis in early pregnancy and pregnancy out-come. Obstet Gynecol. 1992;80:173–177.

[133] Lamont RF. Advances in the prevention of infection-related preterm birth. Front Immunol. 2015;6:566.

[134] Lamont RF, Nhan-Chang CL, Sobel JD, et al.Treatment of abnormal vaginal flora in early preg-nancy with clindamycin for the prevention ofspontaneous preterm birth: a systematic reviewand metaanalysis. Am J Obstet Gynecol. 2011;205:177–190.

[135] Lamont RF, Sobel JD, Akins RA, et al. The vaginalmicrobiome: new information about genital tractflora using molecular based techniques. BJOG.2011;118:533–549.

[136] Farr A, Kiss H, Hagmann M, et al. Routine use of anantenatal infection screen-and-treat program to pre-vent preterm birth: long-term experience at aTertiary Referral Center. Birth. 2015;42:173–180.

[137] Grant A, Glazener CM. Elective caesarean section ver-sus expe