Confidential: For Review Only - BMJ · 19/06/2016 · CV J.P.W.R. Roovers. Wij verzoeken u onze commissie op de hoogte te stellen van de daadwerkelijke start van het on- derzoek,

Confidential: For Review O

nly

A randomized controlled trial comparing atosiban and

fenoterol as a uterine relaxant for external cephalic version (NTR 1877)

Journal: BMJ

Manuscript ID BMJ.2016.032042.R1

Article Type: Research

BMJ Journal: BMJ

Date Submitted by the Author: 19-Jun-2016

Complete List of Authors: Velzel, Joost; AMC, Obstetrics and Gynaecology Vlemmix, Floortje; AMC, Obstetrics and Gynaecology Opmeer, Brent; AMC-CRU, Molkenboer, Jan; Spaarne Gasthuis, Obstetrics and Gynaecology Verhoeven, Corine; Máxima Medical Center, Department of Obstetrics and Gynaecology van Pampus, Maria; OLVG, Obstetrics and Gynaecology Papatsonis, Dimitri; Amphia Ziekenhuis, Obstetrics and Gynaecology Bais, Joke; Medical Centre Alkmaar, Obstetrics and Gynaecology Vollebregt, Karlijn; Spaarne Gasthuis, Obstetrics and Gynaecology Van der Esch, Liesbeth; Sint Antonius Ziekenhuis, Obstetrics and Gynaecology van der Post, Joris; AMC, Obstetrics and Gynaecology Mol, Ben Willem; University of Adelaide Robinson Institute Kok, Marjolein; AMC, Obstetrics and Gynaecology

Keywords: External cephalic version, Tocolytics, Ceaserean delivery

https://mc.manuscriptcentral.com/bmj

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nlyProf.dr. B.W.J. MolVerloskunde/GynaecologieH4-205

arnAcodemisch Med isch Cent rum

Univers i te i t von Amsterdom

Amsterdam, 24 juni 2009uw kenmerk:ons kenmerk: MEC 08/364 # 09.I7.0987betreft:Positief oordeel m.b.t. het project MÊC O8l364zE><ternal cephalic version with uterine relaxation:centre trial.

Medisch Ethische CommissieE2-236

doorkiesnummer: 566 7389/566 5880fax: 5669015

atciban vensus ritodrine, a multi-

Geachte heer Mol,

In vervolg op de ontvangst van uw reactie d.d.22 juni 2009 op onze brief van 18 junijl., delen wiju inzake bovengenoemd project, ons ter beoordeling voorgelegd op 8 december 2008, gaarne meedat onze commissie- tot oordelen bevoegd krachtens artikel 2, tweede lid, onder a/ van de Wet medisch-

wetenschappelijk onderzoek met mensen (WMO);- werkzaam volgens de ICH-GCP richtlijnen;- op grond van de haar voorgelegde stukken als hierna vermeld;- gelet op art ikel 3 van de WMO;- vastgesteld hebbend dat aan de beoogde proefpersonen op adequate wijze informatie wordt

gegeven over het uit te voeren onderzoek;- vastgesteld hebbend dat voor het onderzoek een verzekering is afgesloten conform de WMO en

het Besluit verplichte verzekering bij medisch-wetenschappelijk onderzoek met mensen,heeft besloten tot een positief oordeel over deze studie en de uiWoering daarvan in het AMC.

In de beoordeling betrokken documenten:. protocol versie IV d,d. mei 2009;. patiënteninformatie/toestemmingsformulier versie V d.d, juni 2009;. ABR-formulier nr. 26246, versie 08 d.d.22 juni 2009;r AMC-appendix;. SPC partusisten;r formul ier 'Request for authorisat ion of a cl in ical t r ia l . . . . ' ;. ontvangstbevest iging EudraCT nummer d,d. 7 november 2008;. brief aan de huisarts met informatie over deelname patiënU. CV B.W.J. Mol;. CV J.P.W.R. Roovers.

Wij verzoeken u onze commissie op de hoogte te stellen van de daadwerkelijke start van het on-derzoek, van de (al dan niet voort i jd ige) beëindiging daarvan/ en van t i jdens de studie optredendeonverwachte complicaties, Voorts dienen eventuele protocolwijzigingen ter beoordeling aan onzecommissie te worden voorgelegd. Wij verzoeken u tevens ons jaarlijks een voortgangsrapportagebetreffende de studie te doen toekomen, voor het eerst binnen een jaar na dagtekening van ditbesluit.

Wij wijzen u erop dat op grond van artikel 711 van de Algemene wet bestuursrecht degene wiensbelang rechtstreeks bij dit besluit betrokken is, daartegen binnen zes weken na de dag waarop hetbesluit bekend is gemaakt, bezwaar kan aantekenen bij de Medisch Ethische Commissie,

Tenslotte brengen wij onder uw aandacht dat dit besluit zijn geldigheid verliest als de studie nietbinnen twee jaar na dagtekening van deze brief is gestart. Voorts dient voor de uitvoering van ge-neesmiddelonderzoek naast een positief oordeel van onze commissie ook een verklaring van geen

Meibe rgd ree f 9 Pos tbus22660 l l 00DDAms te rdom Te le foon (020 ) 5óó911 ' l Fox lO20 )56ó4440

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Acodemisch Med isch Cent rum

Un iversi tei t von Amsterdom

bezwaar van de CCMO als bevoegde instantie verkregen te zijn (zie voor de procedure de websitevan de CCMO).

Ten ti jde van de beoordeling van ditprof. dr. R.T. Kredietprof .dr . P.M.M. Bossuytd r . H ,H .F . De rkxmw, mr . M .L .M . van de r Hu l s tdr. R.E. Jonkersmw.dr. J.C. Korevaardr. G.A. van Montfransmw.d r . W.M.C . Mu lde rdr . J ,B. Rei tsmadr . J .F ,M . S lo rsprof. dr. J.G.P. Tijssenmw.dr . M.D. Tr ipdrs. A. Vythmw. C. Webel ingorof .dr . D.L, Wi l lems

Met vriendelijke groet,namens de Medisch Ethische Commissie,

c.c. CCMO - registratienummer NL26246.O18.O8c.c. AMC Medical Research BV (+)

project was de commissie als volgt samengesteld:voorz itter, hoogleraar nefrologieplv . l id , hoogleraar k l in ische epidemiologiekinderarts, sociaal pediatersecretaris, juristlongarts/klinisch farmacoloogplv. l id, klinisch epidemiolooginternistplv. l id, klinisch farmacoloogplv. l id , k l in isch epidemioloogchirurghoogleraar klinische epidemiologie van hart- en vaatziekteninternistziekenhuisapothekerbeoordeelt onderzoek specifiek vanuit de invalshoek van de patiënthoogleraar medische ethiek.

. m r . M . L . M ,

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External Cephalic Version with uterine relaxation: atosiban versus fenoterol, a multi-centre trial

Study protocol

May 2009

Academic Medical Centre

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Version IV, May 2009 - II -

External Cephalic Version with uterine relaxation: atosiban versus

fenoterol, a multi-centre trial

Protocol ID Stuitonderzoek 01-11-2008

Dutch trial registration (NTR)

number

1877

Short title External Cephalic Version with Atosiban

Version IV

Date May 2009

Coordinating investigator/project

leader

Prof. B.W. Mol


Dept Obstetrics and Gynaecology, Room H4-213

PO Box 22700

1105 DE Amsterdam

The Netherlands

Email: [email protected]

Phone number: +31-(0)6-12193331

Prof. J.A.M. van der Post



PO Box 22700

1105 DE Amsterdam

The Netherlands


Principal investigator(s) Prof. B.W. Mol



PO Box 22700

1105 DE Amsterdam

The Netherlands


Phone number: +31-(0)6-12193331

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Version IV, May 2009 - III -

Mevr T. Spaapen

Onze Lieve Vrouwe Gasthuis

Eerste Oosterparkstraat 279

1091 HA Amsterdam

Phone Number: 020-5999111

Dr. D.N. Papatsonis

Amphia ziekenhuis

Langendijk 75 Breda

4819 EV Breda

Phone Number: 076 5951000

Dr. J.M.J. Bais

Medisch Centrum Alkmaar

Wilhelminalaan 12

1815 JD Alkmaar

Phone Number: 072-5484444

Prof. B.W. Mol

Máxima Medisch Centrum

De Run 4600

5500 MB Veldhoven NL

Phone Number: +31 (0)40 8888385

Sponsor

Prof. BW Mol, AMC

Prof. JAM van der Post

Independent physician(s) Dr. J.P. Roovers



PO Box 22700

1105 DE Amsterdam

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Version IV, May 2009 - IV -

TABLE OF CONTENTS 1.1 SCOPE OF THE PROBLEM .......................................................................................................................... 3 1.2 MATERNAL AND FETAL CONSEQUENCES OF CS ......................................................................................... 3 1.3 ECV TO REDUCE BREECH PRESENTATION ................................................................................................. 4

1.3.1 ECV at term without uterine relaxation............................................................................................ 4 1.3.2 ECV at term with uterine relaxation................................................................................................. 4 1.3.3 Fetal risks associated with ECV....................................................................................................... 6

1.4 WHY COMPARING ATOSIBAN WITH FENOTEROL......................................................................................... 7 2.0 OBJECTIVES.................................................................................................................. 8

2.1 PRIMARY OBJECTIVE................................................................................................................................ 8 2.2 SECUNDARY OBJECTIVES ......................................................................................................................... 8

3.0 DESIGN .......................................................................................................................... 9

3.1 FLOWCHART ........................................................................................................................................... 9 4.0 STUDY POPULATION .................................................................................................. 10

4.1 POPULATION (BASE) .............................................................................................................................. 10 4.2 INCLUSION CRITERIA ............................................................................................................................. 10 4.3 EXCLUSION CRITERIA ............................................................................................................................ 10 4.4 SAMPLE SIZE CALCULATION ................................................................................................................... 11

5. TREATMENT OF SUBJECTS ......................................................................................... 12

5.1 INVESTIGATIONAL PRODUCT .................................................................................................................. 12 5.2 INVESTIGATIONAL TREATMENT .............................................................................................................. 12

5.2.1 Description of the procedure ......................................................................................................... 12 5.2.2 Duration of the procedure ............................................................................................................. 12 5.2.3 Clinicians performing ECV ........................................................................................................... 13

5.3 USE OF CO-INTERVENTION ..................................................................................................................... 13 6. INVESTIGATIONAL MEDICINAL PRODUCT.................................................................. 14

6.1 NAME AND DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT ...................................................... 14 6.2 SYMMARY OF PRODUCT CHARACTERISTICS (SPC) .................................................................................. 14 6.3 DESCRIPTION AND JUSTIFICATION OF ROUTE OF ADMINISTRATION AND DOSAGE ....................................... 14 6.4 PREPARATION AND LABELLING OF INVESTIGATIONAL MEDICINAL PRODUCT ........................................... 14

7. METHODS ...................................................................................................................... 15

7.1 STUDY PARAMETERS/ENDPOINTS ........................................................................................................... 15 7.1.1 Main study parameter/endpoint ..................................................................................................... 15 7.1.2 Other outcomes ............................................................................................................................. 15

7.2 STUDY PROCEDURES.............................................................................................................................. 15 7.3 WITHDRAWAL OF INDIVIDUAL SUBJECTS ................................................................................................ 16 7.4 REPLACEMENT OF INDIVIDUAL SUBJECTS AFTER WITHDRAWAL ............................................................... 16 7.5 FOLLOW-UP OF SUBJECTS WITHDRAWN FROM TREATMENT ...................................................................... 17 7.6 PREMATURE TERMINATION OF THE STUDY .............................................................................................. 17 7.7 COMPLIANCE ........................................................................................................................................ 17 7.8 LOSSES TO FOLLOW-UP .......................................................................................................................... 17 7.9 GENERALISATION .................................................................................................................................. 17

8. SAFETY REPORTING .................................................................................................... 18

8.1 SECTION 10 WMO EVENT ...................................................................................................................... 18 8. 2 ADVERSE AND SERIOUS ADVERSE EVENTS.............................................................................................. 18

8.2.1 Suspected unexpected serious adverse reactions (SUSAR).............................................................. 18

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Version IV, May 2009 - V -

8.2.2 Annual safety report ...................................................................................................................... 19 8.3 FOLLOW-UP OF ADVERSE EVENTS........................................................................................................... 19

9. STATISTICAL ANALYSIS ............................................................................................... 20

9.1 INTERIM ANALYSIS ................................................................................................................................ 20 9.2 DESCRIPTIVE STATISTICS ....................................................................................................................... 20 9.3 SUBGROUP ANALYSIS: ........................................................................................................................... 20

10. ETHICAL CONSIDERATIONS ...................................................................................... 21

10.1 REGULATION STATEMENT .................................................................................................................... 21 10.2 RECRUITMENT AND CONSENT............................................................................................................... 21 10.3 OBJECTION BY MINORS OR INCAPACITATED SUBJECTS (IF APPLICABLE) .................................................. 21

11. ADMINISTRATIVE ASPECTS AND PUBLICATION ...................................................... 23

11.1 HANDLING AND STORAGE OF DATA AND DOCUMENTS ........................................................................... 23 11.2 AMENDMENTS ..................................................................................................................................... 23 11.3 ANNUAL PROGRESS REPORT ................................................................................................................. 23 11.4 END OF STUDY REPORT ........................................................................................................................ 23

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Version IV, May 2009 - VI -

LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS

ECV External Cephalic Version

EudraCT European drug regulatory affairs Clinical Trials GCP Good Clinical Practice

IC Informed Consent

IMP Investigational Medicinal Product

IMPD Investigational Medicinal Product Dossier

METC Medical research ethics committee (MREC); in Dutch: medisch ethische

toetsing commissie (METC)

(S)AE Serious Adverse Event

SPC Summary of Product Characteristics (in Dutch: officiële productinfomatie

IB1-tekst)

Sponsor The sponsor is the party that commissions the organisation or performance

of the research, for example a pharmaceutical company, academic hospital,

scientific organisation or investigator. A party that provides funding for a

study but does not commission it is not regarded as the sponsor, but

referred to as a subsidising party.

SUSAR Suspected Unexpected Serious Adverse Reaction

US Ultrasound

Wbp Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens)

WMO Medical Research Involving Human Subjects Act (Wet Medisch-

wetenschappelijk Onderzoek met Mensen

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Version IV, May 2009 - 1 -

SUMMARY

Rationale: External cephalic version (ECV) of the fetus in breech position is a safe and

relatively simple obstetrical intervention that reduces the incidence of caesarean section for

breech position at term. Uterine relaxation can enhance the success rate of ECV

significantly. The most studied and widespread used uterine relaxants are the beta-agonists,

but these are not widely accepted in daily obstetrical practice because of cardiovascular

side effects.

Nifedipine (a calcium channel blocker) and atosiban (an oxytocin-receptor antagonist) have

been proven successful as tocolytics in preventing preterm labour and have replaced beta-

agonists. These studies reported significantly less drop outs because of adverse drug

reactions with nifedipine or atosiban in comparison with beta-agonists. However, a RCT

comparing nifedipine versus placebo for ECV could not show a significant difference on

success rate.

This trial will compare the effectiveness of atosiban with fenoterol (beta-agonist) during ECV

in women with a singleton fetus in breech presentation at term.

Objective: For women with a singleton fetus in breech presentation at term, this study

answers the question if atosiban is more effective compared to fenoterol as a tocolyticum in

external cephalic version.

Study design: The proposed design is an open label randomised controlled trial comparing

atosiban with fenoterol as a tocolyticum during ECV. Patients assigned for randomisation

will be stratified by centre and parity. This trial will be carried out by physicians and midwives

who have experience in the ECV manoeuvre.

Study population: Inclusion criteria: live singleton fetus in breech presentation from 32

weeks gestational age onwards. Exclusion criteria: 1. contraindication to vaginal birth, 2.

contra-indications to ECV, 3. contra-indications to atosiban or fenoterol.

Intervention: One group receives 6.75 mg (0.9 ml of 7.5 mg/ml) atosiban i.v. and the other

group receives an intravenous bolus of 40 µg fenoterol (0.8 ml of 0.5 mg/10 ml).

Main study parameters/endpoints: The primary outcome is a fetus being in cephalic

position immediately after the procedure. Secondary outcome measures include cephalic

presentation at delivery, mode of delivery, side effects and adverse events.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The number of visits and physical examinations needed are similar to

women undergoing an ECV in daily practice. The possible side-effects will be questioned

after ECV. Registered maternal side effects of atosiban as tocolytic to prevent preterm

labour are: nausea (>10%), headaches, dizziness, flushing, vomiting, tachycardia and

hypotension (1-10%). Registered side effects of fenoterol are: tachycardia, chest pain,

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dizziness, hypotension, transpiration, flushes, nausea, vomiting and headaches. Women in

this trial will only receive the bolus used in treatment of preterm labour instead of a two days

therapy. We assume that the frequency of adverse effects will be less than registered during

48 hrs treatment. No neonatal adverse events are known from literature. We hypothesize

that the success rate of ECV will be similar or higher in the fenoterol compared to the

atosiban group and the adverse events will be significantly lower in the atosiban group.

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1. INTRODUCTION AND RATIONALE 1.1 Scope of the problem

Breech presentation occurs in 3% to 4% of all term pregnancies.1 External cephalic

version (ECV) reduces the rate of breech presentation at term by on average 40%, and

leads to a significant reduction in the risk of caesarean section (relative risk (RR) 0.55 95%

confidence interval (CI) 0.33 to 0.91) without significant increased risk to the baby.2 The

actual caesarean section rate with breech presentation is 80%3, which is driven by the

reported increase in perinatal risks for the vaginally delivered breech baby.3;4 Since ECV is a

relatively simple procedure, that carries minimal risk for mother and child5;6 it is considered

an important obstetrical intervention.7;8

1.2 Maternal and fetal consequences of CS

Given the higher incidence in serious immediate neonatal morbidity and mortality

after vaginal delivery of the breech presenting fetus the primary CS rate is rising. This will

have consequences for mother and child.

Short term consequences are hospital admission of at least 4 days, and a higher

maternal morbidity and mortality. A multicentre prospective study in 8 Latin American

countries showed a significant increase on death, admission to an intensive care unit, need

of blood transfusion, hysterectomy and prolonged hospital stay in elective CS compared to

vaginal delivery (overall odds ratio (OR) 2.30, 95% CI 1.69-3.14). The number of women

treated with antibiotics after delivery was four times higher in the elective caesarean group

(OR 4.24, 95% CI 2.78-6.46).9 The number of fetal death was decreased in the elective CS

group (RR 0.65, 95% CI 0.43-0.98).

A sub analysis of this study among fetuses in breech presentation showed no

significant difference in neonatal mortality up to discharge between vaginal and elective or

intrapartum CS. This in contrast to the outcomes of the Term Breech Trial, which showed an

increased neonatal mortality (RR 0.23, 95% CI 0.07-0.81) and morbidity (RR 0.36, 95% CI

0.19-0.65) among planned vaginal birth compared to planned CS.4

Long term consequences of CS are higher incidence of placenta praevia and uterine

rupture for the next pregnancy. A retrospective cohort analysis from 1987 through 1996 with

a total of 20,095 women showed that uterine rupture was more likely among women with

spontaneous onset of labour (RR, 3.3; 95 % CI, 1.8 to 6.0).10 A higher risk for uterine rupture

in the next pregnancy means a higher risk for neonatal morbidity and mortality for the next

child.

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Observed neonatal death in this study was 0.5% in the group without uterine rupture

(100 out of 20.004) and 5.5% in the ruptured uterus group (5 out of 91). The risk of a

ruptured uterus was even higher after induction of labour: induction of labour without

prostaglandins showed a RR of 4.9; 95 % CI 2.4 to 9.7, and induction with prostaglandin’s

even a RR of 16, 95 % CI 8.1 to 30, so there is a problem if these women require induction

of labour (e.g. preeclampsia at term).

A meta-analysis of 36 studies with a total population of 3.7 million pregnant women

showed a RR of 2.6, 95% CI 2.3-3.0 for placenta praevia for the next pregnancy for women

with at least one prior caesarean delivery.11 A placenta praevia is not without obstetrical

risks and affects negatively perinatal outcome. A retrospective cohort study of 78.524

deliveries of which 298 were complicated by a placenta praevia showed for example an

increased risk of second-trimester bleeding (OR 156, 95% CI 87 to 278), abruptio placentae

(OR 13, 95% CI 8.2 to 21), perinatal mortality (OR 2.6, 95% CI 1.1 to 5.6), perinatal Apgar

scores at 5 min lower than 7 (OR 4.4, 95% CI 2.3 to 8.3) and post partum haemorrhage (OR

3.8, 95% CI 1.2 to 10.5).12

So, preventing serious morbidity and mortality for the first child increases maternal

morbidity and mortality and can have harmful consequences for the next pregnancy.

1.3 ECV to reduce breech presentation

1.3.1 ECV at term without uterine relaxation

ECV at term is considered as an effective method to reduce the number of breech

presentations. ECV without uterine relaxation after 36 weeks of gestation can reduce breech

presentation by 41%.13

1.3.2 ECV at term with uterine relaxation

Various studies have investigated the use of uterine relaxation and the effect on the

success rate of the ECV procedure. ECV with uterine relaxation can enhance the relative

success rate with 40% (from 43% to 59%, RR 0.74 95% CI 0.64 to 0.87).13;14 Uterine

relaxants currently available are the beta-agonist, calcium antagonists, nitrates and oxytocin

antagonists.

The most widespread evaluated uterine relaxants are the beta-agonist and most data

we have about the success rates of ECV with uterine relaxation are with this type of

medicine. There is however a high incidence in maternal discomfort due to the

cardiovascular side-effects of these agents.

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One RCT investigated the use of glyceryl trinitrate spray for ECV.15 There were no

significant differences found between placebo and treatment group. The numbers studied in

this trial however were too small for meaningful statistical analysis. As for maternal

discomfort there was also no statistical difference, 9/30 in treatment group and 7/21 in

placebo group (RR 0.90, 95% CI 0.4 to 2.0).

Calcium antagonists like nifedipine have been studied for the use as an uterine

relaxant to prevent preterm labour. It is proven to be equally effective in inhibiting preterm

labour for the first 48 hours compared to beta-agonists (RR 0.80, 95% CI 0.61 to 1.05), but

significantly less participants discontinued treatment because of side effects (0.2% vs. 7%

RR 0.14, 95% CI 0.05 to 0.36]).16 One RCT evaluating the effectiveness of nifedipine for

ECV (n=310) could not show a significant difference between treatment and placebo group

(RR 1.1, 95% CI 0.88 to 1.4).17

In conclusion, beta-mimetics are still the only tocolytics with a proven effect in

increasing successful ECV attempts and therefore reducing the number of CS compared to

placebo.

Table 1. Summary of Term ECV Trials using uterine relaxation vs placebo: effect on success rate Author, date Uterine relaxant Outcomes

ECV with uterine relaxation

ECV with placebo

Trails using terbutaline

Fernandez

199718

Terbutaline: 0.25 mg sc, 15-30 min prior to

ECV

Conclusion: increased succesrate of ECV

n=52

52% successful

version

n=51

27% successful

version

Trials using salbutamol

Tan 198919 Salbutamol 4mg orally three times a day for at

least one day or

Salbutamol IV until maternal HR > 100 bpm

Conclusion: no significant increase in

successrate

n=30

50% successful

version

n=30

40% successful

version

Trial using ritodrine

Robertson

198720

Ritodrine IV 200 µg/min for 20 min prior to

ECV

Conclusion: uterine relaxation did not increase

success rate

n=30

67% successful

version

n=28

68% successful

version

Stock 199321 Ritodrine IV 0.3 mg/min for 30 min prior to

ECV

Conclusion: no significant increase in success

n=21

67% successful

version

n=25

43% successful

version

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rate

Marquette

199622

Ritodrine IV 111 µg/min ≥ 20 min prior to ECV

Conclusion: improved success rate in

nulliparous women.

n=138

52% successful

version

n=145

42% successful

version

Chung 199623 Ritodrine IV 0.4 mg/ml at 1.5 ml/min for 15 min

prior to ECV; increased by steps of 200 µg if

contractions interfering

Conclusion: improved success rate in

nulliparous women and where doctors are

learning

n=25

52% successful

version

n=25

28% successful

version

Trials using hexoprenaline

Stock 199321 Hexoprenaline IV 10 µg 5 min prior to ECV

Conclusion: significant improved success rate

n=21

76% successful

version

n=21

43% successful

version

Trials using nifedipine

Kok 200817 Nifedipine caps 10 mg 30 en 15 min prior to

ECV


rate

n=154

42% successful

version

n=156

37% successful

version

Trials using glyceryl trinitrate

Yanni 200015 Glyceryl trinitrate sublingual spray 800 µg


rate

n=31

29% successful

version

n=26

12% successful

version

Table 2. Summary of Term ECV Trials using uterine relaxation vs placebo: effect on

CS rate Author, date

Uterine relaxant Outcomes

ECV with uterine relaxation

ECV with placebo

Fernandez

199718

Terbutaline: 0.25 mg sc, 15-30 min prior to ECV

Conclusion: uterine relaxation decreases CS rate

n=52

57% CS

n=51

76% CS

Marquette

199622

Ritodrine IV 111 µg/min ≥ 20 min prior to ECV

Conclusion: uterine relaxation decreases CS rate

n=138

55% CS

n=145

65% CS

Robertson

198720

Ritodrine IV 200 µg/min for 20 min prior to ECV

Conclusion: uterine relaxation did not lower CS rate

n=30

26% CS

n=28

18% CS

Kok 200817 Nifedipine caps 10 mg 30 en 15 min prior to ECV n=154

49%

n=156

45%

1.3.3 Fetal risks associated with ECV

The risks associated with the procedure are minimal when there are strict inclusion

criteria and fetal monitoring with ultra sound and fetal heart rate registration takes place.

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There is a risk of fetal death in 1 per 5,000 ECV attempts. The risk of an emergency

caesarean delivery in 1 per 286 versions, thus ECV should only be attempted in settings in

which caesarean delivery services are readily available.

1.4 Why comparing atosiban with fenoterol

There is enough evidence that shows that ECV at term is effective and reduces the

caesarean section rate. It is also known that ECV with uterine relaxation is even more

successful. Furthermore, caesarean section rates are rising after the publication of the

results of the Term Breech Trial, therefore it is becoming more important to reduce the

number of breech presentations before delivery.

The majority of studies evaluating the effectiveness of uterine relaxation have used

beta-agonists24.These studies reported a beneficial effect of the use of beta-agonists over

placebo in external cephalic version from 41% to 57% (relative risk of failed ECV: 0.74 95%

CI 0.64 to 0.87). However, use of beta-agonists in treatment of preterm labour, has known

adverse maternal cardiovascular side effects in terms of flushing, chest pain and

palpitations25. As soon as other tocolytics entered the market, ritodrine became less and

less used, although this change was not based on sound evidence. As a result the

implementation of routine uterine relaxation with betamimetics in ECV is low. This might be

a misconception as uterine relaxation for ECV only takes 15 minutes instead of 48h in

preventing preterm labor. This might lead to less side effects or at least a better toleration of

side effects by patients. None of the studies on betamimetics in ECV report on either the

amount of side effects or the number of cessations due to these side effect. To improve the

success rate of ECV, not only information on the effectiveness of a new drug should be

generated. One needs to prove whether the new drug is better than the current best known

treatment. A low implementation rate of this best known treatment should not chance this

design.

The uterus relaxant atosiban, known for its effectiveness in inhibiting preterm labour,

is the only tocolytic drug which has not yet been tested for the use of ECV. Compared to

betamimetics it has significant fewer side effects. The proposed trial will be a collaborative

project of practising midwives and physicians. The selection criteria for entry to the study will

ensure that only those women who are most likely to benefit from ECV will be included.

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2.0 OBJECTIVES

2.1 Primary objective

What is the success rate of ECV with uterine relaxation with atosiban compared to

fenoterol for women with a singleton at term fetus in breech presentation?

2.2 Secundary objectives

1. Is there a difference in caesarean section rate of ECV with atosiban compared to

fenoterol?

2. Is there a difference in the incidence of fetal complications of ECV with atosiban

compared to fenoterol?

3. Is there a difference in the incidence of maternal complications of ECV with atosiban

compared to fenoterol?

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3.0 DESIGN

Open label, randomised controlled trial. This study will be performed in multiple

centres; training hospitals as well as non-training hospitals.

3.1 Flowchart

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4.0 STUDY POPULATION 4.1 Population (base)

The source population is pregnant women with a gestational age of 32 -41 weeks,

either under supervision of a midwife or gynaecologist. The prevalence of breech

presentation in this population will be around 4%.1 Those women referred to gynaecologists

because of breech presentation will be eligible for this trial.

4.2 Inclusion criteria

1. Live singleton fetus

2. Breech presentation

3. Gestational age of 32 weeks and onwards

4. Maternal age of 18 years or more

4.3 Exclusion criteria

Maternal exclusion criteria;

- Any contra-indications to labour or vaginal birth (eg placenta praevia)

- Any contra-indication to ECV:

o A scarred uterus other than transverse in the lower segment

o Known uterine anomalies

o Placental abruption in the obstetric history

o Preeclampsia or eclampsia

o Third trimester blood loss, 7 days prior to ECV

o Ruptured membranes

- Any contra-indication to atosiban and fenoterol:

o Cardiovascular disease

o Hyperthyreoidism

o Elevated liver enzymes or renal dysfunction

o Infection of the amniotic cavity

o Simultaneous use of prostaglandin inhibitors, beta-blockers (labetalol

(trandate)), xanthine derivatives (theofylline), tricyclic antidepressants,

calcium, vitamin D, mineralocorticoids.

o Use of prostaglandin inhibitors, beta-blockers (labetalol) tricyclic

antidepressants.

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Fetal exclusion criteria;

- Suspected severe intrauterine growth restriction (<P5 for gestational age assessed

by ultrasonography) or severe oligohydramnios (deepest pool < 2 cm)

- Fetal anomalies or an extended fetal head (very rare)

- Non reassuring signs of fetal well-being; non-reassuring fetal heart rate monitoring

4.4 Sample size calculation

The success rates of ECV with placebo or beta-mimetics are very consistent in

literature. Considering these results a success rate of 50% in the fenoterol group, i.e 10%

increase from version with placebo, can be expected. We feel that an improvement of this

success rate to 60% is needed to make treatment with atosiban worthwhile. A 10%

decrease in success rate from atosiban compared to fenoterol, confirms the preference of

betamimetica in ECV. To be able to show this difference of 10% with a power of 80% and

an alpha error of 5%, we need 384 participants in each arm (two sided test). Anticipating a

drop out rate of 5%, we need to enrol a total of 806 participants (403 per group). We chose

not to use a placebo controlled group because beta-mimetics have shown to be more

effective than placebo.24

Study will be closed if all patients are included or July 2013.

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5. TREATMENT OF SUBJECTS

5.1 Investigational product

Atosiban (Tractocile) as oxytocin-receptor antagonist and fenoterol (Partusisten) as

beta-receptor agonist will be used as an intravenous uterus relaxant to increase the success

rate of ECV. The drugs will be administered fifteen minutes before ECV. The relaxant effect

can be expected after 10 minutes.26

5.2 Investigational treatment

ECV will be initiated preferably before 38 weeks gestation in a clinical setting.

Immediately prior to the ECV procedure, the woman will be reassessed to ensure she is still

eligible for ECV. CTG will be performed. The ECV procedure will be undertaken by

experienced clinicians.

5.2.1 Description of the procedure

The procedure begins with the woman lying comfortable on her back with legs

slightly flexed at the knee. Arms should be extended and lying along side the woman in

order to enhance abdominal relaxation. The clinician begins by palpating the fetus to

ascertain the position of the cephalic pole and fetal back. The next step involves lifting the

breech out of the pelvis and to one side, usually on the side opposite the cephalic pole.

When the fetus has been manoeuvred out of the pelvis, it is often useful to have a second

attendant supports the breech pole in that position, thereby minimising the likelihood of the

breech returning to the pelvic area. The fetus will usually turn most easily in a forward

somersault. Once the breech has been successfully dislodged from the pelvic basin, the

clinician will encourage the fetal head downward toward the pelvis. The fetus should

respond to firm but gentle pressure by moving through the uterine midpoint and into a

cephalic presentation. Fetal position will be determined by US. Fetal well being will be

monitored intermittently during the ECV attempt using either auscultation or ultrasound

viewing of fetal heart activity. After the procedure a CTG will be perfomed.

5.2.2 Duration of the procedure

When undertaking the ECV manoeuvre, the practitioner may pause for varying

periods of time, to assess the fetal heart sounds, to allow the mother to relax her abdominal

muscles, or to allow the fetus to settle into the new position. Because of the breaks in the

procedure, the total time for the procedure will vary. However, the total time spent in the

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actual manipulation of the fetus (that is, the time putting pressure on the fetus to move or

change its position) during any one attempt should not exceed 10 minutes. The procedure

ends when the version is successful, the patient asks for it or when the doctor does not

expect the procedure to exceed when continuing.

5.2.3 Clinicians performing ECV

In this study ECV will only be undertaken by either qualified physicians or midwives

or physicians in training. To ensure competency and to uniform the used method all

participating clinicians will attend a demonstration of ECV by an experienced physician.

Competency will be classified by categorisation of the expertise into number of versions

done a year.

5.3 Use of co-intervention

There is no restriction to life style or use of other medication. A literature search for

studies investigating the interaction of atosiban with other drugs in humans generated one

article. This study showed that the co-administration of atosiban with betamethasone or

labetalol had no clinically relevant influence on their bioavailability or tolerability.27 No

suspicion of drug interaction was suggested in trials investigating atosiban as tocolytic in

prevention of preterm labour.28

Fenoterol interacts with calcium, products containing vitamin D, NSAIDs and

mineralocorticoids. Simultaneous application should be avoided. Beta-1- or beta-2-

sympathicomimetics, xanthinederivatives (theofylline) or tricyclic antidepressiva can

reinforce cardiovascular effects and symptoms of over dosage may occur. Simultaneous use

of beta-adrenergic receptor antagonists is a contra-indication for trial participation as it may

interfere with the efficacy of either agent due to pharmacological antagonism.

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6. INVESTIGATIONAL MEDICINAL PRODUCT

6.1 Name and description of investigational medicinal product

Atosiban (Tractocile) is a competitive antogonist oxytocin, leading to a cessation of

uteruscontractions. It is therefore a tocolytic, used as intravenous medication to halt

premature labor.

Fenoterol (Partusisten) is a beta-agonist with a spasmolytic function on the muscles

of the uterus. It is used to prevent preterm labor and as tocolyticum in ECV.

6.2 Summary of product Characteristics (SPC)

For information on the findings from non-clinical trials, clinical trials and potential

risks and benefits see appendix I and II.

6.3 Description and justification of route of administration and dosage

Atosiban is only available as injection fluid and will therefore be administered

intravenously. We will use the bolus dosage used in prevention of preterm labour; 6.75 mg,

0.9 ml (7.5 mg/ml), 15 minutes before version. Fenoterol will be administered in an

intravenous bolus of 40 µg in 0.8 ml (0.5 mg/10 ml)29. The intravenous bolus will be

administered by a medical doctor, the woman will be laying on her side and blood pressure

and heart rate will be measured every 5 minutes during the first 15 minutes. Also CTG

registration will continue during this period.

These dosages are proven efficient in immediate relaxation of the uterus. The

expected benefit of the toclytica will be measured within 1h after administration; tmax will be

derived within 20 minutes (both medicines) and an ECV attempt takes maximum 30

minutes. Repeated administration will not be necessary as T1/2 is 1.4 to 2 hours.

6.4 Preparation and labelling of Investigational Medicinal Product

The study medication will be supplied by the local pharmacy.

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7. METHODS 7.1 Study parameters/endpoints

7.1.1 Main study parameter/endpoint

1. Successful version; number of cephalic presentations half an hour after the procedure

2. Fetal presentation at delivery

7.1.2 Other outcomes

1. Mode of delivery; vaginal delivery (spontaneous or instrumental), CS (prelabor or during

labor).

2. Complications of ECV

a) Persistent non-reassuring fetal CTG after ECV (e.g. basal heart rate less than 110

beats per minute, repeated decelerations)

b) Occult or overt umbilical cord prolapse

c) (P)PROM

d) Placental abruption e) Emergency delivery

f) Fetal death

3. Adverse events due to atosiban or fenoterol:

a) Chest pain (yes /no)

b) Nausea (mild / moderate / severe)

c) Vomiting (yes / no)

d) Headaches (mild / moderate / severe)

e) Flushing (yes / no)

f) Dizziness (mild / moderate / severe)

g) Hypotension; associated with fainting or CTG abnormalities

h) Tachycardia; palpitations (yes / no) (>100 beats/min for at least 5 minutes)

i) Local reaction of the skin on injection of the medication (yes / no)

j) Anaphylactic shock

k) Cessation of treatment due to side effects

7.2 Study procedures

Women with life singleton fetuse in breech presentation will be identified from 32

weeks’ gestation and the study will be explained to them. If they decide not to participate in

the trial, they will be treated according to local protocol. If they wish to participate in the

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study an ultrasound will be scheduled. This ultrasound should provide the following

information: a description of the position of the fetus including identification of type of breech

(frank, complete or footling); a detailed description of placental location; an estimate of fetal

weight; an estimate of amniotic fluid volume including the measurement of the largest

pocket depth; and identification of fetal anomalies. This ultrasound will be used along with

clinical assessments to determine any contraindications to ECV or vaginal delivery and is a

standard procedure in prenatal care of women with a fetus in breech presentation.

Eligible women will give informed consent prior to randomisation. Following collecting

baseline information and consenting, women will be randomised after stratification by centre

and parity. An ECV attempt will be planned within 7 days.

Before initiating the ECV manoeuvre, the maternal bladder should be emptied, the

procedure should be explained again to the woman, and the fetus should be palpated to

assess the fetal position.

Fifteen minutes before starting ECV, the woman will receive an intravenous bolus of

atosiban or fenoterol. If the local protocol describes ECV with intravenous betamimetics, the

study medication will not provide any additional burden.

The ECV will be performed as descriped in paragraph 5.2.1 and 5.2.2. Because

Rhesus sensibilisation is a risk of ECV, non-sensitised Rhesus negative women will be

provided with anti-D immunoglobulin following the ECV procedure (standard clinical

practice), after the procedure blood will be taken from the IV needle to perform a KB test. IG

dosing will be corrected if necessary.

In the study setting, a questionnaire about drug related side effects and a VAS-score

to access maternal discomfort during ECV (§ 7.1.2) will be completed by the mother.

Primary endpoints end fetal complications after the version will be registered before patient

returns home after the ECV attempt. All other outcomes will be derived from the inquiry

form, added to the patient record, after labour.

7.3 Withdrawal of individual subjects

Subjects can leave the study at any time for any reason if they wish to do so without

any consequences. The investigator can decide to withdraw a subject from the study for

urgent medical reasons.

7.4 Replacement of individual subjects after withdrawal

There will be no replacement of individual subjects after withdrawal.

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7.5 Follow-up of subjects withdrawn from treatment

Patients withdrawn from the RCT will not be followed. The number of patients opting

out after inclusion, but before an ECV attempt is expected to be similar to daily practice and

very low. Therefore, this will not cause significant bias.

7.6 Premature termination of the study

A safety monitoring committee will be installed which will guard trial quality and to

anticipate on serious adverse events. If there is a significant difference in severe adverse

events (neonatal side effects, § 7.1.2) between the atosiban and fenoterol group or the

number exceeds the expected number of severe side effects in general, we will put an hold

to the study and termination will be discussed. This scenario is extremely unlikely as no

other trial on ECV, or atosiban or fenoterol in preterm labour, or atosiban or fenoterol in ECV

have mentioned significant severe side effects.

7.7 Compliance

Collected data will be reviewed to ensure patients are included only after they met all

inclusion criteria. Centres with persisting poor compliance will be excluded from this trial.

7.8 Losses to follow-up

Women enrolled in the trial will be followed from 32 weeks’ gestation to

delivery. If women know they will move to a non-trial centre prior to delivery, they will not be

invited to participate. Every effort will be made to obtain all outcome information on all

women enrolled in the study.

7.9 Generalisation

It is anticipated that a high percentage of the midwifery clientele who meet the

eligibility criteria will participate in the study. This should enhance the degree of

generalisation.

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8. SAFETY REPORTING

8.1 Section 10 WMO event

In accordance to section 10, subsection 1, of the WMO, the investigator will inform

the subjects and the reviewing accredited METC if anything occurs, on the basis of which it

appears that the disadvantages of participation may be significantly greater than was

foreseen in the research proposal. The study will be suspended pending further review by

the accredited METC, except insofar as suspension would jeopardise the subjects’ health.

The investigator will take care that all subjects are kept informed.

8. 2 Adverse and serious adverse events

Adverse events are defined as any undesirable experience occurring to a subject

during a clinical trial, whether or not considered related to the investigational drug. All

adverse events reported spontaneously by the subject or observed by the investigator or his

staff will be recorded.

A SAE is any untoward medical occurrence or effect that at any dose results in death;

- is life threatening (at the time of the event);

- requires hospitalisation or prolongation of existing inpatients’ hospitalisation;

- results in persistent or significant disability or incapacity;

- is a congenital anomaly or birth defect;

- is a new event of the trial likely to affect the safety of the subjects, such as an

unexpected outcome of an adverse reaction, lack of efficacy of an IMP used for the

treatment of a life threatening disease, major safety finding from a newly completed

animal study, etc.

All SAEs will be reported to the accredited METC that approved the protocol, according to

the requirements of that METC.

8.2.1 Suspected unexpected serious adverse reactions (SUSAR)

Adverse reactions are all untoward and unintended responses to an investigational

product related to any dose administered. Unexpected adverse reactions are adverse

reactions, of which the nature, or severity, is not consistent with the applicable product

information (e.g. Investigator’s Brochure for an unapproved IMP or Summary of Product

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Characteristics (SPC) for an authorised medicinal product). The sponsor will report

expedited the following SUSARs to the METC:

- SUSARs that have arisen in the clinical trial that was assessed by the METC;

- SUSARs that have arisen in other clinical trial of the same sponsor and with the

same medicinal product, and that could have consequences for the safety of the

subjects involved in the clinical trial that was assessed by the METC.

The remaining SUSARs are recorded in an overview list (line-listing) that will be

submitted once every half year to the METC. This line-listing provides an overview of all

SUSARs from the study medicine, accompanied by a brief report highlighting the main

points of concern.

The sponsor will report expedited all SUSARs to the competent authority, the

Medicine Evaluation Board and the competent authorities in other Member States. The

expedited reporting will occur not later than 15 days after the sponsor has first knowledge of

the adverse reactions. For fatal or life threatening cases the term will be maximal 7 days for

a preliminary report with another 8 days for completion of the report.

8.2.2 Annual safety report

In addition to the expedited reporting of SUSARs, the sponsor will submit, once a

year throughout the clinical trial, a safety report to the accredited METC, competent

authority, Medicine Evaluation Board and competent authorities of the concerned Member

States.

This safety report consists of:

a list of all suspected (unexpected or expected) serious adverse reactions,

along with an aggregated summary table of all reported serious adverse

reactions, ordered by organ system, per study;

a report concerning the safety of the subjects, consisting of a complete safety

analysis and an evaluation of the balance between the efficacy and the

harmfulness of the medicine under investigation.

8.3 Follow-up of adverse events

All adverse events will be followed until they have abated, or until a stable situation

has been reached. Depending on the event, follow up may require additional tests or

medical procedures as indicated, and/or referral to the general physician or a medical

specialist.

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9. STATISTICAL ANALYSIS 9.1 Interim analysis

A safety monitoring committee will be installed which will guard trial quality and to

anticipate on SAEs.

9.2 Descriptive statistics

An intention to treat analysis will be conducted. Baseline data will be analysed

descriptively for the women and their pregnancies in the two groups. The rate of the primary

and secondary outcomes (cephalic presentation at delivery, maternal and fetal

complications) will be compared in the two groups using chi squared test or Fischer’s exact

test for categorical data and T-test for numerical data. As randomisation has been stratified

for parity at randomisation, we anticipate that this variable will not differ between groups. A

P-value of < .05 (2-sided) will indicate statistical significance for the primary and secondary

outcomes.

Rates of other outcomes (mode of delivery, Apgar scores, birth weight, blood loss,

days of admission, blood transfusion and antibiotic trherapy necessary) will also be

compared between groups using Fischer’s exact test for 2 x 2 tables. Relative risks and

appropriate confidence intervals will also be used to report the effects of the intervention on

each outcome.

9.3 Subgroup analysis

For the purpose of hypothesis generation, logistic regression analyses will be used to

test for interactions between baseline characteristics (parity [0 vs. ≥1], BMI [≤25 vs, > 25],

ethnicity, type of breech [frank versus non-frank], placental localization [anterior vs. non

anterior], amniotic fluid index, palpable fetal head and engagement) and treatment group for

the primary and secondary outcomes.

The incidence of non-cephalic presentation at birth, fetal and maternal complications

and caesarean section rates in the two groups will be compared using Chi-square analyses.

If there are differences in potential confounding variables between groups these will be

controlled for in a multivariate logistic regression analysis. A p value of < 0.05 will indicate

statistical significance for the comparison between groups.

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10. ETHICAL CONSIDERATIONS

10.1 Regulation statement

The study will be conducted according to the principles of the Declaration of Helsinki

and in accordance with the Medical Research Involving Human Subjects Act (WMO).

10.2 Recruitment and consent

Subjects will be informed by their gynaecologist or midwifes about the study and

asked for their consent. The patients will have the same amount of time to consider their

decision, as patients offered an ECV attempt in daily clinical practice. Therefore this study is

not in variance with reality.

10.3 Objection by minors or incapacitated subjects (if applicable)

Entry to the study will be contingent upon women of age understanding the study

and agreeing to participate. Before being entered into the study, women will be asked to

sign an IC form. All women will continue to receive their usual prenatal care from their

chosen care provider. A woman’s choice around study participation will not in any way

influence her ongoing prenatal care. All information obtained in the trial will remain

confidential.

10.4 Compensation for injury

The sponsor/investigator has a liability insurance which is in accordance with article

7, subsection 6 of the WMO.

The sponsor (also) has an insurance which is in accordance with the legal

requirements in the Netherlands (Article 7 WMO and the Measure regarding Compulsory

Insurance for Clinical Research in Humans of 23th June 2003). This insurance provides

cover for damage to research subjects through injury or death caused by the study.

1. € 450.000,-- (i.e. four hundred and fifty thousand Euro) for death or injury for

each subject who participates in the Research;

2. € 3.500.000,-- (i.e. three million five hundred thousand Euro) for death or injury

for all subjects who participate in the Research;

3. € 5.000.000,-- (i.e. five million Euro) for the total damage incurred by the

organisation for all damage disclosed by scientific research for the Sponsor as

‘verrichter’ in the meaning of said Act in each year of insurance coverage.

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The insurance applies to the damage that becomes apparent during the study or within 4

years after the end of the study.

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11. ADMINISTRATIVE ASPECTS AND PUBLICATION 11.1 Handling and storage of data and documents

The baseline data and procedure related data will be collected directly by the

clinicians involved in the trial. The data from the hospital birth record will be collected at

each participating site. In the case of home births, midwives in attendance will be asked to

complete the birth data form. Data will be collected with an electronic CRF. The electronic

CRF will store all data in a file which will be sent to a central database through the browser

used for this study: www.stuitonderzoek.nl. All data are protected during transmission as

they will be sent in an encrypted file of which only the researchers have the key. Data will be

stored in an Access database and transferred to an SPSS database with which statistical

analysis will be carried out.

11.2 Amendments

A ‘substantial amendment’ is defined as an amendment to the terms of the METC

application, or to the protocol or any other supporting documentation, that is likely to affect

to a significant degree:

- the safety or physical or mental integrity of the subjects of the trial;

- the scientific value of the trial;

- the conduct or management of the trial; or

- the quality or safety of any intervention used in the trial.

All substantial amendments will be notified to the METC and to the competent authority.

Non-substantial amendments will not be notified to the accredited METC and the competent

authority, but will be recorded and filed by the sponsor.

11.3 Annual progress report

The sponsor/investigator will submit a summary of the progress of the trial to the

accredited METC once a year. Information will be provided on the date of inclusion of the

first subject, numbers of subjects included and numbers of subjects that have completed the

trial, SAEs/ serious adverse reactions, other problems, and amendments.

11.4 End of study report

The sponsor will notify the accredited METC and the competent authority of the end

of the study within a period of 90 days. The end of the study is defined as the last patient’s

last visit.

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In case the study is ended prematurely, the sponsor will notify the accredited METC

and the competent authority within 15 days, including the reasons for the premature

termination.

Within one year after the end of the study, the investigator/sponsor will submit a final

study report with the results of the study, including any publications/abstracts of the study, to

the accredited METC and the Competent Authority.

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Reference List

1. Hickok DE, Gordon DC, Milberg JA, Williams MA, Daling JR. The frequency of breech presentation by gestational age at birth: a large population-based study. Am.J.Obstet.Gynecol. 1992;166:851-52.

2. Hofmeyr GJ, Kulier R. External cephalic version for breech presentation at term. Cochrane.Database.Syst.Rev. 2000;CD000083.

3. Rietberg CC, Elferink-Stinkens PM, Visser GH. The effect of the Term Breech Trial on medical intervention behaviour and neonatal outcome in The Netherlands: an analysis of 35,453 term breech infants. BJOG. 2005;112:205-09.

4. Hannah ME, Hannah WJ, Hewson SA, Hodnett ED, Saigal S, Willan AR. Planned caesarean section versus planned vaginal birth for breech presentation at term: a randomised multicentre trial. Term Breech Trial Collaborative Group. Lancet 2000;356:1375-83.

5. Collaris RJ, Oei SG. External cephalic version: a safe procedure? A systematic review of version-related risks. Acta Obstet.Gynecol.Scand. 2004;83:511-18.

6. Collins S, Ellaway P, Harrington D, Pandit M, Impey LW. The complications of external cephalic version: results from 805 consecutive attempts. BJOG. 2007;114:636-38.

7. ACOG Committee Opinion No. 340. Mode of term singleton breech delivery. Obstet.Gynecol. 2006;108:235-37.

8. Shennan A, Bewley S. How to manage term breech deliveries. BMJ 2001;323:244-45.

9. Villar J, Carroli G, Zavaleta N, Donner A, Wojdyla D, Faundes A et al. Maternal and neonatal individual risks and benefits associated with caesarean delivery: multicentre prospective study. BMJ 2007;335:1025.

10. Lydon-Rochelle M, Holt VL, Easterling TR, Martin DP. Risk of uterine rupture during labor among women with a prior cesarean delivery. N.Engl.J.Med. 2001;345:3-8.

11. Ananth CV, Smulian JC, Vintzileos AM. The association of placenta previa with history of cesarean delivery and abortion: a metaanalysis. Am.J.Obstet.Gynecol. 1997;177:1071-78.

12. Sheiner E, Shoham-Vardi I, Hallak M, Hershkowitz R, Katz M, Mazor M. Placenta previa: obstetric risk factors and pregnancy outcome. J.Matern.Fetal Med. 2001;10:414-19.

13. Hofmeyr GJ. Interventions to help external cephalic version for breech presentation at term. Cochrane.Database.Syst.Rev. 2002;CD000184.

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nly



15. Yanny H, Johanson R, Balwin KJ, Lucking L, Fitzpatrick R, Jones P. Double-blind randomised controlled trial of glyceryl trinitrate spray for external cephalic version. BJOG. 2000;107:562-64.

16. King JF, Flenady VJ, Papatsonis DN, Dekker GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane.Database.Syst.Rev. 2003;CD002255.

17. Kok M, Bais JM, van Lith JM, Papatsonis DM, Kleiverda G, Hanny D et al. Nifedipine as a uterine relaxant for external cephalic version: a randomized controlled trial. Obstet.Gynecol. 2008;112:271-76.

18. Fernandez CO, Bloom SL, Smulian JC, Ananth CV, Wendel GD, Jr. A randomized placebo-controlled evaluation of terbutaline for external cephalic version. Obstet.Gynecol. 1997;90:775-79.

19. Tan GW, Jen SW, Tan SL, Salmon YM. A prospective randomised controlled trial of external cephalic version comparing two methods of uterine tocolysis with a non-tocolysis group. Singapore Med.J. 1989;30:155-58.

20. Robertson AW, Kopelman JN, Read JA, Duff P, Magelssen DJ, Dashow EE. External cephalic version at term: is a tocolytic necessary? Obstet.Gynecol. 1987;70:896-99.

21. Stock A, Chung T, Rogers M, Ming WW. Randomized, double blind, placebo controlled comparison of ritodrine and hexoprenaline for tocolysis prior to external cephalic version at term. Aust.N.Z.J.Obstet.Gynaecol. 1993;33:265-68.

22. Marquette GP, Boucher M, Theriault D, Rinfret D. Does the use of a tocolytic agent affect the success rate of external cephalic version? Am.J.Obstet.Gynecol. 1996;175:859-61.

23. Chung T, Neale E, Lau TK, Rogers M. A randomized, double blind, controlled trial of tocolysis to assist external cephalic version in late pregnancy. Acta Obstet.Gynecol.Scand. 1996;75:720-24.


25. Pryde PG, Besinger RE, Gianopoulos JG, Mittendorf R. Adverse and beneficial effects of tocolytic therapy. Semin.Perinatol. 2001;25:316-40.

26. Farmacotherapeutisch Kompas, College voor Zorgverzekeringen, The Netherlands. Farmacotherapeutisch Kompas 2008.

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27. Rasmussen BB, Larsen LS, Senderovitz T. Pharmacokinetic interaction studies of atosiban with labetalol or betamethasone in healthy female volunteers. BJOG. 2005;112:1492-99.

28. Husslein P, Cabero RL, Dudenhausen JW, Helmer H, Frydman R, Rizzo N et al. Atosiban versus usual care for the management of preterm labor. J.Perinat.Med. 2007;35:305-13.

29. Lippert TH, Peters FD, Kidess E. Dose-response study of fenoterol on uterine activity in labor at term. Gynecol.Obstet.Invest 1980;11:219-24.

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nlyA randomized controlled trial comparing atosiban and fenoterol as a uterine relaxant for external 1

cephalic version (NTR 1877) 2

3

Joost Velzel, Floortje Vlemmix, Brent C Opmeer, Jan F M Molkenboer, Corine J Verhoeven, Mariëlle 4

G Van Pampus, Dimitri N M Papatsonis, Joke M J Bais, Karlijn C Vollebregt, Liesbeth van der Esch, 5

Joris A M Van der Post, Ben Willem Mol, Marjolein Kok 6

7

Joost Velzel MD, Department of Obstetrics and Gynecology, Academic Medical Center, Amsterdam, 8

the Netherlands 9

Floortje Vlemmix, MD PhD, Department of Obstetrics and Gynecology, Academic Medical Center, 10

Amsterdam, the Netherlands 11

Brent Opmeer, PhD, Clinical Research Unit, Academic Medical Center, Amsterdam, The Netherlands 12

Jan F M Molkenboer, MD PhD, Department of Obstetrics and Gynecology, Spaarne Hospital, 13

Hoofddorp, the Netherlands 14

Corine J Verhoeven, midwife, PhD, Department of Obstetrics and Gynecology, Maxima Medical 15

Centre, Veldhoven, the Netherlands 16

Mariëlle G Van Pampus, MD, PhD, Department of Obstetrics and Gynecology, Onze Lieve Vrouwe 17

Gasthuis, Amsterdam, the Netherlands 18

Dimitri N M Papatsonis, MD, PhD, Department of Obstetrics and Gynecology, Amphia Hospital, 19

Breda, the Netherlands 20

Joke M J Bais, MD, PhD, Department of Obstetrics and Gynecology, Medical Centre Alkmaar, 21

Alkmaar, the Netherlands 22

Karlijn C Vollebregt, MD, PhD, Department of Obstetrics and Gynecology, Kennemer Gasthuis, 23

Haarlem, the Netherlands 24

Liesbeth van der Esch, midwife, Department of Obstetrics and Gynecology, St. Antonius Hospital, 25

Nieuwegein, the Netherlands 26

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nlyJoris A M Van der Post, professor, Department of Obstetrics and Gynecology, Academic Medical 27

Center, Amsterdam, the Netherlands 28

Ben Willem Mol, professor, The Robinson Institute, School of Paediatrics and Reproductive Health, 29

University of Adelaide, and the South Australian Health and Medical Research Institute, Adelaide, 30

Australia 31

Marjolein Kok, MD, PhD, Department of Obstetrics and Gynecology, Academic Medical Center, 32

Amsterdam, the Netherlands 33

34

Correspondence to: 35

J Velzel, MD. 36

Amsterdam Medical Center, Department of Obstetrics and Genecology, 37

Meibergdreef 9, Room H4-240, 1105 AZ Amsterdam, the Netherlands. 38

Telephone number: +31630151668 39

Fax number: +31205669675 40

Email: [email protected] 41

42

Word count: 2284 43

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nlyAbstract: 44

Objective: We compared the effectiveness of atosiban and fenoterol as a uterine relaxant in women 45

undergoing ECV for breech presentation. 46

Design: A multicenter, open label, randomized controlled trial. 47

Setting: Eight hospitals in the Netherlands. 48

Participants: Women with a singleton fetus in breech presentation and a gestational age beyond 34 49

weeks were eligible. 50

Intervention: Participants were randomly allocated in a 1:1 ratio to receive either 6.75 mg atosiban 51

i.v. or 40 μg fenoterol i.v. for uterine relaxation. 52

Main Outcomes and Measures: The primary outcome was a fetus in cephalic-position 30 minutes 53

after the procedure. Secondary outcome measures were cephalic presentation at delivery, mode of 54

delivery, neonatal outcome and adverse events during ECV. All analyses were done on an intention-55

to-treat basis. 56

Results: From August 2009 to May 2014, 910 participants were eligible for the study, of which 830 57

participants were randomized. We allocated 416 participants to atosiban and 414 to fenoterol. 58

Cephalic-position 30 minutes after the procedure occurred significantly less in the atosiban group as 59

compared to the fenoterol group (33% versus 40%, RR 0.73 (95% CI 0.55 to 0.93)). Cephalic 60

presentation at birth occurred in 35% in the atosiban group and 40% in the fenoterol group (RR 0.86, 61

95% CI 0.72 to 1.03), while cesarean delivery was performed in 60% versus 55% in the atosiban group 62

and the fenoterol group respectively (RR 1.09, 95% CI 0.96 to 1.2). There were no significant 63

differences in neonatal outcomes or in adverse events. 64

Conclusions: In women undergoing ECV for breech presentation, uterus relaxation with fenoterol is 65

more effective than with atosiban. 66

TRIAL REGISTRATION: Dutch Trial Register, NTR 1877. 67

68

69

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nlyWhat is already known on this topic 70

Breech presentation occurred in 3 to 4% of all term singleton pregnancies, and since publication of 71

the Term Breech Trial, elective caesarean delivery is the dominant mode of delivery in most 72

countries. 73

74

External cephalic version (ECV) is a relatively safe obstetrical procedure that reduces non-cephalic 75

birth and caesarean delivery. 76

77

To enhance ECV success rate, beta-mimetics are widely used. However, beta-mimetics have known 78

adverse maternal cardiovascular side effects. Atosiban could be an alternative. 79

80

What this study adds 81

In women undergoing ECV uterine relaxation with atosiban resulted in a lower rate of fetuses in 82

cephalic-position after the procedure as compared to fenoterol. 83

84

The frequency of both poor neonatal and poor maternal outcome did not differ between the two 85

groups. Emergency delivery did occur twice within the fenoterol group. 86

87

Side effects occurred more often in the fenoterol group compared to the atosiban group. 88

89

90

91

92

93

94

95

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nlyIntroduction: 96

Breech presentation occurred in 3 to 4% of all term singleton pregnancies. Since publication of the 97

Term Breech Trial, elective caesarean delivery is the dominant mode of delivery in most countries.1–3

98

In 2015, the World Health Organization stated that from a global perspective caesarean delivery was 99

overused.4,5

Breech presentation is the third most common indication for elective caesarean 100

delivery.6 External cephalic version (ECV) is a safe obstetrical procedure that reduces non-cephalic 101

birth and caesarean delivery with approximately 50%.7 In 2014, the American College of 102

Obstetricians and Gynaecologists and the Society for Maternal-Fetal Medicine jointly developed a 103

consensus statement on safe prevention of the elective caesarean delivery in which the performance 104

of ECV is highly recommended.6 This recommendation is specifically relevant in low and middle 105

income countries where the impact of caesarean delivery on morbidity and mortality is more severe. 106

Several methods have been proposed to enhance the outcome of ECV, including uterine relaxation, 107

epidural or spinal analgesia and amnioinfusion as well as complementary methods such as vibro-108

acoustic stimulation, acupuncture and moxibustion.8 Drug induced uterine relaxation is known to 109

increase the success of ECV.9 The types of drugs used are nitric-oxide, beta-mimetics, calcium 110

channel antagonists and oxytocin antagonists.6 The majority of studies that evaluated the 111

effectiveness of tocolysis have used beta-mimetics (beta-mimetics versus placebo, nine studies, 112

pooled RR 1.6 (95% CI 1.2 to 2.0) for cephalic presentation after ECV attempt).8 However, beta-113

mimetics have known adverse maternal cardiovascular side effects in terms of flushing and 114

palpitations.8 115

In 2008, we showed in a randomized trial that nifidepine was not effective as a tocolytic compared to 116

women undergoing ECV without tocolysis for cephalic presentation after ECV attempt (RR 1.1, 95% CI 117

0.85 to 1.5).10

Atosiban, an oxytocin antagonist, has no cardiovascular side-effects and is becoming 118

more often used for ECV. However, thus far there has been no randomized controlled trial to assess 119

the effectiveness of atosiban to improve the ECV success rate. Therefore, we evaluated the 120

effectiveness of atosiban compared to the beta-mimetic fenoterol on ECV outcome. 121

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nly 122

Methods: 123

Study Design and participants 124

We performed a multicenter, open-label randomized controlled trial in one academic and seven 125

teaching hospitals in the Netherlands. These hospitals are together responsible for 16,000 increased-126

risk deliveries annually (annual hospital delivery rates ranging from 1,500 to 3,000). The study was 127

approved by research ethics committee of the Academic Medical Center in Amsterdam (reference 128

number MEC 08-364) and by the board of directors of each of the participating hospitals. The study is 129

registered in the Dutch Trial register (NTR 1877). We followed the CONSORT guidelines in the report 130

of the study. 131

Women with a singleton fetus in breech position who were scheduled for ECV were eligible for the 132

study. Exclusion criteria were maternal age less than 18 years old, gestational age below 32 weeks, 133

any contra-indication to vaginal birth (e.g. placenta praevia), any contraindication for ECV according 134

to the Guideline of the Dutch Association for Obstetrics and Gynaecology 11

(scarred uterus other 135

than transverse in the lower segment, known uterine anomalies, placental abruption in history or 136

signs of placental abruption, severe preeclampsia or HELLP syndrome, bleeding less than seven days 137

before ECV attempt, ruptured membranes), any known contra-indication to one of the two drugs, 138

suspected intrauterine growth restriction (defined as estimated fetal weight <P5 for gestational age 139

assessed by ultrasonography), severe oligohydramnios (deepest pool < 2 cm), fetal anomalies or non-140

reassuring fetal heart rate monitoring. Eligible women were identified by the local midwifes, 141

residents or gynecologists. After counseling and reading the patient information form, patients were 142

asked for written informed consent. 143

144

Randomization 145

Just before the ECV procedure, women were randomly assigned to receive atosiban (intervention 146

group) or fenoterol (control group) (allocation ratio 1:1). Group assignment was based on computer-147

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nlygenerated random sequence and stratified by hospital and parity, and rendered by an independent 148

data manager. Participants and investigators were aware of allocation, as blinding was impossible 149

due to obvious and common maternal side effects that occur with fenoterol such as tachycardia, 150

dizziness and flushes. 151

152

Interventions 153

The ECV procedure was performed in all hospitals by a team of experienced obstetricians and 154

midwives who perform ECV on a regular base. An ultrasound examination was performed to assess 155

the position of the fetus including identification of type of breech (frank, complete or footling), 156

placental location, an estimate of fetal weight, an estimate of amniotic fluid volume including the 157

measurement of the largest pocket depth. The ultrasound was performed by a trained sonographer, 158

obstetrician or midwife. Fetal well-being was established by electronic fetal heart rate monitoring for 159

at least 30 minutes preceding and after the procedure. After fetal heart rate monitoring and fifteen 160

minutes before starting ECV. Fifteen minutes before starting ECV, the participating woman received 161

an intravenous bolus of atosiban (6.75 mg in 0.9 ml (7.5 mg/ml)) or fenoterol (40 μg in 0.8 ml (0.5 162

mg/10 ml)) administered by a physician. For the ECV procedure a forward and backward roll was 163

allowed. The fetal heart rate was monitored intermittently by ultrasound scanning during the 164

procedure, followed by electronic fetal heart rate monitoring after the procedure. If fetal bradycardia 165

would occur, the duration was registered. Non-sensitized Rhesus negative women received anti-D 166

immunoglobulin (1,000 international units intramuscularly) after the ECV procedure. 167

168

Outcomes 169

The primary outcome measure was cephalic presentation 30 minutes after the procedure, confirmed 170

by ultrasound. Secondary outcomes are cephalic presentation at delivery, mode of delivery, and 171

complications of ECV events due to atosiban or fenoterol. Complications of ECV were persistent non-172

reassuring fetal CTG after ECV, occult or overt umbilical cord prolapse, placental abruption and 173

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nlyemergency delivery. Adverse events due to atosiban or fenoterol were defined as chest pain, nausea, 174

vomiting, headaches, flushing, dizziness, hypotension (associated with fainting or CTG abnormalities), 175

tachycardia resulting in palpitations, local reaction of the skin on injection of the medication, 176

anaphylactic shock, cessation of treatment due to side effects. 177

Post hoc outcomes were gestational age at delivery, time to delivery, admission to neonatal intensive 178

care for >24 hours, Apgar <7 at 5 minutes, birth weight, blood loss, women requiring blood 179

transfusion, maternal admission in hospital postpartum in days, maternal complication postpartum 180

defined as puerperal fever, (suspected) endometritis, mastitis, operation for placental rest, 181

pulmonary embolism. 182

All data were collected on web-based electronic case record forms and uploaded cases were stored 183

in a database. For participants delivering outside one of the participating hospitals, paper forms to 184

register delivery were supplied. Primary care takers were approached to ensure that these forms 185

were returned after the study. 186

187

Sample size 188

The trial was designed to detect a 10% improvement of the primary outcome, being in cephalic 189

position 30 minutes after the ECV procedure, assuming a 50% success rate in the fenoterol group 190

(beta-error 20%, alpha-error 5%, 2-sided test). We needed to randomize 806 women to show an 191

improvement from 50% to 60% with atosiban. 192

193

Analysis 194

Multiple imputation (five times) was performed on the primary outcome using baseline covariates. 195

The primary analysis was subsequently performed on imputed datasets and estimates from imputed 196

datasets were pooled using Rubin’s rule. Secondary outcome were analysed by complete-case 197

analysis. Baseline data were analyzed descriptively for the women and their pregnancies in the two 198

groups. The rates of the primary and secondary outcomes were compared in the two groups using 199

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nlythe Chi-squared test. A P-value < .05 was considered to indicate statistical significance. Relative risks 200

and appropriate 95% confidence intervals were calculated for each outcome. One interim analysis 201

was planned half way through inclusion to evaluate safety by assessing adverse events. Serious 202

adverse events were reported to an independent Data Safety Monitoring Board. They noted no 203

conditions to stop the trial. 204

205

Patient involvement: 206

As we are unaware of a patient organization for women with breech presentation, patients were not 207

involved in setting the research question or the outcome measures, nor were they involved in the 208

design and implementation of the study. We will use the information in a guideline and information 209

will be added in patient information brochures. 210

211

Results: 212

Between August 2009 and May 2014, we enrolled 830 women, 416 to atosiban (intervention group) 213

and 414 to fenoterol (control group). The mean gestational age at which ECV was performed was 36 214

weeks, and 62% of the women were nulliparous. Baseline characteristics were comparable in the two 215

groups and summarized in Table 1. Primary outcome data were available for 410 women in the 216

atosiban group and 408 in the fenoterol group (Figure 1). 217

218

After ECV with uterine relaxation with atosiban, cephalic position 30 minutes after the ECV 219

procedure was 33% as compared to 40% with fenoterol (RR 0.73 (95% CI 0.55 to 0.93)). At delivery, 220

there were 35% fetuses in cephalic position in the atosiban group and 40% in the fenoterol group (RR 221

0.86 (95% CI 0.72 to 1.03)). Of the women assigned to atosiban, cesarean delivery was performed in 222

60% of the women and 55% in the fenoterol group (RR 1.09 (95% CI 0.96 – 1.22))(see table 2). 223

224

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nlyIn the atosiban group, of the 139 women with a fetus in cephalic presentation, 109 (80.9%) had a 225

spontaneous vaginal delivery, 15 (10.8%) had an instrumental delivery, 9 (6.5%) had an intrapartum 226

cesarean delivery. In the fenoterol group, of the 160 women with a child in cephalic procedure, 125 227

(78.1%) had a spontaneous vaginal delivery, 13 (8.1%) had an instrumental delivery, 19 (11.9%) had 228

an intrapartum cesarean delivery. Emergency caesarean delivery for suspected fetal distress was 229

more common in the fenoterol group: two cases immediately following ECV procedure and the 230

others during labor. To evaluate the significance of this difference we calculated the risk difference 231

for emergency caesarean delivery for all women with a planned vaginal birth. In the atosiban group, 232

4 out of 204 participants had emergency caesarean delivery for suspected fetal distress compared to 233

19 out of 240 participants of the fenoterol group (RR 0.75, 95% CI 0.24 to 1.29). 234

235

Table 3 shows the neonatal and maternal outcomes. The frequency of both poor neonatal and poor 236

maternal outcome did not differ between the two groups. The average time between ECV and 237

delivery was 22 days in both groups. Labor was not induced routinely after a successful ECV, and 238

induction was only done for additional indications like hypertension and others. Perinatal or neonatal 239

mortality did not occur in the atosiban group, while two children died in the fenoterol group. One 240

neonate, born five weeks after the ECV, died due to a postpartum detected autosomal recessive 241

congenital disorder. The other baby died two hours postpartum after a vacuum-assisted delivery for 242

prolonged second stage of labor. ECV had been performed five weeks before labor. The baby had 243

had normal Apgar scores (9/10), and autopsy did not reveal any cause of death. 244

245

Table 4 shows the rates of complications of ECV and adverse events due to medication. There was no 246

significant difference between the atosiban and fenoterol groups in the frequency of complications 247

after ECV was performed and adverse events due to medication. Emergency delivery did not occur in 248

the atosiban group and twice in the fenoterol group. In one woman, there was a non-reassuring CTG 249

after an ECV attempt. In the other woman, the umbilical cord was lying before the fetal head after 250

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nlysuccessful ECV as confirmed by ultrasound, for which an emergency cesarean delivery was 251

performed. One woman in the fenoterol group had severe hypotension during ECV, after which the 252

ECV was stopped. No adverse events due to medication were reported in the atosiban group. In the 253

fenoterol group, one woman had severe hypotension during ECV, after which the ECV was stopped. 254

There was a significant difference between side effects in both groups, with 15 women (5.2%) 255

complaining of palpitations in the atosiban group versus 209 women (71%) in the fenoterol group (RR 256

0.07 (95% CI 0.04 to 0.12)). 257

258

Discussion 259

Principal findings 260

In this randomized controlled trial studying 818 women, we found that in women undergoing ECV 261

uterine relaxation with atosiban resulted in a lower rate of fetuses in cephalic-position after the 262

procedure as compared to fenoterol. This resulted in higher cesarean delivery rate after the use of 263

atosiban as compared to fenoterol. Although the difference was not statistically significant, it is likely 264

to be true, as the number of women in cephalic position after the procedure was significantly 265

decreased after atosiban. 266

267

Strengths and limitations of this study 268

Our study has several strengths. To the best of our knowledge, this is the largest single trial on 269

uterine relaxation with ECV and the first trial evaluating atosiban as uterine relaxant for ECV. 270

We used beta-mimetics in the control group and not placebo, since this was at the start of the trial 271

the best treatment in a clinical setting by improving success rate with a 10% absolute increase of 272

cephalic presentations at delivery.8To allow the drugs to reach a full therapeutic blood level and to 273

overcome unintended protocol violations, the protocol for both drug administrations were equalized; 274

the ECV attempt was started 15 minutes after administration of one of either drug. As the mean time 275

for both drugs to reach its maximum concentration in serum is 30 minutes with half-life times of 1.4 276

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nlyand 2 hours, respectively, adequate drug levels were reached within the time frame, and still high 277

enough to cause relaxation of the uterus during the ECV attempt.12–16

278

A limitation of our study is that, since beta-mimetics result in obvious and frequently occurring side 279

effects, we did not blind participating doctors and patients for the allocated treatment. However, 280

side effects were never a reason to stop the intervention and we think that bias due to non-blinding 281

is virtually absent. Our success rate was lower than the anticipated success rate.8 This could well be 282

the result of selection due to referral of some women after an initial unsuccessful attempt in an out 283

of hospital setting by independent midwives. A recent cohort study of ECV attempts by midwives in 284

an out of hospital setting in the Netherlands reported a higher success rate.17

In addition, the success 285

rate in our study does correspond with other cohort studies and randomized controlled trials 286

comparing tocolytic agents.9,10,18,19

Despite the different success rate that we observed, the sample 287

size calculation is still adequate to detect the anticipated increase in success rate, as lower or higher 288

baseline rates have more statistical power to detect similar changes of 10% absolute risk difference. 289

Therefore, we believe that our study is generalizable. Missing data were balanced between groups 290

averting any bias in outcome. 291

In our trial registration, we announced two primary outcomes, fetal presentation 30 minutes after 292

the procedure and fetal presentation at delivery. In this trial report, we retained the primary 293

outcome of first assessment; fetal presentation 30 minutes after the procedure. This is in line with 294

most other trials evaluating tocolytics in ECV. Also, fetal presentation 30 minutes after the procedure 295

is the first available outcome to assess the effectiveness of the drugs. 296

297

Comparison with other studies 298

A recently published Cochrane review on uterine relaxants for ECV, concluded that beta-mimetics in 299

comparison with placebo, were the most effective drug in increasing cephalic presentation in labor 300

and thereby reducing the caesarean section rate (six studies, 742 participants, RR 0.77, 95% CI 0.67 301

to 0.88).8 Taking this review and our results into account, we can conclude that beta-mimetics are 302

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nlythe most effective in obtaining cephalic presentation after version. Also, fenoterol is much cheaper 303

compared to atosiban (€ 0.90 and € 31.80 respectively for fenoterol and atosiban in the 304

Netherlands). 305

Our study clearly demonstrates that fenoterol has side effects (71% versus 5.2%). However, most 306

side effects were limited to feelings of tachycardia, while severe hypotension occurred in only one 307

participant after the use of fenoterol. In 2011, one in three deliveries in the United States was a 308

cesarean delivery, making cesarean delivery the most common major surgical procedure for women 309

in the United States.20,21

Given the substantial increased rates of caesarean deliveries without clear 310

evidence that there is a decrease in maternal and neonatal morbidity or mortality, cesarean delivery 311

might be overused. Therefore, prevention of planned caesarean section is one of the major topics to 312

improve maternal and neonatal outcome in current obstetric practice.6,22

As breech presentation is 313

the third most common indication for primary cesarean delivery in the United States, and ECV is 314

proven to be a safe procedure, implementation of beta-mimetics as routine uterine relaxant in ECV 315

should be high priorty.23–26

316

317

Conclusion and policy implications 318

In conclusion, we found that in women undergoing ECV uterine relaxation with fenoterol is more 319

effective than with atosiban. We therefore recommend the use of fenoterol as a uterine relaxant to 320

increase the ECV success rate and to decrease the cesarean delivery rate. 321

322

Contributors: 323

FV, BO, DP, JB, JvdP, BM, MK conceived and designed the study. JV, FV, JM, CV, MvP, DP, JB, KV, LvdE, 324

JvdP, BM, MK acquired the data. JV, FV, BO carried out the statistical analysis. BM, MK supervised the 325

study and are the guarantors. BO provided administrative, technical, or material support. All authors 326

analysed and interpreted the data, drafted the manuscript, critically revised the manuscript for 327

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nlyimportant intellectual content, had full access to all of the data in the study, and take responsibility 328

for the integrity of the data and the accuracy of the data analysis. 329

330

Conflict of interest: 331

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf 332

and declare: no support from any organization for the submitted work; no financial relationships with 333

any organizations that might have an interest in the submitted work in the previous three years; no 334

other relationships or activities that could appear to have influenced the submitted work. BM is 335

adviser of ObsEva, Geneva, Switserland. 336

337

Acknowledgements and funding: 338

This study was not externally funded and supported by the Dutch Obstetric Consortium. We thank 339

the research nurses, midwives and administrative assistants of our consortium, and the residents, 340

nurses, midwives, and gynecologists of the participating centers for their help with participant 341

recruitment and data collection. We thank the members of the Data Safety Monitoring Committee. 342

We thank all women who participated in this study. 343

344

Data sharing statement: 345

Full dataset is available from the corresponding author at [email protected] on reasonable request. 346

Participants gave consent was not obtained but the presented data are anonymized and risk of 347

identification is low. 348

349

Transparency: 350

The corresponding author (JV) affirms that the manuscript is an honest, accurate, and transparent 351

account of the study being reported, no important aspects of the study have been omitted, and any 352

discrepancies from the study as planned have been explained. 353

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nly 354

References: 355

1. Hickok, D. E., Gordon, D. C., Milberg, J. A., Williams, M. A. & Daling, J. R. The frequency of 356

breech presentation by gestational age at birth: a large population-based study. Am. J. Obstet. 357

Gynecol. 166, 851–2 (1992). 358

2. Rietberg, C. C. T., Elferink-Stinkens, P. M. & Visser, G. H. A. The effect of the Term Breech Trial 359

on medical intervention behaviour and neonatal outcome in The Netherlands: an analysis of 360

35,453 term breech infants. Br. J. Obstet. Gynaecol. 112, 205–9 (2005). 361

3. Hannah, M. E. et al. Planned caesarean section versus planned vaginal birth for breech 362

presentation at term: a randomised multicentre trial. Term Breech Trial Collaborative Group. 363

Lancet 356, 1375–83 (2000). 364

4. Human Reproduction Programme. WHO Statement on Caesarean Section Rates. 1–8 (2015). 365

doi:10.1111/1471-0528.13526 366

5. Gibbons, L. et al. Inequities in the use of cesarean section deliveries in the world. Am. J. 367

Obstet. Gynecol. 206, 331.e1–331.e19 (2012). 368

6. ACOG & SMFM. Safe Prevention of the Primary Cesarean Delivery. Obstet. Gynecol. 123, 693–369

711 (2014). 370

7. Hofmeyr, G. J., Kulier, R. & West, H. M. External cephalic version for breech presentation at 371

term. Cochrane database Syst. Rev. 4, CD000083 (2015). 372

8. Cluver, C., Gyte, G. M. L., Sinclair, M., Dowswell, T. & Hofmeyr, G. J. Interventions for helping 373

to turn term breech babies to head first presentation when using external cephalic version. 374

Cochrane database Syst. Rev. 2, CD000184 (2015). 375

9. Hofmeyr, G. J. Interventions to help external cephalic version for breech presentation at term. 376

Cochrane Database Syst. Rev. CD000184 (2004). doi:10.1002/14651858.CD000184 377

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nly10. Kok, M. et al. Nifedipine as a uterine relaxant for external cephalic version: a randomized 378

controlled trial. Obstet. Gynecol. 112, 271–6 (2008). 379

11. Obstetrische Werkgroep. Stuitligging. Guidel. Dutch Coll. Obstet. Gynaecol. (2008). 380

12. Lundin, S., Broeders, A. & Melin, P. Pharmacokinetic properties of the tocolytic agent [Mpa1, 381

D-Tyr(Et)2, Thr4, Orn8]-oxytocin (antocin) in healthy volunteers. Clin. Endocrinol. (Oxf). 39, 382

369–74 (1993). 383

13. Akerlund, M., Hauksson, A., Lundin, S., Melin, P. & Trojnar, J. Vasotocin analogues which 384

competitively inhibit vasopressin stimulated uterine activity in healthy women. Br. J. Obstet. 385

Gynaecol. 93, 22–7 (1986). 386

14. Lippert, T. H., Peters, F. D. & Kidess, E. Dose-response study of fenoterol on uterine activity in 387

labor at term. Gynecol. Obstet. Invest. 11, 219–24 (1980). 388

15. Rasmussen, B. B., Larsen, L. S. & Senderovitz, T. Pharmacokinetic interaction studies of 389

atosiban with labetalol or betamethasone in healthy female volunteers. BJOG 112, 1492–9 390

(2005). 391

16. Reinheimer, T. M. et al. Barusiban, a new highly potent and long-acting oxytocin antagonist: 392

pharmacokinetic and pharmacodynamic comparison with atosiban in a cynomolgus monkey 393

model of preterm labor. J. Clin. Endocrinol. Metab. 90, 2275–81 (2005). 394

17. Beuckens, a et al. An observational study of the success and complications of 2546 external 395

cephalic versions in low-risk pregnant women performed by trained midwives. BJOG An Int. J. 396

Obstet. Gynaecol. n/a–n/a (2015). doi:10.1111/1471-0528.13234 397

18. Collins, S., Ellaway, P., Harrington, D., Pandit, M. & Impey, L. W. M. The complications of 398

external cephalic version: results from 805 consecutive attempts. Br. J. Obstet. Gynaecol. 114, 399

636–8 (2007). 400

19. Vlemmix, F. et al. Implementation of client versus care-provider strategies to improve 401

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nlyexternal cephalic version rates: a cluster randomized controlled trial. Acta Obstet. Gynecol. 402

Scand. 94, 518–26 (2015). 403

20. Hamilton, B. E., Hoyert, D. L., Martin, J. A., Strobino, D. M. & Guyer, B. Annual summary of 404

vital statistics: 2010-2011. Pediatrics 131, 548–58 (2013). 405

21. MacDorman, M., Declercq, E. & Menacker, F. Recent Trends and Patterns in Cesarean and 406

Vaginal Birth After Cesarean (VBAC) Deliveries in the United States. Clin. Perinatol. 38, 179–407

192 (2011). 408

22. Gregory, K. D., Jackson, S., Korst, L. & Fridman, M. Cesarean versus vaginal delivery: Whose 409

risks? whose benefits? Am. J. Perinatol. 29, 7–18 (2012). 410

23. ACOG. ACOG Committee Opinion No. 340. Mode of term singleton breech delivery. ACOG 411

Guidel. No 340 108, 235–7 (2006). 412

24. Barber, E. L. et al. Contributing Indications to the Rising Cesarean Delivery Rate. Obstet. 413

Gynecol. 118, 29–38 (2011). 414

25. Collaris, R. J. & Oei, S. G. External cephalic version: a safe procedure? A systematic review of 415

version-related risks. Acta Obstet. Gynecol. Scand. 83, 511–8 (2004). 416

26. Grootscholten, K., Kok, M., Oei, S. G., Mol, B. W. J. & van der Post, J. A. External cephalic 417

version-related risks: a meta-analysis. Obstet. Gynecol. 112, 1143–51 (2008). 418

419

420

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nlyFigures and tables: 421

422

Figure 1. Randomization, treatment and follow-up of participants 423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

Assessed for eligibility (n = 910)

Allocated to atosiban (n = 416)

Received allocated intervention

(n = 416)

Did not receive allocated

intervention (n = 0)

Lost to follow up (n = 6)

Randomized (n = 830)

Excluded (n=80)

Not meeting inclusion criteria

(n= 18)

Declined to participate (n= 58)

Declined ECV (n= 4)

Allocated to fenoterol (n = 414)

Received allocated intervention

(n = 413)

Did not receive allocated

intervention (n = 1)

Lost to follow up (n = 6)

N = 416 for intention to treat

analysis

N = 410 for complete-case

analysis

N = 414 for intention to treat

analysis

N = 408 for complete-case

analysis

Enrollment

Allocation

Follow-up

Analysis

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nlyTable 1. Baseline characteristics of study participants by intervention group

Atosiban (n = 410) Fenoterol (n = 408)

Age in years (mean; SD) 32.1 (4.0) 32.4 (4.3)

Multiparous women (%) 154 (37.6%) 153 (37.5%)

Gestational age at ECV (mean; SD) 35.8 (0.9) 35.9 (1.0)

Caucasian ethnicity (%) 350 (49.6%) 355 (50.4%)

BMI (mean; SD) 24.1 (4.3) 24.2 (4.8)

Estimated foetal weight (mean; SD)1

2622 (391.0) 2572 (457.5)

Frank breech (%)2 300 (76.5) 273 (69.8)

Anterior placental location (%)3

127 (32.9) 144 (37.3)

Estimated Amniotic Fluid Index

(mean; SD)4

13.8 (4.9) 13.7 (4.7)

1 Based on n=234 for atosiban and n=250 for fenoterol due to missing data.

2

Based on n=392 for atosiban and n=391 for fenoterol due to missing data. 3

Based on n=386 for atosiban and n=386 for fenoterol due to missing data. 4

Based on n=263 for atosiban and n=281 for fenoterol

447

448

449

450

451

452

453

454

455

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nlyTable 2. Primary and secondary outcomes

Atosiban

(n = 416)

Fenoterol

(n = 414)

RR (95% CI)

Or P value

Successful ECV (%)1 140 (34%) 166 (40%) 0.73 (0.55 to 0.93)

Cephalic presentation at delivery2

(%)

139 (35%) 160 (40%) 0.86 (0.72 to 1.03)

Mode of delivery3

Vaginal delivery (%) 163 (40%) 180 (45%) 0.89 (0.76 to 1.05)

- Spontaneous 146 167

- Instrumental 17 13

Caesarean delivery (%) 240 (60%) 218 (55%) 1.09 (0.96 to 1.22)

- Elective 199 158

- No progress of labor 27 26

- Suspected fetal distress 4 21

- Other 10 13

1 Imputation for primary outcome.

2 Based on n=402 for atosiban and n=397 for fenoterol due to missing

data. 3 Based on n=403 for atosiban and n=398 for fenoterol due to missing data.

456

457

458

459

460

461

462

Table 3. Neonatal and maternal outcomes

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nly Atosiban

(n = 410)

Fenoterol (n = 408) P-value or

RR (95% CI)

Gestational age at delivery in

weeks (mean; SD)

38.9 (1.3) 38.9 (1.9) 0.70*

Mean time to delivery in days

(mean; SD)

22 (9.1) 22 (9.6) 0.23*

Perinatal or neonatal mortality (%) 0 (0.0%) 2 (0.1%) 0.15*

Admission to neonatal intensive

care for >24 hours (days)1 (%)

16 (0.4%) 17 (0.4%) 0.94 (0.48 to 1.8)

Apgar < 7 at 5 minutes2

(%) 6 (1.5%) 13 (3.2%) 0.45 (0.17 to

1.20)

Birth weight3 (grams; SD) 3356 (460) 3364 (523) 0.81*

Female gender (%) 204 (49.8%) 204 (50.0%) 1.00 (0.87 to

1.14)

Blood loss4 (ml) (mean; SD)) 474 (473.2) 470 (447.3) 0.92*

Women requiring blood

transfusions5

(%)

6 (1.5) 7 (1.7) 0.86 (0.29 to 2.5)

Maternal admission in hospital

postpartum6 (mean in days)

290 (3.1) 287 (3.1) 0.94*

Maternal postpartum

complications7

(%)

15 (3.9) 16 (4.1) 0.94 (0.74 to 1.9)

*P-value;


2 Based on n=399

for atosiban and n=397 for fenoterol due to missing data. 3 Based on n=394 for atosiban and n=396 for

fenoterol due to missing data. 4 Based on n=390 for atosiban and n=389 for fenoterol due to missing


6 Based on n=398 for

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nlyatosiban and n=395 for fenoterol due to missing data.

7 Based on n=385 for atosiban and n=386 for

fenoterol due to missing data. Postpartum complication: puerperal fever, (suspected) endometritis,

mastitis, operation for placental rest, pulmonary embolism.

463

464

465

466

467

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nlyTable 4. Complications of ECV and adverse events due to medication

Atosiban (n = 410) Fenoterol (n = 408) RR (95% CI)

Non-reassuring CTG registration

after ECV attempt resulting in

emergency delivery1

(%)

0 1 (0.2%) -

Placental abruption3 1 (0.2%) 0 -

Emergency delivery4 0 2 (0.4%) -

Adverse events due to medication5

0 1 (0.2%) -

Cessation of treatment due to side

effects6

0 1 (0.2%) -

Minor side effects 7 86 (30.0%) 224 (75.7%) 0.40 (0.33 to 0.48)

Palpitations 8

15 (5.2%) 209 (70.6%) 0.07 (0.04 to 0.12)

Dizziness 9

25 (8.8%) 55 (18.8%) 0.47 (0.30 to 0.73)

Flushes 10

17 (5.9%) 99 (33.6%) 0.18 (0.11 to 0.29)



atosiban and n=394 for fenoterol due to missing data. 3 Based on n=392 for atosiban and n=390 for




atosiban and n=396 for fenoterol due to missing data. 7 Based on n=287 for atosiban and n=296 for




atosiban and n=295 for fenoterol due to missing data. Minor side effects are defined as one or a

combination of the following complaints: palpitations, nausea, vomiting, headaches, flushing, dizziness.

468

469

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nlyPrint abstract: 470

Study question: We compared the effectiveness of atosiban and fenoterol as a uterine relaxant in 471

women undergoing ECV for breech presentation. 472

Methods: We performed an open label randomized controlled trial in eight hospitals in the Nether-473

lands, which included women with a singleton fetus in breech presentation and a gestational age 474

beyond 34 weeks were eligible. Participants were randomly allocated in a 1:1 ratio to receive either 475

6.75 mg atosiban i.v. or 40 μg fenoterol i.v. for uterine relaxation. The primary outcome was a fetus 476

in cephalic-position 30 minutes after the procedure. Secondary outcome measures were cephalic 477

presentation at delivery, mode of delivery, neonatal outcome and adverse events during ECV. All 478

analyses were done on an intention-to-treat basis. 479

Study answer and limitation: We allocated 416 participants to atosiban and 414 to fenoterol. Ce-480

phalic-position 30 minutes after the procedure occurred significantly less in the atosiban group as 481

compared to the fenoterol group (33% versus 40%, RR 0.73 (95% CI 0.55 to 0.93)).The study was not 482

blinded and the anticipated success rate was lower than expected. 483

What this study adds: In women undergoing ECV uterine relaxation with atosiban resulted in a lower 484

rate of fetuses in cephalic-position after the procedure as compared to fenoterol. 485

Funding, competing interest, data sharing: This study was not externally funded and supported by 486

the Dutch Obstetric Consortium. All authors have completed the ICMJE uniform disclosure form at 487

www.icmje.org/coi_disclosure.pdf and declare no competing interests. Full dataset is available from 488

the corresponding author on reasonable request. 489

Study registration: Dutch Trial Register, NTR 1877. 490

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