Induction of labour versus expectant management in women with preterm prelabour rupture of membranes between 34 and 37 weeks (the PPROMEXIL-trial).

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Study protocol

Induction of labour versus expectant m anagem ent in women with

p reterm prelabour rupture of m em branes between 34 and 37

weeks (the PPROMEXIL-trial)

David P van der H am *1, Jan G Nijhuis2, Ben Willem J Mol3, Johannes J van

Beek1, Brent C O pm eer4, Denise Bijlenga5, Mariette G roenew out6,

Birgit Arabin7, Kitty WM Bloem enkam p8, Wim J van W ijngaarden9,

Maurice GAJ W outers10, Paula JM Pernet11, M artina M Porath3,

Jan FM M olkenboer12, Jan B Derks13, Michael M Kars14,

H ubertina CJ Scheepers15, Martin JN W einans16, Mallory D W oiski15,

Hajo IJ W ildschut

17

and Christine Willekes

2

Address: 'D e p a rtm en t o f Obstetrics and Gynaecology, VieCuri Medical Centre Venlo, the N etherlands, 2D epartm ent o f O bstetrics and

Gynaecology, University H ospital M aastricht, th e N etherlands, 3D epartm ent o f Obstetrics and Gynaecology, M axima Medical Centre Veldhoven, the N etherlands, 4D epartm ent o f Clinical Epidem iology, Biostatistics and Bioinform atics, Academic Medical Centre A m sterdam , th e N etherlands, 5D epartm ent o f Social M edicine, Academic Medical Centre A m sterdam , the N etherlands, 6D epartm ent o f O bstetrics and Gynaecology, University Medical Centre G roningen, the N etherlands, 7D epartm ent o f O bstetrics and Gynaecology Isala Klinieken Zwolle, the N etherlands, 8D epartm ent o f Obstetrics and Gynaecology, University Medical Centre Leiden, the N etherlands, 9D epartm ent o f O bstetrics and Gynaecology, Bronovo H ospital th e Hague, th e N etherlands, 10D epartm ent o f O bstetrics and Gynaecology, VU Medical Centre A m sterdam , th e N etherlands,

''D e p a rtm e n t o f O bstetrics and Gynaecology, Kennem er Gasthuis H aarlem , th e N etherlands, 12D epartm ent o f O bstetrics and Gynaecology, Sint A nna H ospital G eldrop, the N etherlands, 13D epartm ent o f O bstetrics and Gynaecology, University Medical Centre Utrecht, the N etherlands, 14D epartm ent o f O bstetrics and Gynaecology, M esos Medical Centre Utrecht, the N etherlands, 15D epartm ent o f O bstetrics and Gynaecology, University Medical Centre S int R adboud N ijm egen, the N etherlands, 16D epartm ent o f O bstetrics and Gynaecology, Gelderse Vallei Hospital Ede, the N etherlands and 17D epartm ent o f O bstetrics and Gynaecology, Erasmus Medical Centre Rotterdam, th e N etherlands

Email: David P van der Ham* - d p v a n d erh am @ z o n n et.n l; Jan G N ijhuis - jnij@ sgyn.azm .nl; Ben W illem J Mol - b.w .m ol@ am c.uva.nl; Johannes J van Beek - beekjj@ xs4all.nl; Brent C O pm eer - b.c.opm eer@ am c.uva.nl; Denise Bijlenga - d.bijlenga@ am c.uva.nl;

M ariette G roenew out - m .vanderzw et@ tiscali.nl; Birgit A rabin - clara-angela@ wxs.nl; Kitty WM B loem enkam p - k.w .m .bloem enkam p@ lum c.nl; W im J van W ijngaarden - m .vanw ijngaarden@ chello.nl; Maurice GAJ W outers - m gaj.w outers@ vum c.nl; Paula JM Pernet - pernet@ kg.nl; M artina M P orath - m .p o rath @ m m c.n l; Jan FM M olkenboer - jfm m @ xs4all.nl; Jan B Derks - jbderks@ hotm ail.com ;

Michael M Kars - m m kars@ freeler.nl; H ubertina CJ Scheepers - L.Scheepers@ obgyn.um cn.nl; M artin JN W einans - w einansm @ zgv.nl; M allory D W oiski - M .W oiski@ obgyn.um cn.nl; H ajo IJ W ildschut - h.w ildschut@ erasm usm c.nl; Christine W illekes - cwi@ sgyn.azm.nl * C orresponding au th o r

Published: 6 July 2007 Received: 29 March 2007

BM C Pregnancy and Childbirth 2007, 7:11 doi:l0.l 186/1471 -2393-7-11 A c c e Pted: 6 Ju|y 2007

This is an O pen Access article distributed under the terms of the Creative Comm ons A ttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original w o rk is properly cited.

Abstract

Background: Preterm prelabour rupture of the membranes (PPROM) is an important clinical problem and a dilemma for the gynaecologist. On the one hand, awaiting spontaneous labour increases the probability of infectious disease for both mother and child, whereas on the other hand induction of labour leads to preterm birth with an increase in neonatal morbidity (e.g., respiratory distress syndrome (RDS)) and a possible rise in the number of instrumental deliveries. Methods/Design: We aim to determine the effectiveness and cost-effectiveness of immediate delivery after PPROM in near term gestation compared to expectant management. Pregnant

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women with preterm prelabour rupture of the membranes at a gestational age from 34+0 weeks until 37+0 weeks will be included in a multicentre prospective randomised controlled trial. We will compare early delivery with expectant monitoring.

The primary outcome of this study is neonatal sepsis. Secondary outcome measures are maternal morbidity (chorioamnionitis, puerperal sepsis) and neonatal disease, instrumental delivery rate, maternal quality of life, maternal preferences and costs. We anticipate that a reduction of neonatal infection from 7.5% to 2.5% after induction will outweigh an increase in RDS and additional costs due to admission of the child due to prematurity. Under these assumptions, we aim to randomly allocate 520 women to two groups of 260 women each. Analysis will be by intention to treat. Additionally a cost-effectiveness analysis will be performed to evaluate if the cost related to early delivery will outweigh those of expectant management. Long term outcomes will be evaluated using modelling.

Discussion: This trial will provide evidence as to whether induction of labour after preterm prelabour rupture of membranes is an effective and cost-effective strategy to reduce the risk of neonatal sepsis.

Controlled clinical trial register: ISRCTN293I3500

Background

Preterm prelabour rupture o f the m em branes (PPROM) is an im portant clinical problem and a dilem m a for the gynaecologist. O n the one hand, awaiting spontaneous labour may lead to an increase in infectious disease for b oth m other and child, whereas o n the other h an d induc tion o f labour leads to preterm birth with an increase in neonatal m orbidity (e.g., respiratory distress syndrome (RDS)) and a possible rise in the num ber o f instrum ental deliveries.

The estim ated incidence o f PPROM between 34 and 37 weeks of gestation is 1.5%, which equals about 3.000 cases per year in the Netherlands. The incidence o f RDS is estim ated to decrease from 15% at 34 weeks to below 1% at 37 weeks' gestation [1]. O n the other hand, the proba bility that sepsis occurs increases w hen expectant m anage m ent is advocated. In case the child is b orn immediately after PPROM, the risk of sepsis is 2.5%, whereas it increases to 7.5% in case of expectant m anagem ent [2,3]. Until now, m anagem ent of PPROM between 34 and 37 weeks' gestation varies in the Netherlands. In the guide line o f the Dutch Society of Obstetrics and Gynaecology (NVOG) expectant m anagem ent is advocated if the gesta tional age is u nder 35 weeks [4]. Beyond 35 weeks, the guideline makes no clear recom m endation, and the deci sion for either induction of labour or expectant m anage m ent (either in hospital or with m onitoring at hom e), is left to local protocols. International guidelines do not make a clear statem ent either [5,6].

This dilem m a can be explained by a lack of good clinical evidence. As a consequence, the course of action o n this subject varies in the Netherlands. Data from the Dutch

National Delivery Registration indicate th at in about 70% o f the patients an expectant m anagem ent has been prac tised, whereas in about 30% of the cases labour was induced preterm. The current national registrations pro vide no insight in the reason for induction in the latter group, as some inductions m ight have been perform ed following signs o f intra-uterine infection.

In view o f the lack of good clinical evidence and the prac tice variation described above, a random ised clinical trial com paring induction o f labour and expectant m onitoring in patients w ith PPROM is needed urgently.

We are aware o f four small studies that have been per form ed to discern between the treatm ent policies for PPROM [7-10]. N aef et al. com pared induction o f labour versus expectant m anagem ent in a group of 120 patients with PPROM occurring at 34 until 37 weeks gestation and found a non-significant decrease o f chorioam nionitis in the induction group w ithout a significant difference in neonatal m orbidity (including RDS) between both groups [7]. Patients with PPROM m anaged expectantly were hospitalised significantly longer. More babies of the expectant group were diagnosed with sepsis and adm itted to the neonatal ward for a longer duration. This difference did n o t reach the level o f significance due to the small num ber o f the study.

Cox et al. com pared m aternal and neonatal outcom e in a group o f 129 patients with PPROM occurring at 30 until 34 weeks' gestation after random ization between expect an t m anagem ent and induction o f labour [8]. Again, no significant differences in neonatal outcom e were noted. However, a non-significant decrease in sepsis was seen in the induction group. Also, chorioam nionitis was

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observed less frequently in the latter group. Mercer et al. perform ed a similar study o f 93 patients with PPROM in a different age category (32 until 36 weeks' gestation) and observed sim ilar differences as Cox and co-workers [9]. Spinnato et al. found no difference in neonatal outcom e between expected m anagem ent and prom pt delivery in 47 patients with premature rupture of m em branes (before 36 weeks) with docum ented foetal pulm onary maturity [10]. However, they dem onstrated an increased risk of m aternal infection w hen expectant m anagem ent was applied. These studies show a trend towards better neonatal out come in the induction group, b u t in these small samples differences were n o t statistically significant. Even m eta analysis did n o t generate sufficient statistical power [11]. In view of the practice variation described above and the lack of sound clinical evidence for this clinical dilemma, we have recently started a multicentre trial.

Methods/Design Aims

The aim o f this study is to systematically compare early initiation of delivery and expectant m anagem ent in case o f preterm prelabour rupture of m em branes in terms of neonatal sepsis and RDS, m aternal health, health-related quality-of-life and costs. As it is im possible to blind the healthcare workers and patients involved for the strategy o f allocation, we will use a m ulticentre random ised con trolled open label trial to assess the effects o f initiation of delivery or expectant m anagem ent on neonatal outcome. This study is set in the Dutch Obstetric Consortium, a col laboration o f obstetric clinics in the Netherlands. Approx imately 40 clinics, including academic hospitals, n o n academic teaching hospitals and non-teaching hospitals will participate in this trial.

Participants/eligibility criteria

W om en presenting with preterm prelabour rupture o f the foetal m em branes between 34+0 and 37+0 weeks' gestation w ho have n o t delivered w ithin 24 hours after rupture of the foetal m em branes are eligible for participation in the PPROMEXIL-trial. Even so w om en presenting with pre term prelabour rupture of foetal m em branes after 26+0 weeks gestation w ho have n o t delivered at 34+0 weeks o f gestation are eligible for participation. Both w om en with singleton and w om en with m ultiple gestations can be included. W om en with a child in breech presentation can also be included, and both an elective caesarean section and a vaginal delivery are allowed for these women. W om en with m onochorionic m ultiple pregnancies, abnorm al (non-reassuring) cardiotocogram (CTG), m econium stained am niotic fluid, signs o f intrauterine infection, m ajor foetal anomalies, labour, HELLP syn

drom e or severe pre-eclampsia, will n o t be included in the study.

Procedures, recruitment, randomisation and collection o f baseline data

The research nurse and /o r the staff o f participating hospi tals will identify eligible women. After the subject has given inform ed consent for participation in the study, she will be random ised to either a policy th at aims at term ina tion o f the pregnancy (intervention group) or a policy th at aims at expectant m anagem ent for spontaneous delivery (expectant group). Once the subject data have been entered anonym ously in a web-based database, either a staff m em ber or the research nurse will random ise using an internet based procedure. Random isation will be 1:1 for intervention or expectant m anagem ent and stratified for centre and previous delivery.

At study entry baseline demographics, past obstetric and medical history will be recorded. Maternal tem perature is m easured and baseline bloo d samples are taken. From all participating w om en a vaginal swab is collected either at adm ission to the hospital w ith prem ature ruptured m em branes or at study entry. Antibiotics are given in accord ance to local policy. All w om en will undergo an ultrasound exam ination at study entry. If a previous ultra sound exam ination was done w ithin a fortnight before study entry in the same hospital, which revealed no abnorm al results, these outcom es m ay be recorded at study entry. W om en fill o u t a baseline quality o f life ques tionnaire containing EuroQoL, 5D3L, HADS, SF-36 and background questions. They are also asked on their prior intervention preference.

At local centres data-collection will be the responsibility o f the local research coordinator and the regional research nurses. The data for this study m ust be collected, coded and processed with adequate precautions to ensure patient confidentially.

Interventions

Intervention group

W om en random ised for intervention will be planned for induction of labour or elective caesarean section as soon as reasonable after random isation. Because of the fact th at random isation will take place preferable 24 hours after rupture o f the foetal m em branes it is im aginable th at due to logistic reasons induction o f labour is postponed until the following m orning, b u t w ithin 12 hours after ran dom isation. Induction o f labour will take place according to local policy. In case of breech presentation, a primary caesarean section is allowed based o n the preference o f b o th the patient and the gynaecologist. Similarly in case o f a dichorionic twin an elective caesarean section may be

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perform ed because of the position o f the presentation of the first twin.

E x p e cta n t group

W om en random ised for expectant m anagem ent will be treated according to local policy. This m ight be either in an outpatient or inpatient setting. If a patient in the expectant group reaches 37+0 weeks of gestation age, induction o f labour is perform ed according to local pol icy. Whenever a patient with an indication for elective cae sarean section will be allocated to expectant m anagem ent the caesarean section will be performed as soon as labour commences.

Follow up o f women and infants

Inform ation is obtained on the condition, weight, length and neonatal m orbidity and m ortality from the infant and m aternal records as well as m aternal com plications and length o f stay. If applicable, neonatal antibiotic treatment, blood samples and cultures are recorded. In case o f adm it tance o f the baby to the neonatal intensive care, high care or m edium care unit, details o f this admittance are also docum ented. The placenta will be sent for histological exam ination on chorioam nionitis and funisitis.

Six weeks and six m onths post partum neonatal length, weight, neurological disabilities, physical disabilities and m aternal disabilities will be recorded. Patients will be asked to fill out follow-up quality o f life questionnaires including EuroQoL, 5D3L, HADS, SF-36, SCL-90 also concerning the developm ent of the child. W om en are also asked to (re)state their intervention preference. Long-term follow up o f the children is n o t yet planned, and depends on future funding.

Outcom e measures

The prim ary outcom e measure is neonatal sepsis. N eona tal sepsis is defined as a positive blood culture, biochem ical infection parameters (C-reactive protein (CRP) above 20 m g/l) or clinical signs o f infection (apnoea, fever, intolerance for feeding, respiratory distress and/or haem odynam ic instability) with positive surface cultures. An independent panel of paediatricians will define between proven or probable sepsis w ithout knowledge of the outcom e data.

Secondary infant outcom e measures are respiratory dis tress syndrome (RDS) (defined according to the Organ dysfunction criteria), transient tachypnoea of the new b o rn asphyxia (defined according to Sarnat), pneum otho rax/pneum om ediastinum , late onset sepsis, hypoglycaemia, m econium aspiration syndrome, necro tizing enterocolitis (NEC) (defined according to Bell stag ing), hyperbilirubinemia, in, traventricular haemorrhage, periventricular leucomalacia, convulsions, other neuro

logical abnormalities and congenital abnormalities [12 14].

Secondary m aternal outcom e measures are ante partum haemorrhage, um bilical cord prolapse, signs o f chorioamnionitis (defined as fever before or during labour as a tem perature greater th an 37,5°C on two occasion m ore than one h our apart or a tem perature > 38,0°C with either uter ine tenderness (or contractions), leucocytosis, m aternal or foetal tachycardia, or a foul-smelling vaginal discharge in absence o f any other cause of hyperpyrexia), m aternal sepsis (defined as tem perature > 38.5 °C and positive blood culture or circulatory instability requiring intensive care m onitoring), throm bo-em bolic complications, uri nary tract infection treated with antibiotics, signs of endom etritis (defined as tem perature o f > 38,0 °C o n 2 occasions at least one our apart after the first 24 h post partum with associated uterine tenderness [15]), p neu m onia, anaphylactic shock, HELLP-syndrome and death, incidence of instrum ental deliveries, m aternal quality of life, m aternal intervention preference and costs. [15] O ther outcomes are direct medical and non-m edical costs generated by m aternal and neonatal resource utilisation during adm ission and post-discharge follow-up until 6 weeks after random isation. The economic evaluation will integrate the primary clinical outcom e and costs in a cost- effectiveness analysis.

Statistical analysis

Sam ple size

This trial is designed to dem onstrate a 66% reduction o f neonatal sepsis from 7.5% in w om en in the expectant group to 2.5% in w om en in the induction group. This requires a total sample size o f 520 patients with 80 % power and a significance level of p = 0.05.

D a ta analysis

Data analysis will be perform ed on an intention to treat basis and study baseline characteristics will be compared. The relative risks and 95% confidence intervals will be cal culated for the relevant outcom e measures. The analysis will be stratified for centre and parity. Moreover, we will evaluate w hether the relative benefits of induction of labour will be stronger in m ultiparous w om en and in w om en with a ripe cervix at baseline.

In case o f continuous data in the secondary outcom e group, t-tests will be used whereas chi-square tests will be used if data are categorical. In case o f equivalence between outcomes, the analysis will be repeated on a par protocol basis. Quality o f life as well as pain scores will be analysed using repeated measures analysis of variance. [16]

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Serious Adverse Events will be reported to an independ ent data safety m onitoring committee. A formal interim analysis is n o t planned.

Ethical considerations

This study has been approved by the ethic com m ittee of the University Hospital Maastricht (Ref. no. MEC 05 240). A total o f about 40 academic and non-academic hospitals have signed an intention form to participate in the trial, m ost o f them have started the m edical ethics com m ittee approval procedure. Before a collaboration clinic may start with random isation o f patients the local ethical com m ittee m ust have given their approval. The trial is registered in the controlled clinical trial register under number: ISRCTN29313500 [17]

Confidentially and data security

Initials of participants as well as a local patient num ber are recorded in the electronic database. Linking names w ith patient's num bers can only be done in the local clin ics. Data will be collected using Oracle Clinical Remote Data Capture (RDC), which is a new generation of appli cation system that enables collection and cleanup of clin ical trial data using the Internet. For detailed inform ation on Oracle RDC, please visit the page o f Oracle RDC prod ucts. Each participating clinic receives a login nam e and password to get access to the web-secured database. The access is restricted to the database of the clinic to which the password and login nam e belongs. Full access to the entire database is restricted to some m em bers o f the research staff.

Discussion

Preterm prelabour rupture of m em branes is still a clinical problem in obstetric practice. Between 34 and 37 weeks there is a lack of good clinical evidence. Induction of labour m ight reduce the risks of neonatal sepsis. O n the other han d it m ight increase the incidence o f instrum ental deliveries and neonatal respiratory distress syndrome. This trial is designed to answer these questions in respect to neonatal and m aternal outcomes and costs-effectiveness.

We are aware o f two other studies on the subject th at are running. In Canada, a trial has been started th at compares induction o f labour to expectant m anagem ent in w om en w ith PPROM. [18] This trial aims to recruit 360 wom en (Safety and Efficacy Study of Intentional Delivery in W om en W ith Preterm and Prelabour Rupture o f the Mem branes, Lacaze N).

In St Leonards, Australia, a trial has been recently started similar to the trial th at we have started (PPROMT - Pre term Prelabour Rupture O f the Membranes close to Term) [19]. This trial aims to recruit 1812 w om en and has been

announced in the journal [20]. The respective investigator groups, including ours, have planned an individual patient data meta-analysis after com pletion o f the trials.

Com peting interests

The author(s) declare th at they have no com peting inter ests.

Authors' contributions

DH drafted the manuscript; DH, BM, DB, and CW partic ipated in the design of the study; BO participated in the design o f the statistical analysis. All authors discussed and fine tuned the final study design. All authors are partici pating in the acquisition o f data. Finally all authors read, revised and approved the final manuscript.

Acknowledgements

This study is funded by Z o n M W (grant number 945-07-212). [21]

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