international study of caesarean section surgical techniques: a randomised factorial trial

International study of caesarean section surgical techniques: a

randomised factorial trial

Rationale for CORONIS• Caesarean section common around the world

• By improving surgical techniques, we have potential

to improve the health of very many women

• Many existing trials have drawbacks (small sample

size, poor methodology, less relevant outcomes)

UK Caesar Trial• Trial of 3,000 women, completed in UK (& Italy) in

2007

• Interventionssingle vs double layer closure of the uterusnon-closure vs closure of pelvic peritoneumliberal vs restricted use of a sub-sheath drain

WHO sponsored meeting 2002

• Delegates from 9 countries met in Oxford for 5 days

• Discussed and agreed list of interventions to explore

in international trial

• NPEU team drew up draft protocol and draft data

collection instrument leading to MRC application

1. Catheterisation• routine catheterisation vs no catheterisation• in-dwelling vs in-and-out catheter• in-dwelling catheter for duration of CS vs for longer

2. Abdominal entry – sharp vs blunt *

* Chosen for CORONIS trial

Interventions considered for CORONIS:

3. Uterusa) Sharp vs blunt uterine entryb) Exteriorisation of uterus for repair vs intra-abdominal repair *c) Uterine swabbing vs no swabbing prior to uterine closured) Single vs double layer uterine closure *e) Uterine repair:

• chromic catgut vs vicryl (polyglactin-910) *• locking vs non-locking suture• continuous vs interrupted sutures

* Chosen for CORONIS trial

Interventions considered for CORONIS:

4. Peritoneuma) peritoneal closure vs non-closure *

pelvicparietalboth

b) Materials for closure of the peritoneum plain catgut vs vicryl (polyglactin-910) vs chromic catgut

5. SheathChromic catgut vs plain catgut vs vicryl (polyglactin-910) for sheath repair

Locked continuous vs non-locked continuous closure

* Chosen for CORONIS trial

Interventions considered for CORONIS:

6. FatSubcutaneous fat closure vs no closure

7. Skin closureSubcutaneous absorbable suture vs interrupted absorbable suture,staples etc

Interventions considered for CORONIS:

Meeting of co-investigators 2006

• Delegates from 6 countries met in Oxford for 3 days

• Reviewed and agreed final list of interventions

Systematic reviews - Cochrane

Long-term follow-up studies

Key outcomes:Febrile morbidityWound infectionEndometritisBlood transfusionInfant outcomes if intervention occurs prior to delivery of baby, such as abdominal entry or uterine entry

Review of the interventions considered

1. Abdominal entry – sharp (Pfannenstiel) vs blunt (Joel Cohen)

Cochrane review

2 RCTs, n=411Both suggest improvement in febrile morbidity with J-CThere was little difference in wound infectionNo data available for endometritis

Review of interventions considered:

Joel-Cohen versus Pfannenstiel incisionOutcome: Postoperative febrile morbidity

Joel-Cohen versus Pfannenstiel incisionOutcome: Wound infection as defined by trial authors

2. Exteriorisation of uterus for repair vs intra-abdominal repair

Cochrane review

6 RCTs, n=1294Exteriorisation associated with reduction in febrilemorbidity but no effect on endometritis, woundcomplication, sepsis or blood transfusion

Review of interventions considered:

Uterine exteriorization vs intraperitoneal repair at CSOutcome: Febrile morbidity for more than 3 days  

Uterine exteriorization vs intraperitoneal repair at CSOutcome: Endometritis  

Uterine exteriorization vs intraperitoneal repair at CSOutcome: Wound complications (infection, haematoma,

breakdown)  

Uterine exteriorization vs intraperitoneal repair at CSOutcome: Postoperative sepsis  

Uterine exteriorization vs intraperitoneal repair at CS Outcome: Blood transfusion  

3. Single vs double layer uterine closure

Cochrane review

2 RCTs, n=1006No effect on endometritis or blood transfusions

Review of interventions considered:

Single vs two layer closure of uterine incision at CSOutcome: Postpartum endometritis  

Single vs two layer closure of uterine incision at CS Outcome: Blood transfusion  

4. Uterine repair• chromic catgut vs vicryl (polyglactin-910)

Cochrane review

No studies found

Review of interventions considered:

4. Closure of both parietal and pelvioc peritoneum vs non-closure

Cochrane review

10 RCTs, n=1761Non-closure associated with less post-op fever but no significant effect on wound infection or endometritis

Review of interventions considered:

Non-closure of both parietal & visceral peritoneum vs closure of both peritoneal layers

Outcome: Postoperative fever  

Non-closure of both parietal & visceral peritoneum vs closure of both peritoneal layers

Outcome: Endometritis  

Non-closure of both parietal & visceral peritoneum vs closure of both peritoneal layers

Outcome: Wound infection  

2 studies of long-term follow-up

Single vs double layer uterine closure• 145 women out of 906 randomised• followed up at time of next pregnancy• no difference found between the groups (not surprisingly)

Chapman SJ, Owen J, Hauth JC. One versus two-layer closure of a low transverse cesarean: the next pregnancy. Obstet Gynecol 1997; 89: 16-18.

Non-closure vs closure of peritoneum• 144 women out of 280 randomised• no differences found between the groups

Bahmanyar E, Boulvain M, Irion O. Non-closure of the peritoneum during cesarean section: long-term follow-up of a randomized controlled trial. Am J Obstet Gynecol 2001; 185: S125.

Uterine exteriorisation vs intra-abdominal repair

- no diff for wound infection, sepsis, endometritis, blood transfusion (less fever in exterioriorisation)

Single vs two layer uterine closure - no difference for substantive outcomes

Chromic catgut vs polyglactin-910 (Vicryl) for uterine repair - no studies identified

Closure vs non-closure of peritoneum

- no diff for wound infection or endometritis (less post-op fever in non-

closure)

Blunt vs sharp abdominal entry - not enough evidence

Conclusions for 5 interventions for CORONIS

The CORONIS Trial

The CORONIS trial is funded by the UK

Medical Research Council in collaboration

with the World Health Organisation

The TrialCollaborating countries

• Argentina

• Ghana

• India: two regions; Delhi and Vellore

• Kenya

• Pakistan

• Sudan

• 18 participating hospitals

Investigator GroupChief Investigator Professor Peter Brocklehurst

Principal Investigators

Argentina Dr Edgardo Abalos

Ghana Dr Victor Addo

India: Delhi Dr Jai Sharma

India: Vellore Dr Jiji Mathews

Kenya Professor James Oyieke

Pakistan Dr Shabeen Masood

Sudan Professor Mohamed ElShiekh

Sample size

15,000 women world-wide

• At least 2000 women from each country

• All women followed-up 6 weeks after discharge from hospital

• 3 year recruitment period: 2007-2010

• Plans for 3 year follow-up of all women recruited are underway

Study design• The study is a multicentre, fractional factorial

randomised controlled trial.

• The collaborating institutions are centres with experience in conducting trials.

• These centres also have experience in detailed follow-up of large numbers of women.

Fractional, factorial designIn the CORONIS Trial five comparisons will be carried outin one trial, using a 2x2x2x2x2 factorial design. Such adesign has rarely been used, but is appropriate forthe evaluation of several procedures which will be usedtogether in clinical practice.

In this trial of different caesarean section techniques, usingfive pairs of possible allocated interventions (1 versus “not1”, 2 versus “not 2”, 3 versus “not 3”, 4 versus “not 4”, 5versus “not 5”), participants can receive one of 32 possiblealternatives.

Interventions• Blunt versus sharp abdominal entry• Exteriorisation of the uterus for repair versus

intra-abdominal repair• Single versus double layer closure of the

uterus• Closure versus non-closure of the peritoneum

(pelvic and parietal)• Chromic catgut versus Polyglactin-910 for

uterine repair

Training in surgical techniques

• Training will vary between countries according to the national standards of training in new surgical techniques employed by each participating country. For example, if the accepted standard for surgical training in a country is that operators must perform a certain number of procedures before they are judged to be competent in that procedure, then this process should be followed.

• If, however, the national standard is that operators are judged to be competent when a senior surgeon judges them to be competent, then this process should be followed. The accepted standard of surgical training in each centre will be determined at the start of the trial.

• To facilitate training, a film of all the interventions being tested in CORONIS will be provided to participating centres. In individual countries, visits by the Regional Co-ordinator to participating hospitals to teach specific surgical techniques may be required so that experience in the participating hospitals can be disseminated rapidly.

• Participating centres will appoint a senior obstetrician to ensure that only clinical staff competent in the various surgical techniques to be used in the trial are ‘authorised’ to operate. A list of these personnel will be kept by the local centre with a copy at the Regional Trial Office.

Training in surgical techniques

Primary outcome Composite outcome of:

Death or maternal infectious morbidity (one or more of the following: antibiotic use for maternal febrile morbidity during postnatal hospital stay, antibiotic use for endometritis, wound infection or peritonitis); or further operative procedures; or blood transfusion.

Secondary outcomesClinical• All components of the primary composite outcome as secondary outcomes• Pain• Interventions used for severe primary post-partum haemorrhage (PPH)• Stillbirth after trial entry • Apgar score < 3 at five minutes• Laceration of baby at time of caesarean section• Death of the baby by six weeks of age• Other severe maternal morbidity

Health Service Utilisation• Duration of operation (from incision to closure)• Duration of hospital stay post-caesarean section• Duration of stay in Intensive Care Unit post-caesarean section• Number and duration of re-admissions to hospital within 6 weeks of

the caesarean section

Eligibility criteria

Women ARE eligible for trial entry if: • they are undergoing delivery by lower

segment caesarean section through a transverse abdominal incision, irrespective of fever in labour, gestational age or whether they have a multiple pregnancy.

Exclusion criteriaWomen are NOT eligible if:• there is a clear indication for a particular surgical

technique or material to be used that prevents any of the allocated interventions being used, e.g. for a woman with a previous vertical abdominal incision it maybe considered inappropriate to do a transverse abdominal incision for this caesarean section. However, if a transverse incision is going to be performed the woman is eligible.

Women are NOT eligible if:• they have had more than one previous

caesarean section.

• they have already been recruited into the trial during a previous pregnancy

Exclusion criteria (cont.)

Informed consent• Information leaflets will be made available to

local centres, in appropriate languages, which explain the justification for the trial, the process of trial entry and follow up.

• Once a woman becomes eligible, the trial should be discussed with her (and her partner as appropriate).

• A signed, or marked, consent form must be provided before the woman is entered into the trial.

Data collection

• At study entry

• Immediately following delivery

• During the postpartum stay in hospital

• At 6 weeks after discharge from hospital

• Data Collection Booklets contain all the necessary data collection forms

International Co-ordinating Team

Chief Investigator Peter Brocklehurst

Trial Statistician Ed Juszczak

Trial Director Barbara Farrell

IT Co-ordinator Patsy Spark

Study Administrator Shan Rich

International Co-ordinating Centre

National Perinatal Epidemiology Unit

University of Oxford

www.npeu.ox.ac.uk/CORONIS