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

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International study of caesarean section surgical
techniques a randomised factorial trial
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• 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)

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• UK Caesar Trial
• Trial of 3,000 women, completed in UK ( Italy)
  in 2007
• Interventions
• single vs double layer closure of the uterus
• non-closure vs closure of pelvic peritoneum
• liberal vs restricted use of a sub-sheath drain

4

• 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

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Interventions considered for CORONIS

• 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

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Interventions considered for CORONIS

• 3. Uterus
• a) Sharp vs blunt uterine entry
• b) Exteriorisation of uterus for repair vs
  intra-abdominal repair
• c) Uterine swabbing vs no swabbing prior to
  uterine closure
• d) 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

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Interventions considered for CORONIS

• 4. Peritoneum
• a) peritoneal closure vs non-closure
• pelvic
• parietal
• both
• b) Materials for closure of the peritoneum
• plain catgut vs vicryl (polyglactin-910) vs
  chromic catgut
• 5. Sheath
• Chromic catgut vs plain catgut vs vicryl
  (polyglactin-910) for sheath repair
• Locked continuous vs non-locked continuous
  closure
• Chosen for CORONIS trial

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Interventions considered for CORONIS

• 6. Fat
• Subcutaneous fat closure vs no closure
• 7. Skin closure
• Subcutaneous absorbable suture vs interrupted
  absorbable suture,
• staples etc

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• Meeting of co-investigators 2006
• Delegates from 6 countries met in Oxford for 3
  days
• Reviewed and agreed final list of interventions

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Review of the interventions considered
Systematic reviews - Cochrane Long-term
follow-up studies Key outcomes Febrile
morbidity Wound infection Endometritis Blood
transfusion Infant outcomes if intervention
occurs prior to delivery of baby, such as
abdominal entry or uterine entry
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Review of interventions considered

• Abdominal entry sharp (Pfannenstiel) vs blunt
  (Joel Cohen)
• Cochrane review
• 2 RCTs, n411
• Both suggest improvement in febrile morbidity
  with J-C
• There was little difference in wound infection
• No data available for endometritis

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Joel-Cohen versus Pfannenstiel
incisionOutcome Postoperative febrile morbidity
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Joel-Cohen versus Pfannenstiel incisionOutcome
Wound infection as defined by trial authors
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Review of interventions considered

• Exteriorisation of uterus for repair vs
  intra-abdominal repair
• Cochrane review
• 6 RCTs, n1294
• Exteriorisation associated with reduction in
  febrile
• morbidity but no effect on endometritis, wound
• complication, sepsis or blood transfusion

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Uterine exteriorization vs intraperitoneal repair
at CS Outcome Febrile morbidity for more than 3
days  
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Uterine exteriorization vs intraperitoneal repair
at CS Outcome Endometritis  
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Uterine exteriorization vs intraperitoneal repair
at CS Outcome Wound complications (infection,
haematoma, breakdown)  

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Uterine exteriorization vs intraperitoneal repair
at CS Outcome Postoperative sepsis  
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Uterine exteriorization vs intraperitoneal repair
at CS Outcome Blood transfusion  

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Review of interventions considered
3. Single vs double layer uterine closure
Cochrane review 2 RCTs, n1006 No effect on
endometritis or blood transfusions
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Single vs two layer closure of uterine incision
at CS Outcome Postpartum endometritis  
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Single vs two layer closure of uterine incision
at CS Outcome Blood transfusion  

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Review of interventions considered

• 4. Uterine repair
• chromic catgut vs vicryl (polyglactin-910)
• Cochrane review
• No studies found

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Review of interventions considered
4. Closure of both parietal and pelvioc
peritoneum vs non-closure Cochrane review 10
RCTs, n1761 Non-closure associated with less
post-op fever but no significant effect on
wound infection or endometritis
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Non-closure of both parietal visceral
peritoneum vs closure of both peritoneal layers
Outcome Postoperative fever  
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Non-closure of both parietal visceral
peritoneum vs closure of both peritoneal
layers Outcome Endometritis  

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Non-closure of both parietal visceral
peritoneum vs closure of both peritoneal layers
Outcome Wound infection  
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• 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.

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Conclusions for 5 interventions for CORONIS
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
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The CORONIS Trial

• The CORONIS trial is funded by the UK
• Medical Research Council in collaboration
• with the World Health Organisation

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The Trial

• Collaborating countries
• Argentina
• Ghana
• India two regions Delhi and Vellore
• Kenya
• Pakistan
• Sudan
• 18 participating hospitals

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Investigator Group

• Chief 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

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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

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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.

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Fractional, factorial design

• In the CORONIS Trial five comparisons will be
  carried out
• in one trial, using a 2x2x2x2x2 factorial design.
  Such a
• design has rarely been used, but is appropriate
  for
• the evaluation of several procedures which will
  be used
• together in clinical practice.
• In this trial of different caesarean section
  techniques, using
• five pairs of possible allocated interventions (1
  versus not
• 1, 2 versus not 2, 3 versus not 3, 4 versus
  not 4, 5
• versus not 5), participants can receive one of
  32 possible
• alternatives.

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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

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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.

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Training in surgical techniques

• 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.

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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.

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Secondary outcomes

• Clinical
• 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 lt 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

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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.

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Exclusion criteria

• Women 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.

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Exclusion criteria (cont.)

• 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

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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.

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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

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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

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International Co-ordinating Centre

• National Perinatal Epidemiology Unit
• University of Oxford
• www.npeu.ox.ac.uk/CORONIS