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

2. 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)

3. UK Caesar Trial Interventions
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

5. 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

6. 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

7. 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

8. Interventions considered for CORONIS:
6. Fat
Subcutaneous fat closure vs no closure
7. Skin closure
Subcutaneous absorbable suture vs interrupted absorbable suture,
staples etc

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

10. 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

11. Review of interventions considered:
Abdominal entry – sharp (Pfannenstiel) vs blunt (Joel Cohen)
Cochrane review
2 RCTs, n=411
Both suggest improvement in febrile morbidity with J-C
There was little difference in wound infection
No data available for endometritis

12. Joel-Cohen versus Pfannenstiel incision Outcome: Postoperative febrile morbidity

13. Joel-Cohen versus Pfannenstiel incision Outcome: Wound infection as defined by trial authors

14. Review of interventions considered:
Exteriorisation of uterus for repair vs intra-abdominal repair
Cochrane review
6 RCTs, n=1294
Exteriorisation associated with reduction in febrile
morbidity but no effect on endometritis, wound
complication, sepsis or blood transfusion

15. Uterine exteriorization vs intraperitoneal repair at CS
Outcome: Febrile morbidity for more than 3 days  

16. Uterine exteriorization vs intraperitoneal repair at CS
Outcome: Endometritis  

17. Uterine exteriorization vs intraperitoneal repair at CS
Outcome: Wound complications (infection, haematoma, breakdown)  

18. Uterine exteriorization vs intraperitoneal repair at CS
Outcome: Postoperative sepsis  

19. Uterine exteriorization vs intraperitoneal repair at CS Outcome: Blood transfusion  

20. Review of interventions considered:
3. Single vs double layer uterine closure
Cochrane review
2 RCTs, n=1006
No effect on endometritis or blood transfusions

21. Single vs two layer closure of uterine incision at CS
Outcome: Postpartum endometritis  

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

23. Review of interventions considered:
4. Uterine repair
chromic catgut vs vicryl (polyglactin-910)
Cochrane review
No studies found

24. Review of interventions considered:
4. Closure of both parietal and pelvioc peritoneum vs non-closure
Cochrane review
10 RCTs, n=1761
Non-closure associated with less post-op fever
but no significant effect on wound infection or endometritis

25. Non-closure of both parietal & visceral
peritoneum vs closure of both peritoneal layers
Outcome: Postoperative fever  

26. Outcome: Endometritis
Non-closure of both parietal & visceral peritoneum vs closure of both peritoneal layers
Outcome: Endometritis  

27. Non-closure of both parietal & visceral
peritoneum vs closure of both peritoneal layers
Outcome: Wound infection  

28. 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:
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.

29. 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

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

31. The Trial Collaborating countries Argentina Ghana
India: two regions; Delhi and Vellore
Kenya
Pakistan
Sudan
18 participating hospitals

32. Investigator Group Argentina Dr Edgardo Abalos
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

33. 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:
Plans for 3 year follow-up of all women recruited are underway

34. 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.

35. 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.

36. 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

37. 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.

38. 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.

39. 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.

40. Secondary outcomes Clinical Health Service Utilisation
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

41. 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.

42. 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.

43. 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

44. 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.

45. 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

46. 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

47. International Co-ordinating Centre
National Perinatal Epidemiology Unit
University of Oxford