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Interventions for preventing blood loss during the treatment of cervical intraepithelial neoplasia

  1. Pierre PL Martin-Hirsch1,*,
  2. Andrew Bryant2

Editorial Group: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group

Published Online: 4 DEC 2013

Assessed as up-to-date: 26 NOV 2012

DOI: 10.1002/14651858.CD001421.pub3


How to Cite

Martin-Hirsch PPL, Bryant A. Interventions for preventing blood loss during the treatment of cervical intraepithelial neoplasia. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD001421. DOI: 10.1002/14651858.CD001421.pub3.

Author Information

  1. 1

    Royal Preston Hospital, Lancashire Teaching Hospital NHS Trust, Gynaecological Oncology Unit, Preston, Lancashire, UK

  2. 2

    Newcastle University, Institute of Health & Society, Newcastle upon Tyne, UK

*Pierre PL Martin-Hirsch, Gynaecological Oncology Unit, Royal Preston Hospital, Lancashire Teaching Hospital NHS Trust, Sharoe Green Lane, Fullwood, Preston, Lancashire, PR2 9HT, UK. martin.hirsch@me.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 4 DEC 2013

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Characteristics of included studies [ordered by study ID]
Dane 2008

MethodsRCT


Participants78 women with histologically documented cervical intraepithelial neoplasia (CIN) 2/3.

Mean age in the trial was 34 years (Range: 22 and 60 years).
There were 32 (41%) women with CIN II and 46 (59%) with CIN 3.


InterventionsIntervention:

Following routine colposcopy a knife cone biopsy was taken with subsequent haemostasis achieved with a cerclage suture using No. 1 Vicryl suturing at 11 to 9 o’clock and 8 to 6 o’clock and 5 to 3 o’clock and 2 to 12 o’clock on the external surface, and knots tied at 11 and 12 o’clock with the aim of limiting blood loss from the uterine vessels.

Comparison:

Following routine colposcopy a knife cone biopsy was taken with subsequent haemostasis achieved with electrical coagulation using a ball electrode.


Outcomes
  • Operative time
  • Intraoperative blood loss
  • Early/late bleeding
  • Dysmenorrhea
  • Transformation zone visible


NotesWomen were followed up at 4 weeks and 6 months following procedure.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Women were assigned to the suture or cautery group using a random-number table."

Allocation concealment (selection bias)Unclear risk“Group allocation (was) predetermined and placed in consecutively numbered sealed envelopes.”

Blinding (performance bias and detection bias)
All outcomes
Unclear risk“At six-month follow-up, symptoms were assessed, a menstrual history was taken, and cytological and colposcopic examinations were performed by an independent observer unaware of which treatment method had been used.”

Unclear as to whether the outcome assessor was blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low risk% analysed: 70/78 (90%)

By treatment arm:

Cerclage: 37/42 (88%)

Electrocautery: 33/36 (92%)

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement.

Other biasUnclear riskInsufficient information to assess whether an important risk of bias exists.

Doyle 1992

MethodsRCT


Participants182 women undergoing Large Loop Excision of the Transformation Zone (LLETZ) of the cervix.


InterventionsMonsel's Solution applied to cervical wound.
No extra treatment.


OutcomesDischarge as measured subjectively by women on daily sanitary pad chart.


Notes50 women failed to complete their follow-up questionnaires excluded from analysis.
2 women had primary haemorrhages, 5 women were deemed to be unsuitable after randomisation.

Assumed that randomisation is 1:1 so 63 randomised to Monsel's solution and 62 randomised to control, "it was calculated that by entering 60 patients into each arm of the study, there would be a greater than 85% chance of detecting a fall of 25% in the discharge score ...".


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Low risk"The women were randomised ... by sealed opaque envelope to either the control or the Monsel's group".

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
High riskFor all outcomes:

% analysed: 125/182 (69%)

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Other biasUnclear riskInsufficient information to assess whether an important risk of bias exists

Gilbert 1989

MethodsRCT


Participants200 consecutive women, 5 women did not wish to participate
All women underwent a knife conisation under general anaesthesia, vasoconstrictors were not used.


InterventionsHaemostatic absorbable lateral sutures and additional sutures as deemed necessary
Vaginal pack with Monsel's solution localised against cervix


OutcomesPerioperative blood loss, primary and secondary haemorrhage, amenorrhoea and dysmenorrhoea, satisfactory colposcopy at follow-up


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDetails about the sequence generation was not given, "Patients were randomly allocated to one or the other haemostatic method".

Allocation concealment (selection bias)Low risk"We performed the method allocation after the cone excision to ensure that previous knowledge of the haemostatic method could not influence the operator as to the size or shape of the cone".

The method of concealment of allocation was carried out, "by opening one of a batch of sealed envelopes containing the appropriate instruction".

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskFor all outcomes:

% analysed: 200/205 (98%)

5 women did not wish to participate

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Other biasUnclear riskInsufficient information to assess whether an important risk of bias exists

Gimpleson 1999

MethodsRCT


Participants48 women undergoing Loop Electrosurgical Excision Procedure (LEEP) with various grades of CIN.

There were 13 (27%) women with CIN 1, 21 (44%) with CIN 2 and 14 (29%) women with CIN 3.


InterventionsIntervention:

Daily administration of intravaginal Amino-Cerv for two weeks following LEEP completed in a private office setting

Comparison:

Routine care: No intravaginal medication, refrain from intercourse, tampon use or douching for four weeks.


Outcomes
  • Vaginal discharge
  • Cervical healing
  • Malodour
  • Inflammation


NotesAll patients were followed up at 2 and 4 weeks

Secondary haemorrhage was deduced by fact that, "No patients needed to be seen for post-LEEP bleeding".

Healing of cervix: At 2 weeks - Amino-Cerv: 19/24 not healed, routine care 24/24 not healed. At 4 weeks - Amino-Cerv: 4/24 not healed, routine care 15/24 not healed.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
Low risk% analysed: 48/48 (100%)

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Other biasUnclear riskInsufficient information to assess whether an important risk of bias exists

Grundsell 1984(a)

MethodsRCT


Participants140 women undergoing laser cone biopsy as an out-patient procedure for severe dyskaryosis. All women had vasopressin injected into the cervix prior to treatment.


InterventionsIntravenous tranexamic acid during procedure and 1 g orally three times daily (tds) for 14 days


OutcomesPrimary and secondary haemorrhage


NotesCitation duplicated to demonstrate two different study groups in analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported, "women ... prospectively randomised into one of two groups".

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskFor primary and secondary haemorrhage:

% analysed: 140/140 (100%)

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Other biasUnclear riskPatient baseline characteristics in the two groups were not reported so possibility of inexplicable differences between two groups.

Grundsell 1984(b)

MethodsRCT


Participants220 women undergoing laser miniconization as an out-patient procedure for mild/moderate dyskaryosis. All women had vasopressin injected into the cervix prior to treatment.


InterventionsIntravenous tranexamic acid during procedure and 1 g orally tds for 14 days


OutcomesPrimary and secondary haemorrhage


NotesCitation duplicated to demonstrate two different study groups in analysis


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported, "patients were prospectively randomised into one group given tranexamic acid ... and another group not given antifibrinolytic therapy".

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskFor primary and secondary haemorrhage:

% analysed: 220/220 (100%)

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Other biasUnclear riskPatient baseline characteristics in the two groups were not reported so possibility of inexplicable differences between two groups.

Howells 2000

MethodsRCT


Participants200 consecutive women undergoing LLETZ of the cervix.

Mean age in the trial was 35.5 years (SD = 10).
Histology was given as follows: Normal: 12 (6%), CIN 1: 67 (33.5%), CIN 2/3: 114 (57%), Others: 5 (2.5%), Missing: 2 (1%).


InterventionsInterventions:

Two different local anaesthetic combinations prior to LLETZ:

  • Prilocaine with felypressin
  • Lignocaine with adrenaline


Outcomes
  • Bleeding
  • Discomfort
  • Pain from injection/LLETZ
  • Nausea


Notes12/200 women had normal histology and 2 had missing histology data.

Inclusion criteria included no prior treatment to the cervix and women within age range 20-60 years.

The colposcopist was required to score his or her perception of the discomfort experienced by the women in a scale of ordered categories (0 = ‘none’; 4 = ‘severe’) and also the degree of bleeding caused by the procedure (0 = ‘none’; 5 = ‘heavy’). Other side effects, such as feeling faint, nausea and shaking, were also scored in a similar fashion (0 = ‘none; 5 = ‘a great deal’).

Prilocaine with felypressin | Lignocaine with adrenaline:
Bleeding: 1.74 (0.98) | 1.33 (1.05)
Pain from injection: 0.99 (0.97) | 1.15 (1.03)
Pain from LLETZ: 0.45 (0.73) | 0.50 (0.79)
Nausea: 0.18 (0.55) | 0.18 (0.64)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Low risk"The women were randomised by an independent observer using simple randomisation with opaque sealed envelopes".

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Other biasUnclear riskInsufficient information to assess whether an important risk of bias exists

Lee 1986

MethodsRCT


Participants50 women undergoing laser vaporization


InterventionsCitanest (prilocaine with octapressin)
No analgesia/ vasoconstrictor


OutcomesSubjective grading of perioperative bleeding by operator


Notes25 women randomised to Citanest

25 women randomised to no analgesia/ vasoconstrictor

All patients were menopausal and aged between 19 and 39 years


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported, merely states, "study was a randomised comparison of two groups of 25 patients each ...".

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot reported

Incomplete outcome data (attrition bias)
All outcomes
Low riskFor troublesome bleeding:

% analysed: 50/50 (100%)

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Other biasUnclear riskInsufficient information to assess whether an important risk of bias exists

Lipscomb 2006

MethodsRCT


Participants100 women undergoing LEEP.

Mean age in the trial was 29.4 years (SD = 9.9).


InterventionsInterventions:

  • Monsel’s paste with fulguration
  • Ball electrode for haemostasis


Outcomes
  • Pain
  • Blood loss
  • Discharge
  • Recurrent abnormal pap


NotesFrom CONSORT diagram it can be deduced that at least 71/77 women had CIN (71 were analysed for recurrent abnormal pap and 23 of initial 100 women enrolled in trial were lost to follow up).

Haemostasis had a mean of 207.5 (SD = 393.6) in the ball electrode group and 118.7 (SD = 179.5) in the Monsel's paste group.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Patients were assigned randomly by computer-generated
numbers".

Allocation concealment (selection bias)Unclear risk"Patients were assigned randomly by computer-generated
numbers were placed in sealed envelopes".

Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Follow-up information was collected by researchers who were
unaware of the assigned treatment method".

Incomplete outcome data (attrition bias)
All outcomes
Low riskFor vaginal discharge:

% analysed: 94/100 (94%)

For all other outcomes specified in our review the number of women analysed is at least 94%

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Other biasUnclear riskInsufficient information to assess whether an important risk of bias exists

Lundvall 1984

MethodsRCT: Placebo-controlled study


Participants230 women undergoing knife cone biopsy under general anaesthesia
80 cones were performed with lateral and continuous wound sutures
150 cones were performed with lateral and Sturmdorf sutures


InterventionsOral tranexamic acid 4.5 g daily for 12 days
Placebo


OutcomesSecondary haemorrhage, diarrhoea, nausea, perspiration, coldness, exanthema


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported, "we have carried out a randomized, double-blind study".

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Double-blind study", but not reported whether or not outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskFor secondary haemorrhage:

% analysed: 228/230 (99%)

Tranexamic acid: 113/115 (98%)

Placebo: 115/115 (100%)

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Other biasUnclear riskInsufficient information to assess whether an important risk of bias exists. "The groups were homogeneous with regard to age and size of conus". However there may have been imbalances in other prognostic factors that were not reported.

Rybo 1972

MethodsRCT: Double-blind placebo-controlled study


Participants50 women undergoing knife cone biopsy under general anaesthesia
Haemostatic sutures were only inserted if troublesome perioperative bleeding
Patients remained in hospital for at least 7 days post surgery


InterventionsOral tranexamic acid 0.5 g tds for 12 days started on evening of surgery
Placebo


OutcomesBlood loss during first 7 postoperative days measured by examination of sanitary towels
Significant secondary haemorrhage


Notes2 patients from treatment group, 1 from placebo group excluded, patients had perioperative intracervical vasopressin
1 patient excluded from placebo group, had perioperative intravenous amino-caproic acid


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Double-blind placebo-controlled study", but not reported whether or not outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskFor secondary haemorrhage:

% analysed: 45/50 (90%)

Oral tranexamic acid; 22/25 (88%)
Placebo; 23/25 (92%)

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Other biasUnclear riskPatient baseline characteristics in the two groups were not reported so possibility of inexplicable differences between two groups.

Sabol 1971

MethodsRCT: Double-blind placebo study


Participants98 women undergoing knife cone biopsy under general anaesthesia
women who were pregnant or had cardiovascular disease were excluded (6 in total)
Cervical sutures were avoided but allowed if significant perioperative bleeding


InterventionsIntracervical vasopressin
Intracervical saline


OutcomesPerioperative blood loss, insertion of perioperative haemostatic sutures, primary and secondary haemorrhage


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Numbered vials containing either 30 ml of saline or 30 ml of saline containing vasopressin were prepared, where the numbers corresponded to a randomised code contrived and kept by member of pharmacy service who didn't participate in the study".

Allocation concealment (selection bias)Low risk"The randomisation code was not broken until the entire study was terminated".

Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Double-blind placebo study", but not reported whether or not outcome assessors were blinded.

Incomplete outcome data (attrition bias)
All outcomes
Low riskFor all outcomes:

% analysed: 92/92 (100%)

Some women were excluded but this was due to exclusion criteria rather than loss to follow up.

Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement

Other biasUnclear riskPatient baseline characteristics in the two groups were not reported so possibility of inexplicable differences between two groups.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Chan 2007Women in trial did not have CIN confirmed by biopsy.

Cruickshank 2005Trial does not report outcome measures as specified in protocol.

Foden-Shroff 1998133 women had negative CIN histology, 5 had stage Ia carcinoma and 1 had adenocarcinoma in situ out of 500 women in the trial.

Harper 1997This study was not an RCT.

Paraskevaidis 2001Quasi-randomised trial, "One hundred one consecutive women ... were assigned alternately to two groups... as groups were assigned alternatively".

Paraskevaidis 2002No comparison of relevant interventions.

Stefanidis 1998Quasi-randomised trial, "Patients were randomly allocated to one of two groups according to the date of the procedure (odd date group A, even date group B)".

 
Comparison 1. Vasopressin versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Measured blood loss (ml)1Mean Difference (IV, Random, 95% CI)Subtotals only

 2 Subjective troublesome bleeding1Risk Ratio (IV, Random, 95% CI)Subtotals only

 3 Bleeding requiring haemostatic sutures, Vasopressin1Risk Ratio (IV, Random, 95% CI)Subtotals only

 4 Cervical stenosis1Risk Ratio (IV, Random, 95% CI)Subtotals only

 
Comparison 2. Tranexamic acid versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Postoperative blood loss1Mean Difference (IV, Random, 95% CI)Subtotals only

 2 Primary haemorrhage2360Risk Ratio (IV, Random, 95% CI)1.24 [0.04, 38.10]

 3 Secondary haemorrhage4633Risk Ratio (IV, Random, 95% CI)0.23 [0.11, 0.50]

 
Comparison 3. Pack versus haemostatic suture

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Perioperative blood loss (ml)1Mean Difference (IV, Random, 95% CI)Subtotals only

 2 Primary haemorrhage1Risk Ratio (IV, Random, 95% CI)Subtotals only

 3 Secondary haemorrhage1Risk Ratio (IV, Random, 95% CI)Subtotals only

 4 Amenorrhoea1Risk Ratio (IV, Random, 95% CI)Subtotals only

 5 Dysmenorrhoea1Risk Ratio (IV, Random, 95% CI)Subtotals only

 6 Transformation zone not visible at colposcopy1Risk Ratio (IV, Random, 95% CI)Subtotals only

 7 Cervical stenosis1Risk Ratio (IV, Random, 95% CI)Subtotals only

 
Comparison 4. Cerclage suture versus electrical coagulation

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of procedure1Mean Difference (IV, Random, 95% CI)Subtotals only

 2 Primary haemorrhage1Risk Ratio (IV, Random, 95% CI)Subtotals only

 3 Secondary haemorrhage1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 4 Dysmenorrhoea1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 5 Unsatisfactory colposcopy1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 
Comparison 5. Vaginal Amino-Cerv versus routine treatment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Secondary haemorrhage1Risk Ratio (IV, Random, 95% CI)Subtotals only

 2 Vaginal discharge at 2 weeks1Risk Ratio (IV, Random, 95% CI)Subtotals only

 3 Vaginal discharge at 4 weeks1Risk Ratio (IV, Random, 95% CI)Subtotals only

 
Comparison 6. Prilocaine with felypressin versus lignocaine with adrenaline in LLETZ

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of procedure1Mean Difference (IV, Random, 95% CI)Subtotals only

 
Comparison 7. Ball electrode versus Monsel’s paste for haemostasis after LEEP

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Blood loss1Mean Difference (IV, Random, 95% CI)Subtotals only