Introduction cers and methodologists. The methodologists (evidence review team) were based at the McMaster University WHO Collaborating Center and had expertise in guideline development and evidence synthesis. A steering group of seven members was then created from the expert guideline panel, to guide the process.
Following a review of the suitability of the initial 45 general questions, these questions were refined to 16 questions for which an evidence review was deemed necessary. The steering group also decided to assess the evidence for the effects of cryotherapy in women with histologically confirmed CIN, to provide the best estimate of the benefits and side-effects of cryotherapy without the potential for confounding the outcomes due to false-positive screening tests or diagnoses.
To determine the outcomes, a scoping review of cryotherapy studies was conducted by the evidence review team. The expert guideline panel was also consulted. A list of outcomes to be considered when making the recommendations was compiled. Nineteen members of the expert guideline panel independently and anonymously scored the outcomes by importance for decision-making, via an electronic The majority of individuals in this situation would want the suggested course of action, but many would not.
Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.

# For clinicians
Most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator.
Recognize that different choices will be appropriate for individual patients and that you must help each patient arrive at a management decision consistent with his or her values and preferences. Decision aids may be useful for helping individuals make decisions consistent with their values and preferences.

# For policymakers
The recommendation can be adopted as policy in most situations.
Policy-making will require substantial debate and involvement of various stakeholders.
survey (5). The mean and median importance of each outcome (scale: 1 -least important to 9critical) was calculated, and 16 outcomes were identified as important or critical (see Box 1).

# Preparation of the evidence profiles and grading of the evidence
The evidence review team conducted a series of systematic literature reviews following the methods of the Cochrane Collaboration, and prepared GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evidence profiles for each question (6). During this process, the steering group held conference calls to discuss issues about the available evidence, the presentation of the results, and their impact on making recommendations. - Resource use (including cost, human resources and length of stay)
- Cervical carcinoma incidence
- Acceptability to women (e.g. satisfaction with process or provider)
- Referrals after cryotherapy for complications or follow-up treatment
- Acceptability according to providers
- HIV transmission (HIV acquisition, HIV shedding)
- All severe adverse events (including major bleeding, major infections, etc.)
- Fertility (e.g. conception)
- CIN (1 or 2-3)
- Spontaneous abortion
- Pain (requiring local treatment)
- Maternal morbidity
- Minor infection (requiring outpatient treatment only)
a In order of importance for cryotherapy versus no treatment or LEEP.
Evidence summaries and profiles, which were based on the evidence of the systematic reviews, were prepared for each question using the GRADEprofiler software (8). GRADE evidence profiles present the effect of the intervention on each outcome (e.g. number of women with recurrent CIN), and the quality of the evidence for each outcome. The quality of a body of evidence is assessed based on the following criteria: risk of bias, imprecision, inconsistency, indirectness, publication bias, magnitude of effect, dose-effect relations and an assessment of the effect of residual confounding and bias. Quality is categorized into four levels, ranging from , being the lowest quality, to , being the highest quality. The GRADE evidence profiles allow the expert guideline panel to base its judgments on the same concisely summarized evidence when making recommendations. One week before the expert guideline panel met to develop the recommendations, panel members were able to review the evidence profiles for each question via a password-protected electronic SharePoint site.

# Development of recommendations
The expert guideline panel met on 22 to 23 September 2010, to review the evidence and make recommendations. This meeting was chaired by a methodologist with experience in guideline development, and cochaired by a gynaecological oncologist. There were 32 panel experts, as well as WHO and International Agency for Research on Cancer (IARC) officers, who provided scientific input and guidance. The key objectives of the meeting were to formulate evidence-based recommendations for each of the priority questions, identify key research gaps and discuss a dissemination plan for the new guidelines.
During the September meeting, the panel developed recommendations based on the GRADE evidence profiles. For each recommendation, the panel considered and agreed on the following: the quality of the evidence; the balance of benefits and downsides; the assumptions about the values and preferences associated with the decision; and the extent of resource use. Recommendations were made by consensus. Before the meeting concluded, the panel used the evidence to classify each recommendation as "strong" or "conditional" and agreed on the wording and remarks for each recommendation.
GRADE evidence profiles were created for 16 key questions about the effects of cryotherapy compared with no treatment or LEEP in women with histologically confirmed CIN1, 2 or 3 (see Appendix B for summary tables for each recommendation; GRADE tables are available from / publications/cancers/9789241502856/en/index. html. The systematic reviews found only a few randomized controlled trials or controlled observational studies (such as cohort or case-control studies) that fulfilled the inclusion criteria. Therefore, most of the recommendations are based on pooled results across observational studies of women who received cryotherapy. For these analyses, results were pooled across all CIN grades (CIN1, 2, 3), and, when possible, tested for differences between outcomes for CIN1 and CIN2/3. However, cryotherapy outcomes stratified by CIN grade at diagnosis were not different enough to make separate recommendations based on CIN grade. For this reason, these recommendations can apply to any CIN grade. There were few studies measuring outcomes that the panel identified as critical to decision-making: fertility and obstetrics outcomes; maternal morbidity; acceptability of the procedure to women or their health-care providers; referrals rates for complications; and HIV acquisition and transmission. Therefore, the recommendations are based primarily on studies that measured cryotherapy treatment failures for CIN (i.e. included any evidence of disease after treatment); major and minor adverse events; and mortality.

# Use of cryotherapy for prevention of CIN
1a. The expert panel recommends cryotherapy over no treatment (strong recommendation,  quality evidence)
Remarks: This recommendation is strong, despite the presence of very-low-quality evidence. The expected benefit of cervical cancer prevention is very high but there is uncertainty related to the occurrence of adverse outcomes. There was very low-quality evidence for the occurrence of spontaneous abortions and infertility but the risk appeared similar to that in the general population. Although neither the risk of HIV acquisition in HIV-negative women nor the risk of HIV transmission by HIV-infected women who undergo cryotherapy is known, the current limited data do not suggest that there is an increase in the risk of HIV acquisition/transmission. Additional data regarding the rate of HIV acquisition/transmission are pending and will need to be assessed in future. However, the panel agreed that the net benefit from cryotherapy outweighs the potential HIV risk.
1b. In settings where LEEP is available and accessible, the expert panel suggests treatment with LEEP over cryotherapy (conditional recommendation,  quality evidence)
Remarks: This recommendation applies to women regardless of HIV status. The benefits of LEEP when compared to cryotherapy were greater, and harms fewer or similar; therefore, LEEP was suggested. However, the panel recognized that there are greater resource implications for LEEP than with cryotherapy and therefore LEEP is not available in all settings. When LEEP is unavailable, cryotherapy is recommended (see recommendation 1a).
Although the risk of HIV seroconversion in HIV-negative women, and the risk of transmission after LEEP or cryotherapy are unknown, the benefits of LEEP were felt to outweigh the harms, and, therefore, this recommendation applies to women regardless of HIV status.

# Lesion size
- Among women with CIN lesions covering more than 75% of the ectocervix, or with lesions extending beyond the cryo tip being used, the expert panel suggests performing or referring for excisional therapy (conditional recommendation,  quality evidence)
Remarks: This recommendation includes considerations that cryo tips should cover the entire lesion and that the largest cryo tip typically only covers lesions that extend over up to 75% of the cervix. Since the quality of the evidence is low for recurrent CIN lesions and for lesions larger than 75% of the cervical surface, the panel made a conditional recommendation.

# Lesions extending into the endocervical canal
In There appear to be better health outcomes when cryotherapy is performed by trained nurses or trained midwives rather than physicians. However, values and preferences for cryotherapy performed by physicians versus midwives or nurses differ across settings. In many settings, the resources required for nurses and midwives are lower than for physicians.
Use of cryotherapy during pregnancy 9a. In pregnant women, the expert panel suggests deferring cryotherapy until after pregnancy (conditional recommendation,  quality evidence)
Remarks: Deferral means that cryotherapy is delayed until the postpartum period. The available limited evidence does not suggest that cryotherapy increases risk of adverse pregnancy outcomes when performed during pregnancy; however, an increased risk of pregnancy loss cannot be ruled out and evidence is required. If women with histologically confirmed CIN lesions are at a high risk of loss to follow-up, or if additional opportunities for treatment are unlikely, treatment during pregnancy may be considered. However, there is an opportunity for enforcing the need for postpartum visits (including opportunities for child vaccination) if lesions are identified during pregnancy. There also are possible negative perceptions if cryotherapy is (erroneously) associated with pregnancy loss by women.
- b. In women whose pregnancy status is unknown (or there is no clinical evidence of pregnancy), the expert panel suggests using cryotherapy (conditional recommendation,  quality evidence)
Remarks: This is based on recommendation 1a.
Retreatment of CIN lesions with cryotherapy 10 a. The expert panel recommends cryotherapy over no treatment for women who screen positive after prior cryotherapy treatment (strong recommendation,  quality evidence)
Remarks: There was no evidence for use of cryotherapy over no treatment in women who screen positive after previous treatment with cryotherapy. Therefore, this recommendation is based on recommendation 1a.
In settings where LEEP is available and accessible, the expert panel suggests treatment with LEEP over cryotherapy for women who screen positive after prior cryotherapy treatment (conditional recommendation,  quality evidence)
Remarks: There was very-low-quality evidence for benefits of LEEP techniques over cryotherapy and no evidence for harm in women who screen positive after previous treatment with cryotherapy. This recommendation is directly related to recommendation 1b.
As part of best practice, detailed counselling and education should be provided with informed consent, prior to performing cryotherapy. Specific involvement of a woman's partner post-treatment should be given special attention, and, in particular, the use of condoms post-cryotherapy. The reviewed evidence was judged by the expert panel as too indirect to make a recommendation for additional education and counselling beyond what would be part of best practice. Evidence from future interventions may inform this question.
This document summarizes the recent WHO recommendations for the use of cryotherapy in women with histologically confirmed CIN. The methods recommended by WHO for guideline development were followed, and a series of systematic reviews were conducted to inform these recommendations. The panel, comprising experts from around the world, developed 14 recommendations, while considering the international audience and application of these guidelines in low-, middle-and high-income countries.
These guidelines are directly applicable to women with histologically confirmed CIN, but may be applicable to women who have been screened positive without histological confirmation. However, this review and the recommendations did not address the issue of "single-visit" or "screen-and-treat" approaches. We recognize that in many cervical cancer prevention and control programmes, treatment is commonly offered on the basis of a screening test result alone, such as VIA, most often because histological confirmation is not available or is programmatically feasible. Thus, although not all women who screen positive will have CIN, treatment by cryotherapy according to these present guidelines can be provided. In addition, the recommendations for cryotherapy using the double-freeze techniques and different gases (CO 2 versus N 2 O) are directly applicable to any populations of women receiving cryotherapy who have positive screening test results without confirmatory histology diagnosis. These cryotherapy recommendations are also essential for the forthcoming development of the WHO "technical specification and procurement of cryotherapy equipment", and for programme managers wanting to scale-up national cervical cancer and prevention programmes.
As in most guidelines, many of these recommendations are conditional, due to the absence of moderate or high quality of evidence. Therefore, clinicians and policy-makers will need to consider available resources (including costs, equipment and human resources), and the presumed values and preferences of women presenting with precancerous lesions found at the time of screening. For suspicion of glandular disease, the evidence was considered too indirect or sparse to develop recommendations, and so the panel did not formulate recommendations. There is also little evidence for cryotherapy use among HIV-positive women and those who are pregnant. For recommendations in these populations, the panel agreed that the benefits of treatment to prevent cervical cancer outweighed the unknown or uncertain harms, but that future research will need to be considered for future updates of the recommendations.
A strength of these recommendations is the process used by the expert panel. Specifically, the recommendations were made considering the totality of the available evidence and using the transparent and rigorous methods recommended for all WHO guidelines. Thus, despite the frequently indirect evidence from studies that lacked independent control groups, the panel had at hand comprehensive evidence summaries when making decisions regarding recommendations. The WHO guideline process also provided a systematic approach to decision-making, and a method to transparently record the benefits, harms, values, preferences and resource use for each recommendation decision.
The limitations of these guidelines are inherent to the lack of available evidence to answer key questions. Guidelines in general, and for WHO in particular, should provide recommendations based on the best available evidence. Much of the best available evidence for these guidelines came from pooled data across observational studies, which did not include independent control or comparison groups. Because of this, the estimates of comparative effects were frequently based on indirect comparisons, that is, comparisons were made across studies rather than within studies, leading to considerable uncertainty about the best estimates of effect. More importantly, the efficacy estimates The higher the quality of evidence, the more likely is a strong recommendation.

#  Yes  No
There is low-to very-low-quality evidence from both randomized and observational controlled studies for recurrence rates and adverse events. In general estimates of effect are obtained from single arm studies with no independent control. Outcomes, such as some fertility outcomes and acceptability were not measured.

# Certainty about the balance of benefits versus harms and burdens (is there certainty?)
The larger the difference between the desirable and undesirable consequences and the certainty around that difference, the more likely a strong recommendation.
The smaller the net benefit and the lower the certainty for that benefit, the more likely is a conditional/ weak recommendation.

#  Yes  No
There is considerable benefit and relatively little harm  Recurrence rates of CIN from observational studies with no independent control show
- CIN II-III, 4%
- CIN I, 2%
- All CIN, 6%  Absolute risk reduction in cervical cancer with cryotherapy was calculated as 18% over 30 years for baseline risk of 1%; 9% over 30 years for 0.5%
- assumptions: from observational studies with no independent control the relative risk reduction with cryotherapy is 86%, but a spontaneous regression of 28% which gives the relative risk reduction with cryotherapy as 61%. Using 1% baseline risk without cryotherapy, the absolute risk reduction with cryotherapy is 0.61% over 1 year or 18% over 30 years. Using 0.5% gives 0.3% over 1 year or 9% over 30 years.  Major adverse effects occurred rarely with cryotherapy, but minor may occur more frequently.  It is unclear whether cryotherapy affects fertility/ obstetric outcomes, or whether cryotherapy is unacceptable to women.  Risk of HIV shedding or acquisition is not known, but this risk is unlikely to outweigh the benefits.

# Certainty in or similar values (is there certainty or similarity?)
The more certainty or similarity in values and preferences, the more likely a strong recommendation.

#  Yes  No
 A high value was placed on avoiding CIN recurrence, avoiding serious adverse events and acceptability to the patient  A low value was placed on minor adverse events

# Resource implications
The lower the cost of an intervention compared with the alternative, and other costs related to the decision -that is, the fewer resources consumed -the more likely is a strong recommendation.

#  Yes  No
Resources required for cryotherapy but they are generally affordable  There are resources required to provide cryotherapy to prevent cervical cancer but these resources are worth the expected benefits and downstream treatment costs for cervical cancer are avoided. The treatment of adverse outcomes is also considered worthwhile.

# Overall strength of recommendation
Recommendation 1b. Should cryotherapy versus LEEP (loop electrosurgical excision procedure) be used in women with histologically confirmed CIN?
Recommendation: In settings where LEEP/LLETZ is available and accessible, the expert panel suggests treatment with LEEP/ LLETZ over cryotherapy.
Population: Women with histologically confirmed CIN Intervention: Cryotherapy versus LEEP

# Factor Decision Explanation
High or moderate evidence (is there high or moderate quality evidence?)
The higher the quality of evidence, the more likely is a strong recommendation.
 Yes  No
There is moderate quality evidence from both randomized and observational controlled studies for recurrence rates. However, there is low quality evidence for other outcomes which were considered critical and important for decision-making (e.g. severe adverse events, cervical cancer). There is uncertainty for fertility and other obstetrical outcomes, and HIV acquisition/ transmission was not measured.

# Certainty about the balance of benefits versus harms and burdens (is there certainty?)
The larger the difference between the desirable and undesirable consequences and the certainty around that difference, the more likely a strong recommendation. The smaller the net benefit and the lower the certainty for that benefit, the more likely is a conditional/ weak recommendation. The more certainty or similarity in values and preferences, the more likely a strong recommendation.

#  Yes  No

# Similar values across women
 High value was placed on CIN recurrence, serious adverse events and acceptability to the patient  Low value was placed on minor adverse events

# Resource implications (are resources worth expected benefits?)
The lower the cost of an intervention compared to the alternative that is considered and other costs related to the decision -that is, fewer resources consumed -the more likely is a strong recommendation. The higher the quality of evidence, the more likely is a strong recommendation.
 Yes  No
There is low quality evidence for recurrence rates. But very-low-quality evidence for other outcomes which were considered critical and important for decisionmaking (e.g. severe adverse events, cervical cancer).
There is uncertainty around acceptability, fertility and other obstetrical outcomes, and HIV acquisition/transmission was not measured.
Certainty about the balance of benefits versus harms and burdens (is there certainty?)
The larger the difference between the desirable and undesirable consequences and the certainty around that difference, the more likely a strong recommendation. The smaller the net benefit and the lower the certainty for that benefit, the more likely is a conditional/ weak recommendation. uncertain for prevention of cervical cancer.  It is uncertain whether there are differences in major or minor adverse events between cryotherapy and LEEP.  There is uncertainty about fertility/obstetric outcomes, acceptability and HIV transmission.

# Certainty in or similar values (is there certainty or similarity?)
The more certainty or similarity in values and preferences, the more likely a strong recommendation.

#  Yes  No
 High value was placed on CIN recurrence, serious adverse events and acceptability to the patient  Low value was placed on minor adverse events

# Resource implications (are resources worth expected benefits?)
The lower the cost of an intervention compared to the alternative that is considered and other costs related to the decision -that is, the fewer resources consumed -the more likely is a strong recommendation.

#  Yes  No
More resources required for LEEP  Need for more skilled providers to perform LEEP  Need for more or expensive equipment/supplies for LEEP  Need for local anaesthesia with LEEP

# Overall strength of recommendation Conditional
Recommendation 2. In women who have histologically confirmed CIN, are there differences in recurrence of CIN by lesion size?
Small lesion defined as 75% covered, large lesion, >2 quadrants, >25 to 30mm.
Meta-analysis of the proportion of women who had recurrence/persistence of CIN at 1 year shows a significant interaction among different lesion sizes.
At 1 year post cryotherapy, recurrence rate was greatest in women who had a large lesion. Recurrence rate of all grades of CIN in women with a
- small lesion is 6% (from 5 to 7%);
- moderate lesion is 7% (from 6 to 8%);
- large lesion is 18% (from 13 to 23%).
See the evidence summaries on the evidence base document at  RHR_12.11_eng.pdf?ua=1
Recommendation 3, a and b. In women who have histologically confirmed CIN, are there differences in recurrence of CIN when the lesion extends into the endocervical canal?
Meta-analysis of the proportion of women with a lesion that DOES or DOES NOT extend into the endocervical canal showed a significant interaction between these two groups for recurrence of all grades of CIN at 1 year.
At 1 year post cryotherapy, the recurrence rate in women was higher in women with endocervical canal extension. Recurrence of all grades of CIN at 1 year in women with a lesion that is:
- ECC positive is 16% (from 13 to 20%);
- ECC negative is 6% (from 5 to 6%).
There was however, inconsistency across studies in both groups of women which could not be explained and therefore decreases our confidence in these results.
Recommendation 4. Should cryotherapy using a double versus single freeze technique be used in women with histologically confirmed CIN?
Recommendation: The expert panel suggests double freeze using a 3 minute freeze, 5 minute thaw, 3 minute freeze cycle over single freeze cryotherapy.
Population: Women with histologically confirmed CIN Intervention: Double versus single freeze

# Factor Decision Explanation
High or moderate evidence (is there high or moderate quality evidence?)
The higher the quality of evidence, the more likely is a strong recommendation.
 Yes  No
There is moderate to low quality evidence from both randomized and observational controlled studies for recurrence rates. There is low quality evidence for other outcomes which were considered critical and important for decision-making (e.g. severe adverse events, cervical cancer). There is uncertainty for fertility and other obstetrical outcomes, and HIV acquisition/transmission was not measured.
Certainty about the balance of benefits versus harms and burdens (is there certainty?)
The larger the difference between the desirable and undesirable consequences and the certainty around that difference, the more likely a strong recommendation. The smaller the net benefit and the lower the certainty for that benefit, the more likely is a conditional/ weak recommendation. The more certainty or similarity in values and preferences, the more likely a strong recommendation.

#  Yes  No
 High value was placed on CIN recurrence, incidence of cervical cancer, serious adverse events, resource use, and acceptability to the patient and providers  Low value was placed on minor adverse events and fertility

# Resource implications (are resources worth expected benefits?)
The lower the cost of an intervention compared to the alternative that is considered and other costs related to the decision -that is, the fewer resources consumed -the more likely is a strong recommendation.

# Factor Decision Explanation
High or moderate evidence (is there high or moderate quality evidence?)
The higher the quality of evidence, the more likely is a strong recommendation.
 Yes  No
There is very-low-quality evidence from observational controlled studies for recurrence rates, cervical cancer, and severe adverse events which were considered critical for decision-making. HIV acquisition/transmission as well as fertility and other obstetrical outcomes were not measured.
Certainty about the balance of benefits versus harms and burdens (is there certainty?)
The larger the difference between the desirable and undesirable consequences and the certainty around that difference, the more likely a strong recommendation. The smaller the net benefit and the lower the certainty for that benefit, the more likely is a conditional/ weak recommendation. The more certainty or similarity in values and preferences, the more likely a strong recommendation.

#  Yes  No
 High value was placed on CIN recurrence, cervical cancer, and serious adverse events  Low value was placed on minor adverse events

# Resource implications (are resources worth expected benefits?)
The lower the cost of an intervention compared to the alternative that is considered and other costs related to the decision -that is, the fewer resources consumed -the more likely is a strong recommendation.

#  Yes  No
More resources required for nitrous oxide  Nitrous oxide is more costly than carbon dioxide  Nitrous oxide requires more safety measures <(e.g. ventilation)
Overall strength of recommendation Conditional Recommendation 6. Should cryotherapy using cough technique be provided to women with histologically confirmed CIN?
Recommendation: The expert panel recommends to not use cough technique during cryotherapy.
Population: Women with histologically confirmed CIN Intervention: cryotherapy using cough technique

# Factor Decision Explanation
High or moderate evidence (is there high or moderate quality evidence?)
The higher the quality of evidence, the more likely is a strong recommendation.

#  Yes  No
 There is very-low-quality evidence for outcomes such as recurrence rates and adverse events. Outcomes, such as acceptability to women or providers, and fertility were not measured or could not be compared between studies using cryotherapy with cough technique or cryotherapy.
Certainty about the balance of benefits versus harms and burdens (is there certainty?)
The larger the difference between the desirable and undesirable consequences and the certainty around that difference, the more likely a strong recommendation. The smaller the net benefit and the lower the certainty for that benefit, the more likely is a conditional/ weak recommendation.

#  Yes  No
The risks may be higher when using the cough technique  It is uncertain whether recurrence rates of CIN increase when using cough technique.
- CIN II-III, OR 1.00 (0.58 to 1.73)
- All CIN, OR 2.75 (1.89 to 4.00)
- CIN I, OR 3.5 (2.22 to 5.51)  The effects on acceptability according to women or their providers is not known.  The risk of major infection and pain may be increased, but this is uncertain.  There may be little difference in cervical cancer rates based on absolute risks.  It is not known what the effects are on fertility outcomes, mortality.

# Certainty in or similar values (is there certainty or similarity?)
The more certainty or similarity in values and preferences, the more likely a strong recommendation.

#  Yes  No
 High value was placed on acceptability to the patient and provider, and adverse events  Low value was on recurrence rates of CIN

# Resource implications (are resources worth expected benefits?)
The lower the cost of an intervention compared to the alternative that is considered and other costs related to the decision -that is, the fewer resources consumedthe more likely is a strong recommendation. The higher the quality of evidence, the more likely is a strong recommendation.
 Yes  No  Indirect comparisons of observational studies with no control group provided very-low-quality evidence for the outcomes that were considered important for decisionmaking (e.g. major bleeding, major infection and minor adverse effects). Acceptability to providers or women was not measured.
Certainty about the balance of benefits versus harms and burdens (is there certainty?)
The larger the difference between the desirable and undesirable consequences and the certainty around that difference, the more likely a strong recommendation. The smaller the net benefit and the lower the certainty for that benefit, the more likely is a conditional/ weak recommendation. The more certainty or similarity in values and preferences, the more likely a strong recommendation.

#  Yes  No
Similar values   Similar value was placed on major and minor adverse events  Burden to women may be a consideration

# Resource implications (are resources worth expected benefits?)
The lower the cost of an intervention compared to the alternative that is considered and other costs related to the decision -that is, the fewer resources consumed -the more likely is a strong recommendation.

# Factor Decision Explanation
High or moderate evidence (is there high or moderate quality evidence?)
The higher the quality of evidence, the more likely is a strong recommendation.

#  Yes  No
 There is very-low-quality evidence from observational studies (with no control) for the outcomes that were considered critical for decision-making (e.g. CIN 2-3, all severe adverse events, cervical carcinoma) or important for decision-making (e.g. minor infections and pain) Unacceptability to women or their providers, and HIV transmission were not measured.
Certainty about the balance of benefits versus harms and burdens (is there certainty?)
The larger the difference between the desirable and undesirable consequences and the certainty around that difference, the more likely a strong recommendation. The smaller the net benefit and the lower the certainty for that benefit, the more likely is a conditional/ weak recommendation.

# Resource implications (are resources worth expected benefits?)
The lower the cost of an intervention compared to the alternative that is considered and other costs related to the decision -that is, the fewer resources consumed -the more likely is a strong recommendation. The higher the quality of evidence, the more likely is a strong recommendation.

#  Yes  No
 There were no randomized controlled trials or observational studies (with or without a control) that evaluated the effects of cryotherapy (only) compared with no treatment or LEEP. Results are from cryotherapy or laser, compared to no surgical procedure or conisation.
Certainty about the balance of benefits versus harms and burdens (is there certainty?)
The larger the difference between the desirable and undesirable consequences and the certainty around that difference, the more likely a strong recommendation. The smaller the net benefit and the lower the certainty for that benefit, the more likely is a conditional/ weak recommendation. It is uncertain whether adverse obstetrical outcomes (e.g. preterm delivery and complications) occur with cryotherapy.

# Certainty in or similar values (is there certainty or similarity?)
The more certainty or similarity in values and preferences, the more likely a strong recommendation.

#  Yes  No
 High value was placed on CIN recurrence, serious adverse events and acceptability to the patient  Low value was placed on minor adverse events  It is unclear whether all women would want or not want treatment

# Resource implications
The lower the cost of an intervention compared to the alternative that is considered and other costs related to the decision -that is, the fewer resources consumed -the more likely is a strong recommendation. Recommendation: The expert panel recommends cryotherapy over no treatment for women who screen positive after treatment for a previous diagnosis of histologically confirmed CIN lesions. In settings where LEEP is available and accessible, the expert panel suggests treatment with LEEP over cryotherapy for women who screen positive after previous cryotherapy treatment.
Population: women who have been already treated with cryotherapy but screen positive or histologically diagnosed CIN at follow-up testing (>12 months)
Intervention: retreatment with cryotherapy versus other intervention

# Factor Decision Explanation
High or moderate evidence (is there high or moderate quality evidence?)
The higher the quality of evidence, the more likely is a strong recommendation.

#  Yes  No
There is very-low-quality evidence from observational studies for recurrence rates between cryotherapy and conisation for retreatment. Other outcomes which are considered critical and important for decision-making (e.g. major adverse effects) were not measured in the studies.
Certainty about the balance of benefits versus harms and burdens (is there certainty?)
The larger the difference between the desirable and undesirable consequences and the certainty around that difference, the more likely a strong recommendation. The smaller the net benefit and the lower the certainty for that benefit, the more likely is a conditional/ weak recommendation.

#  Yes  No
Risks may be greater with cryotherapy  It is uncertain whether the risk of CIN recurrence is greater with cryotherapy than conisation All CIN, OR 2.35 (0.82 to 6.7)
Certainty in or similar values (is there certainty or similarity?)
The more certainty or similarity in values and preferences, the more likely a strong recommendation.

#  Yes  No
Uncertain  High value was placed on CIN recurrence, acceptability and severe adverse events  Low value was placed on minor events

# Resource implications (are resources worth expected benefits?)
The lower the cost of an intervention compared to the alternative that is considered and other costs related to the decision -that is, the fewer resources consumed -the more likely is a strong recommendation.