The definitions for the quality of the evidence (++++, +++0, ++00, +000) and the strength of the recommendations (strong, conditional) are provided at the end of the "Major Recommendations" field.
Use of Cryotherapy for Prevention of Cervical Intraepithelial Neoplasia (CIN)
1a. The expert panel recommends cryotherapy over no treatment (strong recommendation, +000 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 human immunodeficiency virus (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 loop electrosurgical excision procedure (LEEP) is available and accessible, the expert panel suggests treatment with LEEP over cryotherapy (conditional recommendation, ++00 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.
2. 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, ++00 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 women with CIN lesions extending into the endocervical canal, prior guidelines recommend excisional procedures; this panel operated under this assumption.
3a. In settings where LEEP is available and accessible, and women present with CIN lesions extending into the cervical canal, the expert panel suggests treatment with LEEP over cryotherapy (conditional recommendation, ++00 quality evidence).
Remarks: The benefits of LEEP were greater than those of cryotherapy, and the harms were fewer in these women. However, since there are greater resource implications for LEEP than cryotherapy, and thus LEEP is not available in all settings, a conditional recommendation was made.
3b. In settings where excisional procedures (e.g. LEEP, laser or cold knife conization [CKC]) or referral to additional treatment are not available, the expert panel suggests that women with lesions extending into the endocervical canal be treated with cryotherapy (conditional recommendation, +000 quality evidence).
Remarks: The risk of treatment failure is higher in women with CIN lesions extending into the cervical canal than in women whose lesion margins are clearly demarcated or do not extend into the cervical canal. The rationale for treating these women is that women left untreated may be lost to follow-up (i.e., they may not receive further treatment and are at risk for developing cervical cancer). This recommendation should be considered in the context of recommendation 3a.
Cryotherapy Technique and Procedure
4. The expert panel suggests double freeze using a 3 minute freeze, 5 minute thaw, 3 minute freeze cycle over single-freeze cryotherapy (conditional recommendation, ++00 quality evidence).
Remarks: The evidence stems from studies in which a single-freeze technique was performed for up to 3 minutes. This recommendation takes into consideration that during a cryotherapy procedure, the iceball should extend beyond the edge of the cryo tip. Data from trials regarding the benefits and harms of single-freeze versus double-freeze techniques are pending and will be assessed in the future. The panel commented that randomized controlled trials should be performed to specifically address this issue.
5. The expert panel recommends cryotherapy using either carbon dioxide (CO2) or nitrous oxide (N2O) gas (strong recommendation, ++00 quality evidence); in settings where both gases are available, the expert panel suggests cryotherapy with CO2 rather than with N2O (conditional recommendation, +000 quality evidence).
Remarks: Due to the limitations in the available evidence, it is uncertain whether CO2 provides better or worse health outcomes, but the existing evidence suggests that there is no difference. Laboratory studies suggest no difference in temperature at the cryo tip between different grades of CO2 (e.g., medical or industrial). Although, N2O gas is less available and requires more resources due to higher cost and additional requirements for ventilation, in settings where N2O gas is more likely to be available or has other advantages, this conditional recommendation suggests that N2O gas may be used. Studies addressing the use of CO2 versus N2O are being conducted.
6. The expert panel recommends that the "cough technique" should not be used during cryotherapy (strong recommendation, +000 quality evidence).
Remarks: The "cough" or "freeze–clear–freeze" technique was historically used because of technical deficiencies in a particular cryotherapy device from a single manufacturer, which caused instrument clogging. This device has been removed from the market, and so this is a strong recommendation despite very low-quality evidence.
7. The expert panel suggests that prophylactic antibiotics should not be used when providing cryotherapy (conditional recommendation, +000 quality evidence).
Remarks: While there may be fewer minor adverse events and fewer minor infections with prophylactic antibiotic use, there is a risk of increased antimicrobial resistance and allergic reactions that is unlikely to outweigh any potential benefits. Resources also appear to be increased with the use of antibiotics.
8. The expert panel recommends that healthcare workers (including non-physicians) trained in cryotherapy perform the procedure for women when it is indicated (strong recommendation, ++00 quality evidence); the expert panel also suggests that trained nurses or trained midwives rather than physicians may perform cryotherapy (conditional recommendation, +000 quality evidence).
Remarks: The importance of cryotherapy training of the health-care worker was considered when making this recommendation. 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, +000 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.
9b. In women whose pregnancy status is unknown (or there is no clinical evidence of pregnancy), the expert panel suggests using cryotherapy (conditional recommendation, +000 quality evidence).
Remarks: This is based on recommendation 1a.
Retreatment of CIN Lesions with Cryotherapy
10a. The expert panel recommends cryotherapy over no treatment for women who screen positive after prior cryotherapy treatment (strong recommendation, +000 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.
10b. 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, ++00 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.
Assessment of the Strength of the Recommendation
In keeping with WHO guideline terminology, the recommendations are either "strong" or "conditional". For strong recommendations, the guideline uses the words "the Expert Panel recommends", and for conditional recommendations, "the Expert Panel suggests". Suggested interpretations of "strong" and "conditional" recommendations are provided in the table below. Understanding the interpretation of these two grades – either strong or conditional – is essential for health-care decision-making.
Interpretation of Strong and Conditional Recommendations
||Most individuals in this situation would want the recommended course of action, and only a small proportion would not.
||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.
||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 the clinician 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.
||The recommendation can be adopted as policy in most situations.
||Policy-making will require substantial debate and involvement of various stakeholders.
Quality of Evidence
||High quality: Further research is very unlikely to change confidence in the estimate of effect.
||Moderate quality: Further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate
||Low quality: Further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate.
||Very low quality: Any estimate of effect is very uncertain.