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Year : 2022  |  Volume : 67  |  Issue : 4  |  Page : 478
Formaldehyde 5% in flexible collodion compared to cryotherapy for treatment of female genital warts: A randomized clinical trial

1 From the Infertility Research Center, Shiraz University of Medical Sciences; Department of Obstetrics and Gynecology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
2 Department of Obstetrics and Gynecology, Shiraz University of Medical Sciences, Shiraz, Iran
3 Department of Dermatology, Molecular Dermatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
4 Department of Obstetrics and Gynecology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
5 Department of Dermatology, Shiraz University of Medical Sciences, Shiraz, Iran
6 From the Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

Date of Web Publication2-Nov-2022

Correspondence Address:
Bahia Namavar Jahromi
Infertility and IVF, Infertility Research Center, Shiraz University of Medical Sciences, Shiraz
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijd.ijd_1035_21

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Objectives: Genital wart is a sexually transmitted disease caused by human papillomavirus (HPV) and is responsible for discomfort, and decreased quality of life and productivity in victims with a high recurrence rate after treatments. This study aimed to compare the efficacy and safety of formaldehyde 5% with cryotherapy for the treatment of female genital warts. Methods: Eighty women with at least two similar genital warts who visited the outpatient dermatology clinic of Shahid Faghihi hospital, Shiraz, Iran, were enrolled in this study. One lesion of each patient was self-treated with formaldehyde 5% in flexible collodion gel once daily for 28 days and the other matched lesion was treated by weekly repeated cryotherapy courses. The number of eradicated lesions and the mean days needed to treat, pain scores, complications and patient satisfaction were compared between the treatment methods. Results: Complete clearance of lesions was observed in 58.7% of formaldehyde-treated lesions compared to 88.7% for cryotherapy (P value = 0.000). With formaldehyde-treated lesions, 51% complained of pain, 36.3% had pruritus, 86.3% had skin dryness, 88.8% complained of burning sensation and 93.7% showed erythema. In the cryotherapy group, 92.5% complained of pain, 15% had burning sensation, 75% showed erythema, 5% had atrophy, 80% developed post-inflammatory hyper or hypopigmentation (PIH) and 92.5% suffered from ulceration. Seventy-five (93%) found it easy to apply and (47) 58% were satisfied with their treatment results. Conclusions: Self-administration of formaldehyde 5% resulted in a lower clearance rate but had better cosmetic outcomes with lower pain scores compared to cryotherapy.

Keywords: Cryotherapy, female, formaldehyde, genital warts, HPV

How to cite this article:
Jahromi BN, Razeghi M, Dastgheib L, Fazelzadeh A, Miri A, Vakili S, Foruhari S, Sabetian S. Formaldehyde 5% in flexible collodion compared to cryotherapy for treatment of female genital warts: A randomized clinical trial. Indian J Dermatol 2022;67:478

How to cite this URL:
Jahromi BN, Razeghi M, Dastgheib L, Fazelzadeh A, Miri A, Vakili S, Foruhari S, Sabetian S. Formaldehyde 5% in flexible collodion compared to cryotherapy for treatment of female genital warts: A randomized clinical trial. Indian J Dermatol [serial online] 2022 [cited 2023 Jun 7];67:478. Available from:

   Introduction Top

Genital wart (condylomata acuminate) is the most common viral sexually transmitted disease with a prevalence of about 7 to 12% caused by certain types of human papillomavirus (HPV)[1] types 11 and 6 which have been detected in 90% of affected individuals.[2],[3] HPV prevalence is higher among sexually active teenagers with multiple partners.[4] Warts may appear as solitary lesions or in huge clusters.[3] Genital warts cause increased economic burden and decrease life quality.[5] Studies on the management of genital warts are very conflicting.[6] In fact, there is no curative treatment for HPV infection.[7] The success of therapy depends on various clinical factors including size, location, the thickness of warts, duration of disease and general health of the patient.[8] Some believe that topical treatments might be used in the first step according to the size and extent of warts.[2],[9]

There are several therapeutic methods to treat genital warts, including destructive agents (cryotherapy, laser, keratolytics, photodynamic therapy, curettage and cautery), immune stimulants (cimetidine, topical sensitizer), antimitotic agents (bleomycin, podophyllin, retinoids) or topical virucidal agents (glutaraldehyde).[10] Imiquimod, which upregulates interferon and tumour necrosis factor (TNF) is expensive, requires multiple applications and may lead to erythema or erosions.[11],[12] Podophyllotoxin, which inhibits cell cycle replication by disrupting microtubules is also relatively expensive. Although other methods like trichloroacetic acid (TCA) are cheap and somehow effective, their side effects are common including pain, irritation and peeling.[4]

Cryotherapy is a simple cost-effective procedure that is considered the method of choice for warts that are not self-accessible or failed to be treated by the other methods.[3],[13] In cryotherapy, liquid nitrogen at a temperature of –196°C is used to make cell necrosis around and below the wart. The clearance rate of cryotherapy is 80% to 88% without systemic side effects.[2] Cryotherapy is usually performed every other week for twelve weeks.[14],[15],[16] However, there is a high rate of recurrence of 25–40%, and like other procedural therapies such as laser and electrocauterization, it is time-consuming, needs expensive instrumentation, frequently requires multiple therapeutic courses and may cause scarring.[4],[13]

Formaldehyde is a powerful disinfectant that was accidentally discovered in early 1943 to be effective for the treatment of warts.[17] A clinical trial conducted by Vickers in 1961,[18] suggested that 10% formaldehyde is a safe and efficacious therapy for the treatment of plantar warts. Many other studies demonstrated the effectiveness of formaldehyde on extra-genital warts.[10],[17],[19] For these purposes, formaldehyde is prepared as a 3–10% solution, added to unguentum Merck base (Almirall Co, Barcelona, Spain) (20%) or incorporated into gels (0.75%).[10] But formaldehyde has not been reported yet to be used for the treatment of female genital warts.

According to the limitations associated with current therapeutic methods and to introduce an alternative self-treatment method for genital warts, the current study was designed to evaluate the therapeutic effects of formaldehyde 5% compared to cryotherapy for treating genital warts.

   Materials and Methods Top

Between March 2017 and March 2018, 124 women who attended outpatient clinic of dermatology at Shahid Faghihi Hospital, Shiraz, Iran, for the treatment of newly diagnosed external genital warts with at least two similar lesions were assessed to participate in this project, 112 cases were invited and finally, 80 subjects accepted to participate. After complete explanations and signing written informed consents, the patients were enrolled. [Figure 1] shows the flow of study participants.
Figure 1: Flow diagram for the lesions under treatment by formaldehyde and cryotherapy

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For every patient, the length, width and depth of the lesions were measured by Collis rulers, and careful mapping of the lesions was documented in their charts. One self-accessible lesion in every patient was chosen to be treated with topical formaldehyde 5% in flexible collodion 10 min daily for 28 days and the other lesion of a similar size in the same patient was planned to be treated by repeated cryotherapies every 7 days. Formaldehyde was left to dry for 10 min. Patients were free to wash the site with water any time after 10 min, while taking a bath or in the toilet. If the patient had more than two lesions, all the other lesions were treated by cryotherapy. If the formaldehyde-treated lesion was not eradicated after 28 days, cryotherapy was planned to be performed. According to the clinical guidelines practiced in our centre, cryotherapy was performed on each lesion with a 2 mm margin for 20 s in 2 cycles every week and was repeated weekly until complete eradication of the lesions.

As formaldehyde was not previously reported to be used for female genital warts, and since genital skin is thin and very sensitive due to crowding of nerve endings, at the beginning we started a pilot study, and weak alcohol-based formaldehyde 3% solution was tried for six lesions that showed poor efficacy without any complications. So, we decided to try 5% formaldehyde solution in flexible collodion as the solvent due to its adhesive properties to create a more potent and longer-acting thin layer of medication on the lesions. Better results were noticed in the pilot study with 5% formaldehyde in flexible collodion. So, we continued the main study by using 5% formaldehyde in flexible collodion. Flexible collodion has been shown to improve the efficacy of topical treatment of warts in previous studies.[20] The prepared solution in 10 ml bottles and droppers was given to the patients with complete instructions on how to use it. We visited the patients weekly for close observation, size documentation and to repeat cryotherapy until complete eradication of the lesions. Patients were planned to continue the therapeutic modality for up to four weeks or until the wart was no longer visible. At their final visit, they were asked to rate the ease of use and their overall satisfaction with their therapeutic experience.

Complications of each treatment method were documented in every visit, including pain score, burning sensation, erythema, pruritus, dryness, ulcer, atrophy and post-inflammatory hyper or hypopigmentation (PIH). Pain intensity was measured by visual analogue scaling (VAS) score from 0 to 10 reported by the subjects. Nonresponsive lesions that remained despite 4 weeks of continuous treatment as well as missed lesions that belonged to the patients who left the study due to side effects or poor efficacy were considered treatment failures.

The subjects were excluded from the beginning if they had pregnancy or lactation, coagulation disorders, wounds or other active skin disorders at the treatment site, history of human immunodeficiency virus (HIV) or immunodeficiency, existence of other sexually transmitted diseases, topical antiviral drug usage in the last two weeks, co-existence of internal warts (cervical, vaginal, clitoral) or sensitivity to formaldehyde preparations.

This study was approved by the Scientific and Ethics Committee of Shiraz University of Medical Sciences as a randomized clinical trial (RCT) with the code of IR.sums.REC.1395.S171 and RCT registration number of IRCT20190714044200N1.

An unpaired two-tailed student T-test and Chi-square tests (two related samples using the McNemar test) were used to compare the results (using SPSS v. 25 for windows). Also, McNemar's test was used for matched pairs of lesions. A P value of 0.05 or less was considered statistically significant in this study.

   Results Top

In this study, the therapeutic effects of topical formaldehyde 5% in flexible collodion and weekly repeated cryotherapies were compared in 80 patients with paired-genital wart lesions. The mean age of patients was 32.2 ± 9.00 years (range 17–56). At the beginning of the study, the mean diameter of the compared lesions in the formaldehyde and cryotherapy groups was 4.24 ± 3.75 and 4.42 ± 3.99 mm, respectively (P value = 0.25).

Of 80 lesions that were treated with formaldehyde, 43 (53.75%) were completely eradicated after 7 days vs 45 (56.25%) in the cryotherapy group (P value = 0.44). Nine patients left the study in the first week due to cryotherapy complications and severe pain. So, nine lesions were excluded from both study groups. Seventeen cases decided to change their therapeutic modality from formaldehyde to cryotherapy. So only 11 lesions continued with formaldehyde and 26 lesions continued with cryotherapy. After 14 days, 4/11 (36.36%) lesions were completely treated with formaldehyde compared to 22/26 (84.61%) lesions that were completely eradicated after two courses of cryotherapy. In this step, another patient discontinued formaldehyde because of its poor efficacy and only six patients continued formaldehyde for 21 days and the same subjects continued for 28 days without any therapeutic effect. Three lesions disappeared after three courses and one lesion after four courses of cryotherapy. The eradication outcome is presented in [Table 1].
Table 1: Comparison of complete eradication of lesions in four weeks of treatment by formaldehyde and cryotherapy

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Seventy-one lesions (88.7%) were completely treated cumulatively after four weeks of cryotherapy vs 47 lesions (58.8%) in the formaldehyde group (P value = 0.00). Treatment failures of formaldehyde were 33/80 (41.25%) compared to 9/80 (11.25%) in the cryotherapy group (P value = 0.00).

Side effects of treatments in both groups were evaluated and the results are presented in [Table 2]. Formaldehyde had more burning sensation (15% vs 88.8%) and erythema (75% vs 95%) compared to cryotherapy (P = 0.000). Also, pruritus and skin dryness were only seen with formaldehyde and were not reported with cryotherapy. PIH, ulcer and atrophy were seen after cryotherapy while none of these complications were seen with formaldehyde administration [Table 2].
Table 2: Side effects of treatments

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Finally, patients were asked about the ease of use of formaldehyde. Despite the side effects, 75 patients (93%) found it easy to apply topical formaldehyde in flexible collodion on their lesions and 47 patients (58%) were satisfied with their treatment process and recommended it to other patients.

   Discussion Top

Genital warts are common with considerable influence on the general health of sexually active couples by a decrease in their quality of life and costs of treatments for the health system and the affected person. The mean loss of quality-adjusted life-years (QALY) is calculated to be about 6.6 days of healthy life for only one episode of genital warts.[5] On the other hand, a perfectly curative, popular and easily accessible method of treatment is not yet known despite several treatment modalities that are in practice nowadays. The recurrence rate of 10-40% for genital warts is reported in different studies. The established association of the high-risk types of HPV with the cancer of the uterine cervix increases the psychological burden of the disease.[21]

Several studies demonstrated the effectiveness of formaldehyde on extra-genital warts, especially plantar warts. This RCT aimed to compare the efficacy, safety and complications of formaldehyde 5% in collodion with cryotherapy for the treatment of 80 paired lesions of genital warts. We decided to test both therapeutic modalities on the same patient to decrease several patient-dependent biases and study confounders. To our knowledge, this is the first trial on formaldehyde 5% in collodion on genital warts.

In our study, a clearance rate of 88.7% was calculated for cryotherapy compared to 58.7% for formaldehyde. There was no previously published study on formaldehyde 5% for genital warts to be compared but Jennings et al.[17] conducted a study on the improving effects of formaldehyde 10% for the treatment of simple plantar verrucae and suggested that 10% formaldehyde is a safe and efficacious therapy for the treatment of simple plantar verrucae with the cure rate of 58.1% that is compatible with our results. However, our results on the lesions that had cryotherapy are in agreement with the previous trials on cryotherapy that reported a cure rate of 60%–97%.[22]

In our study, 47 lesions that were finally eradicated by formaldehyde 5% disappeared in the first two weeks of treatment, and continuation of formaldehyde with this concentration for two more weeks on the remaining types of warts was not effective anymore, as shown in [Table 1].

In our study, formaldehyde showed faster recovery and less pain compared to cryotherapy. Furthermore, the possibility of easy self-application at home without the need for expensive equipment and trained operators is considered the advantage of formaldehyde.

Patients in this study were carefully monitored for side effects. In the formaldehyde-treated lesions, patients complained of skin dryness, burning sensation, erythema and pruritus. When treated by cryotherapy, patients experienced side effects such as pain, atrophy, PIH and ulcers. However, none of the formaldehyde-treated lesions developed PIH, atrophy or ulcer, instead, some complained about pruritus and dryness.

PIH was reported in 64% of lesions after cryotherapy in our study. Melanocytes are sensitive to the cold and are destroyed at temperatures lower than –4°C, so post-cryotherapy hypopigmentation is a frequent complication.[23] Previous studies suggested that for cosmetic issues, cryotherapy would be better for patients with lighter skin types and a high prevalence of PIH is predictable after cryotherapy.[19]

Several studies can be found that provided evidence of the positive effects of other energy-based therapeutic methods for the treatment of genital warts including electrocautery, CO2 lasers and photodynamic therapy. In some reports, photodynamic therapy showed a near 100% clearance rate and was suggested as a good 'third-line therapy'/alternative. However, the need for special equipment has limited its use.[3],[24],[25]

Our study had some limitations including a lack of information about genotyping of HPV in the lesions and short-term follow-up. It would be much better if we could have followed the patients for a longer period to evaluate the recurrence rates of the treatments performed along with the clearance cure rates. We believe that probably a more concentrated formaldehyde collodion might be more efficacious and should be confirmed against the probable complications by future studies. On the other hand, special HPV genotypes might be resistant to formaldehyde and judgement is possible only when the HPV genotyping for all of the lesions is performed and compared.

This trial indicates that formaldehyde 5% is somehow effective, has fewer side effects and yields a better scarless cosmesis and requires less recovery time. Although the effectiveness of formaldehyde 5% in collodion was less than cryotherapy in this study, formaldehyde can serve as a potential therapeutic modality for patients who care about cosmetic issues and do not have access to the necessary facilities for cryotherapy and desire self-treatment at home. However, we suggest for a general HPV vaccination to prevent genital warts as the best strategy for public health.

   Conclusion Top

Formaldehyde 5% can be considered as a potential treatment method for genital warts in patients who care about cosmetic issues, do not have access to the necessary facilities for cryotherapy and want to be treated at home. However, because of the lower effectiveness of formaldehyde 5% compared to cryotherapy, further studies are needed on the optimization of its composition, concentration and method of use.


This paper was partly extracted from a thesis written by Mahsa Razeghi and financially was supported by Vice-Chancellor for Research Affairs of Shiraz University of Medical Sciences with the reference number of 94-01-01-9397. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole and have given their approval for this version to be published.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

This work was supported by Vice-chancellor for Research Affairs of Shiraz University of Medical Sciences with the reference number of 94-01-01-9397.

Conflicts of interest

There are no conflicts of interest.

   References Top

Hathaway JK. HPV: Diagnosis, prevention, and treatment. Clin Obstet Gynecol 2012;55:671-80.  Back to cited text no. 1
Scheinfeld N, Lehman DS. An evidence-based review of medical and surgical treatments of genital warts. Dermatol Online J 2006;12:5.  Back to cited text no. 2
Ockenfels HM. Therapeutic management of cutaneous and genital warts. J Dtsch Dermatol Ges 2016;14:892-9.  Back to cited text no. 3
Recanati MA, Kramer KJ, Maggio JJ, Chao CR. Cantharidin is superior to trichloroacetic acid for the treatment of non-mucosal genital warts: A pilot randomized controlled trial. Clin Exp Obstet Gynecol 2018;45:383-6.  Back to cited text no. 4
Woodhall S, Jit M, Soldan K, Kinghorn G, Gilson R, Nathan M, et al. The impact of genital warts: Loss of quality of life and cost of treatment in eight sexual health clinics in the UK. Sex Transm Infect 2011;87:458-63.  Back to cited text no. 5
Na C, Choi H, Song S, Kim M, Shin B. Two-year experience of using the measles, mumps and rubella vaccine as intralesional immunotherapy for warts. Clin Exp Dermatol 2014;39:583-9.  Back to cited text no. 6
Soori T, Hallaji Z, Noroozi-Nejad E. Genital warts in 250 Iranian patients and their high-risk sexual behaviors. Arch Iran Med 2013;16:518-20.  Back to cited text no. 7
Park HS, Choi WS. Pulsed dye laser treatment for viral warts: A study of 120 patients. J Dermatol 2008;35:491-8.  Back to cited text no. 8
Claesson U, Lassus A, Happonen H, Hogstrom L, Siboulet A. Topical treatment of venereal warts: A comparative open study of podophyllotoxin cream versus solution. Int J STD AIDS 1996;7:429-34.  Back to cited text no. 9
Leman JA, Benton EC. Verrucas. Am J Clin Dermatol 2000;1:143-9.  Back to cited text no. 10
Moore RA, Edwards JE, Hopwood J, Hicks D. Imiquimod for the treatment of genital warts: A quantitative systematic review. BMC Infect Dis 2001;1:3.  Back to cited text no. 11
Kollipara R, Ekhlassi E, Downing C, Guidry J, Lee M, Tyring SK. Advancements in pharmacotherapy for noncancerous manifestations of HPV. J Clin Med 2015;4:832-46.  Back to cited text no. 12
Balsdon M. Cryosurgery of genital warts. Br J Vener Dis 1978;54:352-3.  Back to cited text no. 13
Dall'Oglio F, D'Amico V, Nasca MR, Micali G. Treatment of cutaneous warts. Am J Clin Dermatol 2012;13:73-96.  Back to cited text no. 14
Leszczyszyn J, Lebski I, Lysenko L, Hirnle L, Gerber H. Anal warts (condylomata acuminata)-current issues and treatment modalities. Adv Clin Exp Med 2014;23:307-11.  Back to cited text no. 15
Scheinfeld N. Update on the treatment of genital warts. Dermatol Online J 2013;19:18559.  Back to cited text no. 16
Jennings MB, Ricketti J, Guadara J, Nach W, Goodwin S. Treatment for simple plantar verrucae: Monochloroacetic acid and 10% formaldehyde versus 10% formaldehyde alone. J Am Podiat Med Assoc 2006;96:53-8.  Back to cited text no. 17
Vickers CF. Treatment of plantar warts in children. Br Med J 1961;2:743-5.  Back to cited text no. 18
Raziee M, Balighi K, Shabanzadeh-Dehkordi H, Robati R. Efficacy and safety of cryotherapy vs. trichloroacetic acid in the treatment of solar lentigo. J Eur Acad Dermatol Venereol 2008;22:316-9.  Back to cited text no. 19
Rao KS, Naidu V, Savitha K, Ankad BS. Cryosurgery Vs 40% Salicylic Acid in treatment of warts. Medica Innovatica. 2014;5:1.  Back to cited text no. 20
Woodhall SC, Jit M, Cai C, Ramsey T, Zia S, Crouch S, et al. Cost of treatment and QALYs lost due to genital warts: Data for the economic evaluation of HPV vaccines in the United Kingdom. Sex Transm Dis 2009;36:515-21.  Back to cited text no. 21
Ghiasy S, Fallah-Karkan M, Razzaghi MR, Ranjbar A, Rahavian A, Javanmard B. Is holmium laser an appropriate modality to treat genital warts? J Lasers Med Sci 2019;10:70-4.  Back to cited text no. 22
Hexsel DM, Mazzuco R, Bohn J, Borges J, Gobbato DO. Clinical comparative study between cryotherapy and local dermabrasion for the treatment of solar lentigo on the back of the hands. Dermatol Surg 2000;26:457-62.  Back to cited text no. 23
Wang H-W, Zhang L-L, Miao F, Lv T, Wang X-L, Huang Z. Treatment of HPV infection-associated cervical condylomata acuminata with 5-aminolevulinic acid-mediated photodynamic therapy. Photochem Photobiol 2012;88:565-9.  Back to cited text no. 24
Liang J, Lu XN, Tang H, Zhang Z, Fan J, Xu JH. Evaluation of photodynamic therapy using topical aminolevulinic acid hydrochloride in the treatment of condylomata acuminata: A comparative, randomized clinical trial. Photodermatol Photoimmunol Photomed 2009;25:293-7.  Back to cited text no. 25


  [Figure 1]

  [Table 1], [Table 2]


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