Abstract

Background: This real-world study aims to investigate clinical efficacy and safety of CO2 cryotherapy combined with Kushen gel for chronic cervicitis. Methods: From June 2021 to December 2021, a total of 363 patients with chronic cervicitis treated in the Center for Diagnosis and Treatment of Cervical Diseases were selected. A total of 208 patients were treated with CO2 cryotherapy combined with Kushen gel, while 155 cases only received cervical CO2 cryotherapy. Results: The total effective rate of combined therapy for chronic cervicitis was 100%, with a higher cure rate than CO2 cryotherapy alone (p = 0.004), and it was significantly correlated with the degree of cervical inflammation (p <0.050). Cure rate increased with decreasing severity of inflammatory response. Conclusions: CO2 cryotherapy combined with Kushen gel for chronic cervicitis has definite clinical efficacy with few adverse reactions and the combined treatment of CO2 cryotherapy with Kushen gel could enhance the therapeutic effect.

1. Introduction

One of the most prevalent gynecologic conditions is chronic cervicitis, which primarily affects women who have previously given birth. Approximately 60% of married women experience persistent cervicitis [1]. The clinical symptoms of chronic cervicitis mainly include increased vaginal discharge, mucous purulence, pruritus of the vulva and contact bleeding in severe cases [2, 3].

The are several main treatments of chronic cervicitis [4]. Surgical therapy is the most commonly used method and comprises laser, microwave, cryotherapy, or loop electrosurgical excision procedure (LEEP) [5]. Among these, CO2 cryotherapy for cervical lesions is a designated treatment method in China’s Guidelines for Comprehensive Prevention and Control of Cervical Cancer, as well as World Health Organization (WHO) Basic Practical Guidelines for Comprehensive Prevention and Treatment of Cervical Cancer [6]. CO2 cryotherapy uses carbon dioxide refrigerant to quickly reach the ultra-low temperature of minus 67 degrees celsius, and contact is made to the cervical tissue through a low temperature freezing head, so as to achieve the purpose of wound tissue repair [7, 8].

Following surgical therapy, there usually follows adverse reactions, such as continuous vaginal drainage, vaginal bleeding and cervical stenosis, the latter resulting in secondary infertility and cervical dystocia [4, 5]. Kushen gel is a semisolid gel made of a mixture of matrine (C15H24N2O) and carbopol. Matrine is an alkaloid from the traditional Chinese herb medicine sophora flavescens reported to exhibit anti-inflammatory, anti-bacterial, and protective effects [9]. It is a topical preparation that is absorbed through the tissue mucosa without any irritation. Because it is in gel form, the drug can flow evenly to the cervix and every corner of the vagina after being applied [10]. This study aimed to investigate the clinical efficacy and safety of CO2 cryotherapy combined with Kushen gel for chronic cervicitis.

2. Materials and Methods
2.1 Patients

This real-world study was conducted in the Center for Diagnosis and Treatment of Cervical Diseases of Changzhou Maternity and Child Health Care Hospital, Changzhou, China in 2021. After obtaining the approval of the ethics committee (Changzhou Maternal and Child Health Care Hospital, NO. 2020), and obtaining signed consent, 363 women with chronic cervicitis were enrolled. Among them, 208 patients were treated with CO2 cryotherapy combined with Kushen gel (study group), while 155 cases only received cervical CO2 cryotherapy (control group) (Fig. 1).

Fig. 1.

Study flowchart.

Inclusion criteria included normal cytology with the absence of human papillomavirus (HPV), cleanliness of vaginal secretions is I–II, and consent to undergo cervical CO2 cryotherapy. Exclusion criteria included pregnancy, and lactation, pelvic examination demonstrating acute or subacute inflammation, and having received other treatments within 3 months.

2.2 Grouping

Two hundred and eight patients agreed to CO2 cryotherapy combined with Kushen gel for treatment, which was listed as the study group. In study group, CO2 cryotherapy was performed on the patient first. CO2 cryotherapy involves freezing temperatures of –22 to –30 °C, which results in crystallization and evaporation of intracellular fluid and ultimately, destruction of cells at –85 °C. The procedure is performed until the formation of an ice ball is noted, which takes up to five minutes, most often with freeze-thaw cycle [11]. Following CO2 cryotherapy, the patient had a once-daily Kushen gel vaginal suppository placed for two weeks.

One hundred and fifty-five cases only received cervical CO2 cryotherapy, which this being the control group. The control group received the same CO2 cryotherapy technique as the experimental group without the use of Kushen gel.

2.3 Follow-up

The women received follow-up visits one, two, and three months post-treatment and their symptoms were reassessed using the four-stage scoring evaluation (Supplementary Table 1).

The scores for symptoms and signs increased as cervical inflammation worsened. Efficacy was evaluated according to changes in patients’ symptoms and signs and through laboratory examination. Therapeutic effect calculation method: Efficacy index = (total score before treatment – total score after treatment)/(total score before treatment) × 100%; Recovery: efficacy index 90%; significantly effective: efficacy index 60%–89%; effective: efficacy index 20%–59%; not effective.

2.4 Statistical Analysis

Chi-square tests were used to assess the measured data. SPSS 23.0 (IBM Corp, Armonk, NY, USA) was utilized for all data analysis in this study, with a two-sided significance level of 0.05.

3. Results
3.1 General Data

Of the 363 women enrolled in the study, there was no significant difference in age between the study and control group (30.0 ± 11.2 vs. 29.2 ± 8.7; p > 0.050). In the terms of the age of first sexual intercourse and number of abortions, there was no significant difference between the study and control group (p > 0.050). Chronic cervicitis was classified as mild, moderate or severe according to the degree of columnar epithelial ectasia. In the study group, there were 45 patients with mild chronic cervicitis, 89 moderate and 74 severe; in the control group, there were 34 patients with mild chronic cervicitis, 66 moderate and 55 severe cervicitis. There was no significant difference between the two groups (p = 0.949) (Table 1).

Table 1.Patients demographic data.
Variables Study group Control group p-value
Age 30.0 ± 11.2 29.2 ± 8.7 >0.05
Age of first sexual intercourse 22.0 ± 2.71 21.7 ± 3.31 >0.05
Number of abortions 0.4 ± 0.6 0.3 ± 0.4 >0.05
Severity of cervicitis 0.949
Mild 45 34
Moderate 89 66
Severe 74 55

Significant difference within groups (p < 0.05).

3.2 Comparison of the Efficacy of Different Degrees of Cervicitis

A total of 208 patients were treated with CO2 cryotherapy combined with Kushen gel (study group); 144 (69.2%) were cured, marked improvement was observed in 59 cases (28.4%), some effectiveness was observed in 5 cases (2.4%). One hundred and fifty-five patients were treated with CO2 cryotherapy (control group); 89 (57.4%) were cured, marked improvement was observed in 51 cases (32.9%), and some effectiveness was observed in 15 cases (9.75%). Both treatments were effective overall for inflammation in patients with chronic cervicitis, but the cure rate in the study group (69.2%) was 1.21 times higher than that in the control group (57.4%), while the rate of minimal effectiveness in the control group (9.7%) was significantly higher than that in the study group (2.4%) by a factor of 4.04. The overall effect of CO2 cryotherapy combined with Kushen gel was better than that of the CO2 cryotherapy alone group (p = 0.004) (Table 2).

Table 2.Comparison of the efficacy of different degrees of cervicitis.
Degree of inflammation Case number (N) Therapeutic effects p
Recovery (n (%)) Significantly effective (n (%)) Effective (n (%)) Total effective rate (n (%))
Mild 79 79 (100)
Study group 45 (100) 0 0 100 -
Control group 34 (100) 0 0 100
Moderate 155 108 (69.7)
Study group 68 (76.4) 20 (22.5) 1 (1.1) 100 0.035
Control group 40 (63.6) 23 (33.9) 3 (2.5) 100
Severe 129 46 (35.7)
Study group 31 (41.9) 39 (52.7) 4 (5.4) 100 0.013
Control group 15 (27.3) 28 (50.9) 12 (21.8) 100
Total 363 233 (64.2) 110 (30.3) 20 (5.5) 100
Study group 208 144 (69.2) 59 (28.4) 5 (2.4) 100 0.004
Control group 155 89 (57.4) 51 (32.9) 15 (9.7) 100

Significant difference within groups (p < 0.05).

Among the 363 patients, they were classified as mild, moderate or severe cervicitis according to the degree of inflammation, and their cure rates gradually decreased with the increasing amount of inflammation. Seventy nine cases with mild inflammation had a 100% cure rate; 108 cases with moderate inflammation had a 69.7% cure rate; and 46 cases with severe inflammation had a 35.7% cure rate. Among the patients with moderate and severe inflammation, the treatment effect after 3 months was significantly better in the study group than in the control group (p = 0.035, p = 0.013) (Table 2). Significant difference was found between groups (p < 0.05).

3.3 Comparison before and after Treatment between the Study Group and the Control Group

Before treatment, there was severe columnar epithelium migration on the cervical surface, covering two–thirds of the entire cervix (Fig. 2A and Fig. 3A). One month after CO2 cryotherapy, the recovery of the research group was significantly better than that of the control group (Fig. 2B and Fig. 3B). Two months after treatment, most of the cervical wounds had been repaired in the study group (Fig. 2C), while in the control group, a small part of the lower lip of the cervix was not completely repaired (Fig. 3C). Three months after CO2 cryotherapy, the cervical wound was completely repaired and healed with a smooth surface in the study group (Fig. 2D). The wound in the control group had also basically recovered, but the surface was still a little red (Fig. 3D).

Fig. 2.

Comparison before and after therapy in study group. (A) prior treatment. (B) 1 month after treatment. (C) 2 months after treatment. (D) 3 months after treatment.

Fig. 3.

Comparison before and after therapy in control group. (A) prior treatment. (B) 1 month after treatment. (C) 2 months after treatment. (D) 3 months after treatment.

3.4 Comparison of Postoperative Reactions

With mild inflammation, 26.5% of patients in the control group had vaginal discharge for more than 2 weeks, which was 3.96 times more than that in the study group (6.7%) (p = 0.015); with moderate inflammation, 48.5% of patients in the control group had vaginal discharge for more than 2 weeks, which was 1.54 times more than that in the study group (31.5%) (p = 0.031); with severe inflammation, the proportion of patients with vaginal discharge for >2 weeks in the control group was 69.1%, 1.51 times higher than in the study group (45.9%) (p = 0.015).

Among the patients in the study group, 12 cases had various amounts of vaginal bleeding 1–3 weeks after treatment, most of which were minimal and lasted less than 2 weeks, with 1 patient with severe cervicitis had increased postoperative bleeding (less than menstrual volume). In contrast, in the control group, 22 patients had vaginal bleeding; 1 with moderate inflammation and 2 with severe inflammation for more than 2 weeks; 3 patients with severe cervicitis had moderate vaginal bleeding (less than menstrual volume), which was 3.93 times more than the study group (Table 3).

Table 3.Comparison of postoperative reactions.
Degree of inflammation Case number (N) Vaginal discharge time (d) Vaginal bleeding time (d) Vaginal bleeding volume p
1–15 16–20 7–15 16–20 Mild Moderate Severe
(n (%)) (n (%)) (n (%)) (n (%)) (n (%)) (n (%)) (n (%))
Mild 79
Study group 42 (93.3) 3 (6.7) 1 (2.2) 0 1 (2.2) 0 0 0.015
Control group 25 (73.5) 9 (26.5) 1 (2.9) 0 1 (2.9) 0 0
Moderate 155
Study group 61 (68.5) 28 (31.5) 3 (3.4) 0 3 (3.4) 0 0 0.031
Control group 34 (51.5) 32 (48.5) 5 (7.6) 1 (1.5) 6 (9.1) 0 0
Severe 129
Study group 40 (54.1) 34 (45.9) 8 (10.8) 0 7 (9.5) 1 (1.4) 0 0.009
Control group 17 (30.9) 38 (69.1) 13 (23.6) 2 (3.6) 12 (21.8) 3 (5.5) 0
Total 363
Study group 143 (68.8) 65 (31.2) 12 (5.8) 0 11 (5.3) 1 (0.5) 0 0.000
Control group 76 (49.0) 79 (51.0) 19 (12.3) 3 (1.9) 19 (12.3) 3 (1.9) 0

Significant difference within groups (p < 0.050).

4. Discussion

Many women experience repeated or sustained symptoms of cervicitis. These symptoms can affect the quality of life and marital relationships and consequently, affect the health of the family atmosphere [11]. According to Sukru’s research, there was a statistically significant improvement in vaginal discharge, pelvic pain, and postcoital bleeding symptoms after the cryotherapy [12]. However, Shabnam’s findings highlighted the equal effect of tranexamic acid and cryotherapy for treating cervical ectropion [13, 14]. Chinese traditional medicine believes that cervicitis belongs to leukorrheal diseases, which is mainly due to unsteadiness of Ren and belt channel dysfunction by dampness and heat. The treatment should be based on clearing heat and dehumidification [15]. Kushen gel is a pure Chinese medicine preparation, and its main component is matrine, which has heat-clearing and detoxifying effects as well as antibacterial and insecticidal properties and removes saprophytic muscles [16, 17].

In this study, CO2 cryotherapy combined with Kushen gel treatment was compared with CO2 cryotherapy alone. The study demonstrated that the cure rate of both treatments was 100% in patients with mild chronic cervicitis, but the cure rate of patients with moderate to severe inflammation was slightly higher in the combined treatment than in the simple CO2 cryotherapy group. A significant correlation between cure rate and severity was found; that is, cure rate increased with decreasing severity of inflammation. The reason is that the area with mild cervicitis erosion is small, and the frozen probe makes adequate contact with the treatment area, exerting biological effect to eliminate local inflammation [18, 19]. In terms of postoperative vaginal discharge time, vaginal bleeding time and bleeding volume, Kushen gel makes full use of its advantage as a Chinese herbal medicine, and its unique benefits are conducive to wound healing [20]. Only 5.8% of the patients in the study group had bleeding, with the majority (91.7%) having minimal bleeding. Moderate amount of bleeding was found in only 0.5% of patients. Compared with simple CO2 cryotherapy, the combined treatment could reduce postoperative vaginal discharge time, bleeding time and amount, shorten the time to wound healing, and promote rapid wound repair.

The postoperative use of Kushen gel makes up for the vulnerability of wound infection after simple CO2 cryotherapy. Mahira’s study [21] shows that wound infection caused by Enterococcus fecal may become a risk factor for cervical intraepithelial neoplasia. The active ingredients in Kushen gel can quickly enter damaged tissues and increase blood circulation [22]. This feature causes necrotic tissues to separate and exfoliate rapidly, and new epithelium grow rapidly. The gel plays a protective role in cervical wound healing, preventing a wound from being infected by bacteria [23, 24].

There are some limitations of this study. First, randomized clinical trials (RCTs) can draw more reliable conclusions, but we were unable to conduct RCT studies because of the inability to achieve double blinding. Second, we cannot avoid the selective bias due to the patient’s own condition.

5. Conclusions

The combined treatment of CO2 cryotherapy with Kushen gel can significantly improve the therapeutic effect and reduce the occurrence of postoperative reactions. Using Kushen gel for the postoperative treatment of chronic cervicitis can significantly improve the quality of life of patients after CO2 cryotherapy.

Availability of Data and Materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author Contributions

LZ and YZ were involved in the analysis and interpretation of study data, drafting and critical revision of the manuscript; YL and WP were involved in the collection of research subject information; JL was involved in the analysis and interpretation of data; XX and MX were involved in the acquisition of data; SL was involved in the conception and interpretation of study data, drafting and critical revision of the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Ethics Approval and Consent to Participate

The studies involving human participants were reviewed and approved by the research program of the Ethics Committee of Changzhou Maternal and Child Health Care Hospital, NO. 2020. The patients/participants provided their written informed consent to participate in this study. The authors received participants’ consent to publish photographs. This study was conducted in accordance with the Helsinki Declaration of 1964 and its later amendments.

Acknowledgment

The authors thank Changzhou Maternity and Child Health Care Hospital for their support for this study, and we thank the participants of the study.

Funding

Scientific Research Project of Maternal and Child Health of Jiangsu Province (F202166). Key talents in maternal and child health care in Jiangsu Province and Leading Talent of Changzhou “The 14th Five-year Plan” High-Level Health Talents Training Project (2022CZLJ030). 2023 Changzhou Policy Guidance Project (International Science and Technology Cooperation) (CZ20230020), Clinical Research Project of Changzhou Medical Center (CMCC202314), and 2023 Jiangsu Province Traditional Chinese Medicine Science and Technology Development Plan (MS2023089).

Conflict of Interest

The authors declare no conflict of interest.

References

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