Analysis on pregnancy outcomes and risk factors of cervical polypectomy during the first and second trimester pregnancy

To evaluate the risk factors of miscarriage in patients attempted cervical polypectomy during the first and second trimester pregnancy.


Introduction
Cervical polyp is a common gynecological disease, occurring in 2%-5% of adult women. 1 During pregnancy, cervical polyps can be found irrespective of gestational age. The exact prevalence in pregnant women is unknown at present. In some cases, a cervical polyp can be asymptomatic, which is incidentally discovered by routine pelvic examination. 2,3 In others a pregnant woman with cervical polyp may present with vaginal discharge, vaginal bleeding, postcoital bleeding, and cervical infection. 4,5 Cervical polyps during pregnancy with recurrent vaginal bleeding may often be misdiagnosed as threatened abortion. These polyps can raise concern and discomfort to the pregnant women.
A controversial question is whether a cervical polyp during pregnancy needs to be removed. While, there are no standardized guidelines to answer this question. Some practitioners hold the opinion that cervical polyps detected during pregnancy increase the risk of chorioamnionitis, and hence favor to remove the polyps. 6 Others believe that patients undergoing polypectomy in pregnancy have high risks of miscarriage or spontaneous premature delivery. [7][8][9] Although most cervical polyps are benign, malignant change can be found in 0.2%-1.63% of cases in the general population. 1,10,11 In pregnant persons, the risk of malignancy is not clear and limited reports have describe rare forms of cancerous cervical polyps. [12][13][14] There is a lack of evidence to evaluate the risk for patients with cervical polyps and management to provide full information to patients on their chances of a healthy pregnancy. Finding factors that are associated with a poor prognosis could provide opportunities to improve the pregnancy outcome. Thus, first, the present study is aimed to analysis whether polypectomy of cervical polyps during pregnancy is associated with the adverse pregnancy outcomes. Second, we further to explore the risk factors associated with a poor prognosis for the pregnancy outcomes in patients with cervical polyps.

Patient's characteristics
Pregnant women with singleton infants who were diagnosed with cervical polyps and underwent polypectomy during pregnancy at Women's Hospital School of Medicine Zhejiang University between January 2013 and May 2019 were evaluated. Most patients had vaginal bleeding before surgery, surgical indications were determined by the clinician based on the risk assessment of spontaneous miscarriage and preterm delivery. Exclusion criteria were as followed: termination of pregnancy due to an obstetric indication, such as abruption of the placenta, placental previa, and preeclampsia. Patients who delivered because of severe complications of medical and surgical diseases, such as congenital heart disease, renal failure, and appendicitis, were not included. Gestational weeks were calculated according to the last menstrual period and confirmed by ultrasound in early pregnancy. We retrospectively reviewed the patients' age, gravida, parity, relevant past gynecological history, vaginal bleeding before polypectomy and the clinical course, and pregnancy outcomes after polypectomy. All patients were examined for vaginal discharge before surgery and no bacterial vaginosis was found. According to our national definition of miscarriage, preterm birth and term birth, we divided patients into three groups: miscarriage group (gestational weeks at termination of pregnancy was <28 weeks), preterm group (gestational weeks at termination of pregnancy was 28-36 + 6 weeks), term group (gestational weeks at termination of pregnancy was ≥37 weeks). This study was approved by the Research Ethics Committee of the Women's Hospital School of Medicine Zhejiang University, China. The procedures used in this study adhere to the tenets of the Declaration of Helsinki.

Informed consent
The consent of the study participants was deemed unnecessary as the study only concerned the retrospective review of the medical database. The need of informed consent was waived by the ethics committee {Medical Ethics Committee of the Women's Hospital, Zhejiang University School of Medicine} for this retrospective study.

Treatment
Approaches of cervical polypectomy: we resected cervical polyp by twisting and rotating the base of the polyp until it came of off using a pair of ring forceps mostly without anesthesia; for polyps with a thick stalk usually require a electrosurgical excision or coil ligation removal. After the excision of cervical polyps, gauze packing could be used to prevent bleeding and taken out after 24 h. If there was still dark red of bright red vaginal bleeding 24 h after surgery, it was judged as postoperative bleeding. Inhibitors of uterine contractions, progesterone preparations and antibiotics can be administered prophylactically during perioperative period. The inhibitors of uterine contractions are as follows: intravenous drip of 25% magnesium sulfate injection 30-40 mL or phloroglucinol injection 80 mg (in 5% glucose injection). Progesterone preparations are as follows: dydrogesterone tablet 10 mg twice daily and/or progesterone injection 20-60 mg once daily intramuscular injection.
Every removed polyp must be sent for further histological examination to rule out malignancy. According to the histological patterns, the excised polyps were divided into four groups: decidual polyps, endocervical polyps, both, and others. Endocervical polyps are focal, hyperplastic protrusions of endocervical folds, including the epithelium and substantia propria. 15 Decidual polyps include extruded fragments of decidua, a polypoid protrusion from the endocervix with the stromal pseudodecidual change. It frequently presents as a raised plaque or pseudopolyp if the pseudodecidual occurs on the exocervix.
The cells develop abundant pink cytoplasm, with well-defined cellular border. 15 (Figure 1).

Statistical analyses
The data were presented as the mean AE SD or median (range) and analyzed using IBM SPSS 21.0. First, the distribution state of measurement data were tested. Kruskal-Wallis H test or Mann-Whitney U test were used for non-normal distribution data. Categorical data were compared using the χ 2 -test or Fisher's exact test where appropriate. The multivariate analysis was based on a logistic regression analysis. A p value <0.05 was considered to be significant.

Results
A total of 307 pregnant females were eventually included in our study. The number of cases in the first and second trimesters was 50 and 257, respectively. There was no significantly difference in the higher risk for miscarriage or preterm delivery between the first and second trimester cervical polypectomy as shown in Table 1. Among them, 243 patients delivered at ≥37 weeks, 27 patients had a miscarriage before 28 weeks, others had a preterm delivery. The minimal week of miscarriage is at 7 weeks of gestation and the spontaneous miscarriage occurred 8 days after surgery. Table 2 shows a comparison of clinical features between miscarriage group, preterm delivery group and term delivery group. The maternal age, history of conization of cervix, frequency of preterm deliveries, the proportion of decidual polyps, and bleeding after polypectomy were significantly different between three groups.
As shown in Table 3, the risk factors were identified by a univariate analysis and a multiple logistic regression analysis for patients in pregnancy who had undergone polypectomy. The independent risk factors identified by a multiple logistic regression analysis for miscarriage were the presence of decidual polyps (odds ratio [OR] 2.346, 95% confidence interval (CI) 1.330-4.141, p = 0.003) and vaginal bleeding after polypectomy (OR 2.248, 95% CI 1.207-4.191, p = 0.011).
The pathological diagnoses include 197 cases of endocervical polyps, 101 cases decidual polyps, 5 cases of both pathological changes and 4 others, no malignant or precancerous case was found. The clinical   Table 4. The proportion of nulliparity, use of inhibitors of uterine contractions during perioperative period and gestational age at polypectomy was significantly higher among the patients with endocervical polyps than in those with decidual polyps. The gestational weeks at polypectomy of decidual polyps group was significantly earlier than that of endocervical polyp group. The decidual polyp group had a higher percentage of progesterone drugs usage to protect the fetus during early pregnancy (64.4%-36.0%, p < 0.001). The incidence of miscarriage (14.9%-5.6%, p = 0.010) was significantly higher in the patients with decidual polyps than in those with endocervical polyps.

Discussion
Cervical polyps with recurrent vaginal bleeding during pregnancy are usually misdiagnosed as an inevitable miscarriage. They can cause considerable emotional stress. However, the clinical treatment of pregnancy with cervical polyps is still controversial by far. Some scholars found that the granulocyte elastase activity in cervical mucus decreased significantly after polypectomy compared with prepolypectomy. They suggested that cervical polyp during pregnancy should be removed since the cervical polyp may increase the risk of inflammation and chorioamnionitis. 6  Our study showed that with cervical polypectomy during the first and second trimester, the frequency of miscarriage before 28 weeks of gestation was 8.8% (27/307), which was slightly higher than a Japanese study. 7 In present study, we found that "vaginal bleeding after polypectomy" was identified as strong risk factors for miscarriage. Prolonged vaginal bleeding can alter the cervix environment, especially in the condition of vaginal bacterial flora, it can aggravate the inflammatory response and promote ascending infections. In most research, cervical polyps during pregnancy were removed by forceps grasping the base and twisting. However, others prefer electrosurgery because they think this method has a better hemostasis. 16 Discussion on methods of cervical polypectomy during pregnancy has been ongoing. Aoki et al. 8 reported a case of premature rupture of membrane (PROM) at 22 weeks of gestation in a 29-year-old primigravida who received a cervical polypectomy using an Endoloop polydioxanone suture (PDS) II™ at 11 weeks of gestation. Our study demonstrated that there was no significant difference in pregnancy outcome between different excision methods. Postoperative gauze filling did not increase the risk of miscarriage and premature delivery. Therefore, it should pay attention to prevent postoperative vaginal bleeding when cervical polypectomy is undertaken during gestation period regardless of the method. If necessary, gauze or hemostatic material can be used for hemostasis.
Our study showed that the risk of miscarriage associated with polypectomy during pregnancy was related to the pathological type of cervical polyps. Females with decidual polyps were more likely to have a poor pregnancy outcome than females with cervical polyps. Cervical decidual polyp is uncommon, only sporadic reports have described this special type polyp. Seo et al. 17 described a case with a decidual polyp resulted in first trimester miscarriage after diagnostic polypectomy at 5 weeks of gestation. Tokunaka et al. 18 found that the removal of decidual polyps during pregnancy carried a risk of spontaneous abortion (12.2%) and preterm delivery (34.2%), which were higher than that of endocervical polyps. Decidual polyps include decidualized endocervical polyps and prolapsed fragments of decidua. The removal of decidual polyps maybe cause trauma to the endometrial mucosa and/ or inflammation may affect the endometrium. 18 Levin et al. postulated that disruption of blood vessels and injury to the decidual membranes may promote local inflammation and procoagulant changes associated with placental abruption. 19 In addition, because the pedicle of some decidual polyps is often wide and deep, most of the surgical treatment can only be cut from the external os of cervix, but cannot achieve complete resection. So that decidual polypectomy is more likely to take a risk of miscarriage and/or preterm delivery. Decidual polyps are presumably mediated by the high levels of progesterone during pregnancy. With the extensive development of assisted reproductive technology (ART), the application of luteal support may also increase the incidence of decidual polyps. In our study, there were a total of eight females who were pregnant by ART, and half of them were pathologically indicated to be decidual polyps. Our research found that pregnant patients with decidual polyps had a significantly higher percentage of early progesterone use than those with endocervical polyps. Based on our results and the above studies, we suggest that if it is not necessary in the early stage of pregnancy, progesterone should not be used as much as possible, so as to avoid the development of decidual polyps which maybe lead to adverse pregnancy outcomes. Ectopic decidua can become smaller or regress in the second and third trimester and postpartum spontaneously without any complications. 20 Thus, we has reason to believe that asymptomatic deciduous polyps during pregnancy do not need any therapeutic intervention. In addition, according to our research, decidual polyps are more likely to be observed in multiparous women. It may be thought that recurrent childbirth increases the exposure of the cervical stroma to high levels of estrogen and progesterone.
Mostly, cervical polyps during pregnancy are found in gynecological examination. However, it is difficult to distinguish cervical polyps from decidual polyps by their appearance. While, in fact, pathological diagnosis is needed to clear polyp type. Therefore, when decidual polyps are highly suspected, we suggest that biopsy of superficial polyps may be able to confirm the diagnosis and avoid surgical risk. For pregnant females with vaginal bleeding caused by decidual polyps, maybe we can perform surgery in stages: remove the necrotic surface first, and continue to observe if there is no subsequent bleeding. Further prospective case-control studies are needed to determine the optimal management of decidual polyps.

Limitations
There are some potential limitations for our study. Only those who underwent cervical polypectomies during pregnancy were included. Patients who received conservative treatment for cervical polyps were excluded from our study and pregnancy outcomes were not compared between the two groups. It is unclear whether polypectomy or the polyps itself induce miscarriage and/or preterm delivery. We also do not know if there is an underlying choritis that can cause miscarriage and preterm delivery before the cervical polypectomy. The clinical data were gathered from a single hospital, more higher-level evidence is needed.

Author contributions
Yu-luan Huang and Fang Le designed the study. Ruizhe Chen and Yu-luan Huang acquisited data and performed the statistical analysis.