Cervical and Vaginal Deciduosis: Insights on Management and a Systematic Review of Observational Studies on Pregnancy Complications and Management Outcomes (Including Vaginal Birth)

Introduction. Deciduosis is an ectopic transformation of connective tissue into decidual-like cells. This is the first systematic review describing the clinical course, associated pregnancy complications, and management outcomes of cervical and vaginal deciduosis. Methods. Our search covered worldwide observational studies published in English in five databases (PubMed, PubMed Central (PMC), Europe PMC, ScienceDirect, and Google Scholar) from inception to February 24, 2023. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and critically appraised studies using CAse REport (CARE) and Joanna Briggs Institute (JBI) tools. Then, we extracted patient characteristics, clinical features, management-related information, and outcomes. Results. The selection process identified 15 studies describing 30 pregnancies. Macroscopic cervical and vaginal deciduosis presented as recurrent vaginal bleeding in over 16 of 24 women (57%). Differential diagnoses included miscarriages, cervical pregnancy, placenta previa, and malignancy. Significant antenatal hemorrhages, preterm rupture of membranes, and preterm birth were the most frequent pregnancy complications. Only one of 27 electively performed procedures resulted in biopsy-induced uncontrolled vaginal bleeding (0.04%), suggesting the relative safety of the interventions. Lesion resection led to the cessation of recurrent symptoms in eight of eight patients (100%) compared to eight of 15 women (53%) under observation management. All women with polypoid deciduosis over 1.5 cm entered labor and delivered without complications. Conclusions. We described the clinical course, pregnancy complications, diagnostic-related challenges, management, and associated outcomes in women with macroscopic cervical and vaginal deciduosis. We supported the analysis with the current state of the problem and discovered gaps for prospective studies.


Introduction And Background
Deciduosis, an extra-uterine transformation of connective tissue into decidual-resembling cells, mainly occurs during pregnancy.Microscopically, 70.2% of biopsies obtained during a cesarean section [1] and 15.2%-34% of cervical cytological smears [2,3], as well as up to 90% of cervical biopsies [4], revealed decidual cells.The incidence of macroscopic lesions is unknown.
Deciduosis is generally considered a benign reaction.However, it might lead to significant pregnancy complications and management challenges.Existing systematic reviews [5][6][7] listed deciduosis-associated complications, such as spontaneous hemoperitoneum in pregnancy, (peri)appendicitis, bowel perforation, endometriotic lesion decidualization, disruptions of such lesions (especially threatening when approximated to vulnerable areas like uterine vessels and ureters), urinary bladder or ovarian pseudotumor formation, hemothorax, catamenial pneumothorax, etc.However, to our best knowledge, no systematic review has analyzed deciduosis confined to the lower genital tract location and its impact on pregnancy.
Moving externally from the endocervix, deciduosis of the lower genital tract presents as polyp and ectopy, including its papillary, polypoid, and infiltrative forms [8].Polyp and papillary ectopy arise from the stroma under the columnar epithelium and appear as multicolored "beans" and pale grape-like columnar epithelial villi enlargement, respectively.Polypoid ectopy occurs under the columnar and squamous epithelium, frequently includes a transformation zone, and presents as a friable, yellow-brown mass.Infiltrative ectopy originates under the squamous epithelium as multiple small elevations.Lesion ulceration is common.
Studies identified that pregnancy-associated changes in the cervix, including decidual cells or the Arias-Stella reaction, are sometimes mistakenly recognized as atypical [9,10].Colposcopic impressions can be misleading while performing a biopsy during pregnancy might be risky because of the possibility of excessive bleeding and coincidental pregnancy complications [11].Contrary to popular belief, it is most important to rule out the coexistence of malignancy in suspicious cases.
Accumulated data suggest that cervical deciduosis increases the risks of late miscarriages and preterm birth because of a premature rupture of membranes [12][13][14].Besides, large lesions in labor, especially those that lead to intrapartum bleeding, can raise additional challenges [15][16].
Therefore, this study aims to review the clinical course and management of pregnancies in patients with deciduosis of the lower genital tract.We have included all the possible pregnancy complications and analyzed the incidence of intervention-associated complications, symptoms, and lesion resolution according to the chosen management and, if lesions persisted, the size of the lesions and problems accompanying vaginal delivery.Summarizing these data, we describe the possible challenges, pregnancy complications, and management outcomes.Additionally, we discover knowledge gaps that might serve as a guide for subsequent report descriptions.

Search Strategy and Selection Process
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines released in 2020 to prepare a systematic review [17].Our search strategy, using keywords such as deciduosis, ectopic decidua, ectopic decidual reaction, and ectopic decidualization, was introduced in five databases (PubMed, PubMed Central (PMC), Europe PMC, ScienceDirect, and Google Scholar) and retrieved the references from inception to February 24, 2023.Complete queries and the search results are provided in Table 1.

TABLE 2: Full eligibility criteria
Besides, checking reference lists retrieved three additional studies for the analysis.During the whole process, we did not use any automatic tools.The entire process is shown in Figure 1.We made certain assumptions whenever information could not be recovered or clarified.If the authors reported multiple elevations on the cervix, we suspected an infiltrative form of deciduosis [18,19].When the authors described the lesion as a single ectocervical or vaginal "mass," we interpreted it as a polypoid form of ectopy [20][21][22].We recognized the case of having a decidual polyp during the previous pregnancy as a polyp [23].In one case, it was hard to differentiate a polyp from a potentially papillary form of deciduosis or expulsed fragments of the decidua described as the endocervical "grayish membranes" [24].If vaginal bleeding was not followed by any emergent workup, we considered it insignificant.Additional workup to rule out differential nosologies and concerns mentioned in the discussion sections of the articles contributed to the differential diagnosis analysis.We also recalculated the patient's age based on the provided chronology [25] and the term of gestation based on the last menstrual period day or, if unavailable, the confinement date or size of uterus enlargement [22,23].The "reassuring" result of cytology was interpreted as normal [19].Given the diverse terms of gestation and circumstances of revealing the pathology, we categorized pregnancies as managed expectantly if: (1) there were no planned interventions [24,26]; (2) patients underwent urgent or emergent procedures [27,28]; (3) unprovoked pregnancy complications led to pregnancy termination [20,25]; or (4) patients presented initially after 37WG [15,16,21,23].When reports included a scheduled remote postpartum follow-up for cervix re-evaluation within eight weeks, we suspected lesion persistence [19,22,28].
We excluded underreported and unrestored information from the corresponding analysis, marking them as "not reported" or "not applicable."The extracted data is organized in Tables 3-5.   a The column "WG" refers to the initial revealing of pathology.The term of gestation for delayed or additional procedures was mentioned additionally in the corresponding fields.
b The term polypectomy included polypectomy and/or removal of the ectopic mass.
c The term pseudobiopsy means gentle tissue removal without obtaining a baseline layer.
Author, Year  After completing the data extraction, two reviewers (ZB and HD) critically appraised the studies independently by using the CAse REport (CARE) assessment tool for case reports [31] and the Joanna Briggs Institute (JBI) critical appraisal tools for case series [32].The third reviewer (MS) resolved doubts and disagreements.The studies that scored 70% or higher contributed to our systematic review.This threshold was lowered to 60% for the studies published before 2013, as we did not want to lose clinically relevant information due to differences in the requirements of reporting cases.
We summarized clinically relevant qualitative variables by frequencies and presented them as percentages supported by a numerator and denominator.Continuous variables were presented as the mean and range in a normal data distribution and the median and interquartile range in a non-normal data distribution.
We did not develop the protocol and register the systematic review at the International Prospective Register of Systematic Reviews (PROSPERO) due to the short timeline for its completion.The protocol was substituted with data extraction tables in Microsoft Excel and subsequent analysis.

Patients' Characteristics
The mean patient age was 28 years (± 4.86).Nulliparous women represented the majority -18 of 30 women (60%).Among preexisting pathologies, there was a history of cervical intraepithelial neoplasia (grade 3) treated with loop electrosurgical excision of the transformation (four cases), cervical "erosion" treated with diathermy (one case), and recurrent decidual polyps (three cases).
Clinically, deciduosis presented an accidental finding only in four of 29 patients (14%).The rest of the patients complained of leukorrhea or infectious vaginal discharge (21%, six of 29 women) and/or vaginal bleeding, which was the chief complaint in 22 of 29 women (76%) and had a recurrent character in more than 16 of 24 patients (57%) based on the previous and subsequent course of the pregnancies.
Differential diagnoses included threatened abortion and ectopic pregnancy (one case), cervical adenoma (one patient), placenta previa (four cases), and cervical or vaginal malignancy (11 cases), including one patient with suspicious rectovaginal deep infiltrative endometriosis malignization.

Management
Deciduosis was revealed before 24WG in 18 of 30 pregnancies (60%).All reported cytological findings were normal.Only one study documented the details of colposcopy.According to that study, the possible challenges are incomplete visualization of the transformation zone, "grayish-white" epithelium after applying acetic acid, and "atypical vessels." Eleven of the patients were managed expectantly (37%).The rest of the pregnant women underwent a total of 27 planned procedures: before 24WG (12 cases), during 24-to-33 6/7WG (seven cases), and after 34WG (eight cases).In the eight weeks postpartum, five of 12 patients (42%) had residual findings, including "erosions" and diffuse adenomatosis.

Outcomes
Studies reported the following complications of the pregnancies: significant antenatal bleeding (four studies), late abortion (one case), IAI and/or PROM (two cases), preterm birth (two cases), and operative delivery with uterine scar formation (four patients).
Among the 27 scheduled procedures, only one case of uncontrolled vaginal bleeding occurred at 32WG (0.04%).
Observation, including pregnancies managed expectantly or biopsied, was followed by recurrent symptoms (vaginal bleeding, urinary tract infections, vaginal discharge) or uneventfully (none, single, or provoked episode) in eight (53%) and seven (47%) women, respectively.Recurrent vaginal bleeding resolved in all eight cases (100%) of performed polyp or polypoid mass ectomies.
Spontaneous regression of lesions during observation happened in 20% (three of 16 patients) at 12WG, 20WG, and 35WG.All of these lesions were polyps, including one case of ulcerated ectopy.
Nine studies reported lesion persistence until vaginal birth.Almost all of these women had large polypoid lesions during their pregnancies.Among them, six women entered labor with the reported size of the lesions ranging from 1.5-2 cm to "large."None of the cases were complicated with significant intrapartum hemorrhage, although one study reported fetal distress of unknown etiology in the early stage of labor.

Discussion
Deciduosis of the lower genital tract was observed in women of 22 to 39 years of age, appearing on the cervix (83%) and/or vaginal fornices.Unfortunately, most case reports did not report the prior history of cervical or vaginal pathologies, limiting the opportunity to suggest the recurrence nature of the pathology, although decidual polyps demonstrated the tendency [23,25].
We noted that macroscopic cervix and/or vaginal fornice deciduosis was most commonly symptomatic, presenting as recurrent painless vaginal bleeding in more than half of the patients.Three pregnancies with lesions exceeding 2 cm in diameter were complicated by spontaneous antenatal hemorrhage of over 250 ml between 24WG and 34WG [20,[27][28].According to the literature, the lesions start regression around 25WG and, in 60%-70%, disappear completely by 38WG [8].Because of this, it seems reasonable to diagnose the condition early, while ruling out cancer and locating the placenta, and consider respiratory distress syndrome prevention, especially if a biopsy is unavoidable during the late term of gestation.
Reviewing a previous history of cervical dysplasia, its treatment, and subsequent surveillance, including cervical cytology obtained in the first trimester of pregnancy, might help establish the diagnosis while minimizing the risks associated with cervical biopsy.For example, in one study [19], a patient underwent treatment for cervical intraepithelial neoplasia (grade 3) with subsequent normal cytological results before conception.She developed an infiltrative form of deciduosis, followed by reassuring cytological plus colposcopy surveillance until 25WG when the biopsy was performed because of the growth of the lesions.This case highlights the importance of cervical cancer screening before 20WG [40] when the lesions do not obscure the transformation zone and awareness of the pathology (in this case, the infiltrative form does not include the transformation zone and is multifocal form, therefore can allow avoiding a biopsy).Moreover, the absence of a high-grade pattern, surrounding foci of lower-grade abnormalities, and intensive necrosis of the lesions during colposcopy might help to avoid biopsy if local guidelines do not require it, regardless of the dense whitening of the lesions.However, it is the polypoid form that seems to be the most problematic one from a differential perspective and the most reported form of ectopy (58%), as it includes a transformation zone.In addition to taking a history and performing the mentioned diagnostics, this form of deciduosis presents as confusingly friable compared to relatively solid cancer.The less frequently reported form of ectopy was the papillary one, which may be the less recognizable form of deciduosis, as likely shown in an example [24].Still, in this case, expulsed fragments of the decidua are a suitable explanation too.
Previous studies noted that performing a biopsy of the cervix during pregnancy is generally safe in terms of the occurrence of significant bleeding or pregnancy complications [40][41][42].We obtained similar findings based on 27 electively performed procedures before 24WG (44%), during 24-to-33 6/7WG (26%), and after 34WG (30%).Our analysis also reflects the relative safety of biopsy decidual lesions that might be more prone to hemorrhages due to their friability, frequent association with chronic inflammation, and susceptibility to necrosis [24], especially with pregnancy progression [8].For instance, the included studies reported severe antepartum hemorrhage [20,27,28], profuse bleeding provoked by gynecologic evaluation [21], and biopsy-induced uncontrolled bleeding [18] in women between 24-41 WG.These lead to two conclusions: (1) a cervical biopsy or stiff brush procedure is needed if there are any doubts regarding cervical cancer [11], and (2) respiratory distress prophylaxis may be considered if the procedure is planned after 24WG.Lately, remote studies have indicated that misleading results might lead to unnecessary procedures such as cervical conization during pregnancy [39], postpartum hysterectomy, and cold knife conization [23].
The authors cite that cervical and/or vaginal deciduosis does not require special pregnancy management unless complications develop.However, there are a few considerations.First, a retrospective cohort study of 550 pregnant women with cervical polyps noted that 45.45% of cases accounted for decidualized ones, which led to a greater frequency of pregnancy complications than non-decidualized polyps (28.1% vs. 6.1%)[43].Thus, managing decidualized polyps in certain circumstances can be distinct from those without changes.Second, decidual polyp or polypoid mass ectomies might be helpful in resolving recurrent symptoms, though it is uncertain who might benefit from the procedure and whether resection reduces the risk of pregnancy complications.Perhaps pregnant women over 11WG with a polyp width greater than 11 mm, recurrent vaginal bleeding (in our opinion, recurrent inflammatory discharges in the setting of either multicolored or fragile lesions), and visualized roots could be good candidates [25,[44][45][46].At the same time, one study noted that spontaneous regression of the lesions, which is common, did not reduce the risk of cervical insufficiency and pregnancy loss [13].Again, the authors did not evaluate these outcomes based on the histological type of the polyps.Lastly, one case report showed a 6-to-2 cm polyp size reduction in two months on local treatment with Neosporin [23].Although a natural regression process can explain it, similar options could be considered when the risk of symptomatic lesion removal is high (e.g., non-visualized roots) and infected and edematous lesions are suspected.
In labor, macroscopic polypoid lesions, especially large ones (e.g., covering the entire posterior lip or an 8cm mass), are inflamed, and those that are initially revealed in the peripartum period concern providers regarding intrapartum bleeding and its differential diagnosis [15,16].However, at least six old studies with the size of lesions between 1.5 and large cm were not complicated by significant intrapartum hemorrhage.In one report, the 2-cm polypoid lesion remained "silent" even in the early postpartum period until biopsy [21].Finally, accelerated regression of cervical deciduosis is to be expected shortly after delivery and complete

FIGURE 1 :
FIGURE 1: PRISMA flow diagram on the selection of studies PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analysis; PMC: PubMed Central

TABLE 1 : The databases, search queries, and results
The initial search showed: a 139 results on PubMed (applied filters: case reports, observational study); b 249 results on ScienceDirect (applied filters: case reports, research articles) PMC: PubMed Central

TABLE 4 : Data extraction of the management results
WG: weeks of gestation; NR: not reported; N/A: not applicable; VB: vaginal bleeding; NILM: negative for intraepithelial lesion or malignancy; cm: centimeter(s)

TABLE 5 : Data extraction of the outcomes
VB: vaginal bleeding; N/A: not applicable; C-section: caesarean section; IAI: intraamniotic infection; PROM: preterm rupture of membranes; UTI: urinary tract infection(s); NR: not reported; WG: weeks of gestation; VD: vaginal discharge; cm: centimeter(s); IOL: induction of labor a The term polypectomy included polypectomy and/or removal of the ectopic mass.bTheterm pseudobiopsy means gentle tissue removal without obtaining a baseline layer.