Outcomes of ureteroscopy and internal ureteral stent for pregnancy with urolithiasis: a systematic review and meta-analysis

Objectives To investigate the outcomes of internal ureteral stents in comparison with ureteroscopy (URS) for pregnant women with urolithiasis. Data sources Relevant studies published from January 1980 to June 2022 were identified through systematic literature searches of MEDLINE, EMBASE, Web of Science and the Cochrane Library. Methods of study selection A total of 499 studies were initially identified. We included pregnant women in any stages of gestation who underwent double-J (D-J) stent insertion only or ureteroscopy for the treatment of urolithiasis; for a study to be included, the number of participants needed to exceed 10. This systematic review was registered on the PROSPERO website (Reference: CRD42020195607). Results A total of 25 studies were identified with 131 cases undergoing serial stenting and 789 cases undergoing URS. The pooled operative success rate was 97% for D-J stent insertion and 99% for URS. Only a few patients passed stones spontaneously after serial D-J stenting. The pooled stone free rate (SFR) in URS operations was about 91%. For internal ureteral stent therapy, the rate of normal fertility outcomes was 99%, although the pooled incidence of complications was approximately 45%. For group receiving URS treatment, the rate of normal fertility outcome was 99% and the pooled incidence of complications was approximately 1%. However, the pooled rate of premature birth and abortion were the similar between the two groups (< 1%); the rate of serious complications was also similar between the two groups. Conclusions Although internal ureteral stents may cause more minor complications, both ureteroscopy and internal ureteral stents showed had low rates of adverse effects on fertility outcomes when used to treat pregnant women with symptomatic urolithiasis. Evidence suggests that URS may have a greater advantage for pregnant patients with urinary stones when conditions permit. Since, it has been proven to be safe and effective, internal ureteral stents could be considered in emergency or other special situations. Supplementary Information The online version contains supplementary material available at 10.1186/s12894-022-01100-w.


Introduction
The incidence of pregnant women with symptomatic urinary tract stones is reported to range from 1 in 2000 to 1 in 200 [1]. Symptomatic urolithiasis can lead to renal colic, urinary tract infection and ureteral obstruction, thus, creating significant morbidity and potential mortality for both the mother and the fetus. The main complications are pre-term delivery and premature rupture of the membranes; this can create serious health risks for the fetus [2,3]. It is important for urologists and obstetricians to be aware of how to manage this condition.
When managing a pregnant patient with urolithiasis, conservative management is favoured where possible. Surgical intervention is available for those that do not improve with conservative measures [4]. Ureteroscopy (URS) and internal ureteral stents are the most widely used treatments for pregnant females with symptomatic urolithiasis [5]. The insertion of a double-J (D-J) stent until definitive treatment during the postpartum period is a temporary measure and studies relating to this procedure are scarce. With continuous advancement in endoscopic technology and endourological techniques, URS has become the first-line treatment for the management of ureteric stones in pregnancy. Although the latest 2020 European Association of Urology (EAU) guidelines recommends URS as a reasonable alternative option [6], there is still a lack of evidential evaluation for URS in comparison with internal ureteral stents. In this systematic review and meta-analysis, we provide an up-to-date comparison between the outcomes of internal ureteral stent and URS treatments for pregnant women with urolithiasis.

Methods
We performed a systematic review according to a predetermined protocol which was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines [7]. We registered our systematic review on the PROSPERO website (www. york. ac. uk/ inst/ crd, registration number: CRD42020195607). Two reviewers independently undertook the literature search (XJ and BL), assessment for eligibility (XJ and BL), data extraction (YS and WT) and qualitative assessment (DW and YX). Any inconsistencies between the two reviewers were reviewed by a third reviewer (LZ) and resolved by consensus. If data sources were duplicated in more than one study, only the original study was included in the meta-analysis as per consensus among all three reviewers (XJ, BL and LZ).

The definition of PICOS used in this study
Participants: Pregnant women of any gestation with urolithiasis.
Outcome: Fertility results and complications. Study design: RCTs and observational studies (casecontrol, cross-sectional and cohort) were included in this systematic review and meta-analysis.

Eligibility criteria
Studies were included if they (1) Featured pregnant women in any stage of pregnancy and underwent D-J stent insertion only or ureteroscopy for the treatment of urolithiasis, (2) Had been published between January 1980 and June 2022, and (3) Featured more than 10 participants.
Studies were excluded if they (1) Were reviews, comments, letters, guidelines, or meta-analyses (2) Lacked data relating to pregnancy or interventions, (3) lacked photography, equipment evaluation or diagnosis criteria for urolithiasis in pregnancy, (4) Involved research on neonates, (5) Involved physiological hydronephrosis without stone disease, and (6) If they featured extracorporeal shock wave lithotripsy, percutaneous nephrostomy or other treatments for pregnancy with urolithiasis.

Search strategy
We conducted a literature search using PubMed (MED-LINE), Embase, Web of Science and the Cochrane Library of articles published from January 1980 to June 2022. Medical Subject Heading (MeSH) terms were used in conjunction with the following keywords: ( Table S1. References from relevant articles, editorials, conference abstracts, letters, and reviews were thoroughly reviewed to identify additional studies. Full manuscripts of every article with a relevant title and abstract were then reviewed for eligibility.

Data extraction and qualitative assessment
Two reviewers (YS, WT) independently extracted the following study-level characteristics from each eligible study: first author, year of publication, country where the study was conducted, journal, study period, age, trimester, diagnose method, stone location and size, anaesthetic method, intervention and sample size, operation success rate, stone free rate (SFR), fertility outcome, complications and follow-up pattern. Two groups were set as different treatment procedures: an internal ureteral stent (D-J stent) therapy group and a URS group. Fertility outcomes included normal delivery, cesarean section, premature labor, abortion and others (which are listed in the tables below). Final fertility results were used to assess treatments, and only premature labor and abortion were considered as serious fertility outcomes (which imply failure to save the fetus). Fertility outcomes and complications were also assessed with the Clavien-Dindo classification, as shown in Additional file 1: Table S2. A Clavien-Dindo classification of III-V was regarded as a serious complication.
We applied the Newcastle-Ottawa Scale (NOS) quality assessment tool to evaluate the quality of the selected observational studies. This tool was used to measure key aspects of the methodology in selected studies with regards to design quality and the risk of biased estimates based on three design criteria: (1) Selection of study participants, (2) Comparability of study groups, and (3) The assessment of outcome and exposure with a star system (with a maximum of 9 stars). We judged studies that received a score of 7-9 stars to be of a low risk of bias, studies that scored 4-6 stars to be of a medium risk, and those that scored 3 or less to be of a high risk of bias. A funnel plot was used to assess publication bias. Any disagreement on the data extraction and quality assessment of the studies were resolved through comprehensive discussion (DW, YX and LZ).

Statistical analysis
Study-specific prevalence rate estimates were combined using a random-effects model that considered withinstudy and between-study variations. Corresponding 95% confidence intervals (CIs) were extracted directly from articles where available. Statistical heterogeneity among studies was evaluated using Cochran's Q test and the I 2 statistic, with values of 25%, 50%, and 75% representing low, moderate and high heterogeneity, respectively. The criterion for identifying heterogeneity was P < 0.05 for the Q test.
An estimation of publication bias was evaluated by Begg's funnel plot, in which the standard error (SE) of the log odds ratio (OR) of each study was plotted against its log OR. An asymmetrical plot suggested potential publication bias. Egger's linear regression test was used to evaluate funnel plot asymmetry on the natural logarithm scale of the rates. All statistical analyses were performed using Stata (version 14.2; StataCorp LP, College Station, Texas). All P values were two-sided, and P < 0.05 was considered as statistically significant.

Selection of studies
A detailed PRISMA flow diagram showing the literature search and inclusion criteria is given in Fig. 1. A total of 499 studies were initially identified with this literature search (144 from PubMed, 161 from Embase, 153 from Web of Science and 41 from Cochrane Library). Of these, 215 studies were excluded due to duplication and 233 were excluded after screening the titles and abstracts. Then, 26 other studies were excluded after full-text review. Finally, a total of 25 studies were identified as eligible for systematic review and meta-analysis.
The time span of the 25 studies included in this analysis was 1995-2018, and the research period of cases ranged from 1984 to 2016. Common information from publications is shown in Table 1. Of the 25 studies, one was from Norway [8], one from Italy [9], two from America [10], one from Brazil [11], one from Pakistan [12], four from Egypt [13,20,27,29], five from China [14,22,28,30,32], six from Turkey [15-18, 21, 25], two from Iran [23,31], one from Iraq [24] and one from Romania [26]. The age range of the patients involved was 16 to 41 years and urolithiasis occurred most often in the second trimester. Ultrasound was the most commonly used diagnostic method. The most common sites for calculi were the distal ureter, medium ureter and proximal ureter. The mean stone size was between 6 and 17 mm.
Detailed data of internal ureteral stent therapy was showed in Table 2. The most commonly used form of anaesthesia was local. The pooled operation success rate was 97% [ Fig. 2; 95% CI: 0.94-1.01]. Only one related study [22] mentioned a stone passing spontaneously in three patients; this was reported as an accident situation. The pooled ORs for a normal fertility outcome was 99% [ Fig Detailed data relating to URS therapy is shown in Table 3. General anaesthesia and spinal anaesthesia was widely used. The pooled operation success rate was 99%    Meta-analysis indicated that there was no evidence of statistical heterogeneity between the two treatments with regards to operation success rate (Fig. 2, I 2 = 12.1%, P = 0.280), normal fertility outcome (Fig. 3, I 2 = 0.0%, P = 0.989) and adverse pregnant outcome (Fig. 4, I 2 = 0.0%, P = 1.000). However, overall, complications for internal ureteral stent therapy were more common than for URS (Fig. 5, I 2 = 91.0%, P < 0.001). We also analyzed pooled ORs for serious complications in the two treatments (Fig. 6). There was no evidence of significant statistical heterogeneity among the included studies (I 2 = 0.0%, P = 1.000).

Qualitative assessment and publication bias
The NOS tool was used to perform qualitative assessment of the selected studies to review the quality of the studies and detect possible bias (Tables 4 and 5). Of the 25 studies, eight were at a low risk of bias (7-9 stars); 16 studies were at a medium risk (4-6 stars), mainly due to bias from the representativeness of cases or controls, control definition and comparability. One study was at high risk (3 stars) mainly due to bad representativeness, Fig. 3 Meta-analysis about normal fertility outcome in D-J stent therapy group and URS group lack of control and unclear control exposure. A funnel plot showed publication bias in the studies included in the meta-analysis (Begg's test with P < 0.001) (Additional file 1: Figure S1).

Discussion
From the best of our knowledge, this is the first systematic review to investigate and compare the outcomes of ureteroscopy and serial D-J stenting therapy for pregnant females with urolithiasis. To determine the efficacy and safety of the two treatments, we analysed the available information in as much detail as possible. This meta-analysis featured 25 studies with a total of 920 cases of urolithiasis during pregnancy. This meta-analysis contained studies selected from several countries; as shown in Table 1, most studies originated from Asia (15 studies), followed by Africa (four studies), Europe (three studies) and America (including Our analysis showed that operative success rates were almost the same for internal ureteral stents and URS (97% vs. 99%, P = 0.280). Internal ureteral stents were associated with more complications than URS (45% vs. 1%, P < 0.001); however, most complications were minor or could be adequately managed (serious complication rates were < 1% in the two groups, P = 1.000) and there was no statistical difference in normal delivery rate between the two treatments (99% vs. 99%, P = 0.989). In summary, both ureteroscopy and internal ureteral stents are safe and effective for pregnancy with symptomatic urolithiasis. Urolithiasis in pregnancy is the most common nonobstetric reason for hospital admission; 80-90% of such cases are diagnosed in the 2 nd or 3 rd trimester of their pregnancy when the disease becomes symptomatic [33][34][35][36]. As the majority of calculi can be passed following the administration of intravenous fluids and analgesia, the first-line treatment for urolithiasis in pregnancy is conservative management. This is recommended by the latest guidelines from both the European Association of Urology (EAU) and the American Urological Association (AUA). However, if complications develop and affect fetal safety, or the patient does not experience adequate symptom relief, more aggressive treatments should be considered. Shock wave lithotripsy is absolutely contraindicated in pregnancy because of potential fetal death [37]. Percutaneous nephrostomy (PCN) drainage is also not an     appropriate choice as it raises the risk of septic complications and imposes the additional burden of an external drain [38]. The common utilization of the prone position and fluoroscopy also represent limitations for the use of PCN in pregnancy [39]. Therefore, internal ureteral stents and URS are the most common treatments in the clinic for pregnant patients.
Following the failure of initial conservative treatment, the insertion of a D-J stent might be a safe choice. Serial stenting for pregnancy with urolithiasis is commonly used in clinic although there are not many relevant studies. After scanning articles over the past 30 years, only six related articles were included in this meta-analysis [10,22,24,27,28,32]. Historically, serial stenting was considered as the gold standard of surgical treatment for pregnancy with urolithiasis as it was less invasive and could be performed under local anaesthesia [40]. This amount of anaesthetic and the reduced level of surgical trauma is considered to be safer for the fetus [24]. Our meta-analysis also indicated that this treatment relieves obstruction and pain while maintaining the pregnancy. However, there are still some negative opinions. On the one hand, serial stenting may be poorly tolerated by some pregnant women as it can cause pain and reduce the quality of life. On the other hand, insertion of a D-J stent is a temporary measure; such stents require regular replacement. Furthermore, the increased concentration of calcium and urate in urine during pregnancy can led to a tendency for encrustation; thus, these invasive operations need to be performed more frequently [20,41]. However, an increase frequency of such invasive operations also leads to an increase in complications, including UTI and stent migration [27,32,42]; there is also an increase in cost [39]. Our meta-analysis demonstrated that the pooled ORs of complications after serial stenting was 45%. However, the pooled ORs for serious complications (Clavien-Dindo III-V) after serial stenting was < 1%. There was no evidence that serial stenting treatment was harmful for pregnancy as the pooled ORs for adverse pregnant outcomes was < 1%. Internal ureteral stents were thus proven to be safe for both the pregnant woman and the fetus.
Unlike internal ureteral stent operations, the use of URS to treat urolithiasis in pregnancy has been studied by many urologists; 23 papers were included in this meta-analysis [8,9,[11][12][13][14][15][16][17][18][19][20][21][22][23][25][26][27][28][29][30][31][32]. We found that the most common forms of anaesthesia were general and spinal. Although there are risks associated with anaesthesia and surgery, technological advancement provided a safeguard for perioperative safety. After systematic analysis, we calculated that the pooled ORs for complications was approximately 1% and the pooled ORs for normal fertility outcomes were 99%. Another advantage of URS was the high SFR (91%). High stone clearance rates and low complication rates made URS the recommended method in the 2020 EAU guideline. We noticed that most of cases of ureteroscopy involved the rigid option rather than the flexible option and that the choice of ureteroscope was related to the location of the stone. As shown in Table 1, Table 4 Newcastle-Ottawa Scale review for cohort studies from systematic review Guidelines for review Selection S1, Representativeness of the exposed cohort; ★a) representative of the community (e.g. community-based colorectal cancer-screening programme or registry) or (single hospital or clinic); b) selected group of people (e.g. nurses, volunteers); d) no description of the derivation of the cohort S2, Selection of the non-exposed cohort: ★a) drawn from the same community as the exposed cohort; b) drawn from a different source; c) no description of the derivation of the non-exposed cohort S3, Ascertainment of exposure: ★ a) secure record (eg medical records); ★b) structured interview; c) written self-report; d) no description S4, Demonstration that outcome of interest was not present at start of study: ★ a)yes; b) no Comparability C1, ★ Study controls for one most important factor; C2, ★ Study controls for any additional factors (1 > additional factors) Outcome O1, Assessment of outcome: ★a) independent blind assessment; ★b) record linkage; c) self-report; d) no description O2, Follow-up was long enough for outcomes to occur (after delivery or longer): ★a) yes; b) no O3, Adequacy of follow-up of cohorts: a) complete follow up-all subjects accounted for; b) subjects lost to follow up unlikely to introduce bias-small number lost > 10%; c) follow up rate < 90% and no description of those lost; d) no statement
In the latest 2020 EAU guidelines [6], URS appears to be the better selection for pregnancy with urolithiasis in comparison with internal ureteral stents while stent insertion therapy is only mentioned for symptomatic moderate-to-severe hydronephrosis during pregnancy. It appears that ureteral stent insertion is not an appropriate treatment for pregnant women with urolithiasis. However, the success of URS surgery depends on detailed preoperative preparation and stringent obstetric care. During emergencies or where there is a lack of obstetric care, an internal ureteral stent might be the better choice as it is also safe and effective and could gain time for URS later. Moreover, for pregnant females who do not want to take general anesthesia before childbirth, the insertion of a ureteral stent seems to be the only choice for relieving symptomatic urolithiasis. Urologists and obstetricians should work together to ensure the safety of the mother and fetus in such cases. Table 5 Newcastle-Ottawa Scale review for case-control and cross-sectional studies from systematic review Guidelines for review Selection S1, Case definition adequacy: ★a) requires independent validation (> 1 person/record/time/process to extract information, or reference to primary record source such as colonoscopy or medical/hospital records); b) record linkage or self-report with no reference to primary record; c) no description S2, Representativeness of the cases: ★a) consecutive or obviously representative series of cases; b) potential for selection biases or not stated S3, Selection of controls: ★a) community controls; b) hospital controls, within same community as cases; c) no description S4, Definition of controls: ★a) no history of colorectal cancer or adenoma; b) no description of source Comparability C1, ★ Study controls for one most important factor; C2, ★ Study controls for any additional factors (1 > additional factors) Exposure E1, Ascertainment of exposure: ★a) secure record (e.g. medical records); ★b) structured interview where blind to case/control status; c) interview not blinded to case/ control status; d) written self-report or medical record only; e) no description E2, Same method of ascertainment for cases and controls: ★a) yes; b) no E3, Non-response rate: ★a) same rate for both groups; b) non respondents described; c) rate different and no designation There were several inherent limitations to this meta-analysis. First, most of the included studies were retrospective studies. This might cause inevitable methodological defects, including data bias, insufficient baseline comparison, and insufficient data collection. Urolithiasis during pregnancy is not a rare disease, but for urologists, it is not easy to handle both urolithiasis and obstetric care. After failed initial conservative treatment, such cases may become a urological emergency that requires a rapid response. Thus, well-designed RCTs are difficult to accomplish. Secondly, performance bias should also be considered. Although various centres perform similar operations, the medical equipment and medical teams are different. Surgery is a complex process; these differences may also lead to different outcomes. Furthermore, there was inevitable bias when the data were pooled. Therefore, further well-designed, prospective studies are required; these studies should take into account selection bias, performance bias and the issue of confounding. Finally, funnel plots showed certain publication bias in the included articles; however, we retained all of the studies as the sample size was small. Despite these limitations, this updated meta-analysis provides an important clinical reference for urolithiasis during pregnancy.

Conclusion
Although internal ureteral stents may cause minor complications, both ureteroscopy and internal ureteral stents showed less adverse effects on fertility results in pregnant women with symptomatic urolithiasis. Evidence suggests that URS therapy may have a greater advantage for pregnant women with urinary stones when the condition permits. As it has been proven to be safe and effective, internal ureteral stents can be considered in emergency or other special situations.