DOI: 10.1111/1471-0528.15457 www.bjog.org Systematic review The effect of unilateral tubal block diagnosed by hysterosalpingogram on clinical pregnancy rate in intrauterine insemination cycles: systematic review and meta-analysis J Tan, a S Tannus, b O Taskin, a A Kan, a AY Albert, a MA Bedaiwy a a Department of Obstetrics and Gynecology, The University of British Columbia, Vancouver, BC, Canada b Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, McGill University Health Care Centre, Montreal, QC, Canada Correspondence: MA Bedaiwy, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, The University of British Columbia, D415A-4500 Oak Street, Vancouver, BC V6H 3N1, Canada. Email: mohamed.bedaiwy@cw.bc.ca Accepted 16 August 2018. Published Online 24 October 2018. Background Fallopian tube occlusion is a common cause of infertility, but the effect of unilateral tubal block (UTB) on pregnancy rates (PR) after controlled ovarian hyperstimulation and intrauterine insemination (COH-IUI) remains controversial. Objective To evaluate PR after COH-IUI among infertile women with proximal and distal UTB diagnosed by hysterosalpingogram (HSG), compared against women with bilateral patent tubes experiencing unexplained infertility. Search strategy We searched EMBASE, MEDLINE, Google Scholar, Cochrane Library, and PUBMED from inception to 14 January 2018. Selection criteria Studies that report PR/cycle or cumulative PR among women with UTB and controls were included. Data collection and analysis Two authors independently selected and extracted study characteristics and data. Methodological quality was assessed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Main results Among 2965 patients and 5749 IUI cycles across ten studies, no significant difference in PR/cycle (odds ratio, OR = 0.88; 95% confidence interval, 95% CI = 0.69 1.12) and cumulative PR (OR = 0.80, 95% CI = 0.62 1.04) was observed. Patients with proximal UTB demonstrated similar PR/cycle (OR = 1.06, 95% CI = 0.68 1.66) and cumulative PR (OR = 1.10, 95% CI = 0.75 1.62), compared with controls, whereas patients with distal UTB had significantly lower cumulative PR (OR = 0.49, 95% CI = 0.25 0.97, P = 0.04). Patients with proximal block also demonstrated significantly improved cumulative PR, compared with patients with distal block (OR=2.41, 95% CI = 1.37 4.25, P = 0.002). Conclusion Infertile patients with proximal UTB diagnosed by HSG can expect similar pregnancy rates after COH-IUI, compared with those with bilateral tubal patency and unexplained infertility, whereas patients with distal UTB have lower odds of pregnancy. These differences may reflect inherent diagnostic limitations of HSG or differences in underlying pathologies. Keywords Fallopian tube, Hysterosalpingogram, Infertility, intrauterine insemination, meta-analysis, unilateral tubal block. Tweetable abstract Meta-analysis evaluates pregnancy outcomes after COH-IUI in women with unilateral tubal block diagnosed by HSG. Linked article This article is commented on by H Burks, p. 236 in this issue. To view this mini commentary visit https://doi.org/10. 1111/1471-0528.15481. Please cite this paper as: Tan J, Tannus S, Taskin O, Kan A, Albert AY, Bedaiwy MA. The effect of unilateral tubal block diagnosed by hysterosalpingogram on clinical pregnancy rate in intrauterine insemination cycles: systematic review and meta-analysis. BJOG 2019;126:227 235. Introduction Tuboperitoneal factors are implicated in up to 40% of cases of infertility. 1 For normal fallopian tube function, the tube must be patent, freely mobile, and in close proximity to the ovary. 2 Several pathologies are implicated in distorting this normal physiology, however, including pelvic infections, endometriosis, and surgical adhesions. Depending on the aetiology, tubal pathology may involve the proximal, distal, or entire tube, and may be transient as a result of obstruction or permanent as a result of occlusion. Laparoscopy and dye chromopertubation remain the gold 227
Tan et al. standard for diagnosing tubal and pelvic abnormalities, although hysterosalpingogram (HSG) is typically employed as a first-line investigation, owing to its non-invasive nature and low cost. Despite a high specificity, the low sensitivity of HSG often leads to misdiagnosis, yet a confirmatory laparoscopy is typically not recommended because it rarely warrants a change in treatment approach. 1,3 HSG diagnosis of bilateral tubal occlusion has been associated with poor reproductive outcomes, and management consists of either laparoscopy, to establish a clear aetiology, or referral for in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI). 4 Conversely, an HSG finding of unilateral tubal pathology has more limited prognostic significance, and management strategies range from diagnostic laparoscopy, COH-IUI through the available patent tube, or proceeding directly to IVF. Evidence in support of COH-IUI in cases of unilateral tubal occlusion is still lacking, however. In a retrospective case control study, Farhi et al. 5 demonstrated that similar cumulative pregnancy outcomes can be achieved through controlled ovarian hyperstimulation and intrauterine insemination (COH-IUI) in cases of proximal tubal occlusion diagnosed by HSG, compared with patients with unexplained infertility and bilateral patent tubes; however, distal tubal occlusion yielded lower cumulative pregnancy outcomes after three consecutive IUI cycles. Conversely, several more recent studies demonstrated significantly lower clinical pregnancy and live birth rates in cases of unilateral tubal occlusion, regardless of location. 6,7 Hence, a consensus has yet to be reached on this topic, and the purpose of this meta-analysis is to evaluate whether pregnancy outcomes after COH-IUI among infertile women with unilateral tubal block diagnosed by HSG are different compared with women with bilateral patent tubes and unexplained infertility. Furthermore, we conducted a subgroup analysis to evaluate differences in pregnancy outcomes between proximal and distal occlusion. Methods This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Metaanalysis (PRISMA) guidelines 6. 8 Identification of the literature The following databases were reviewed: Ovid MEDLINE, EMBASE, Google Scholar, Cochrane Library, and PUBMED, from inception until 14 January 2018. The following subject headings and keywords were searched: IUI.mp. OR Intrauterine adj5 inseminat* OR Exp Insemination, Artificial/ AND Tubal adj5 occlus*.mp. OR Tubal adj5 block*.mp. OR Exp Fallopian Tube Diseases/. All original research articles including randomised and non-randomised controlled trials, cohort studies and crosssectional studies were included. All included studies reported either pregnancy rates (PR) per cycle and/or cumulative pregnancy rates (CPR). Clinical pregnancy was defined as a positive serum or urinary beta human chorionic gonadotropin (b-hcg) value after 12 14 days from the insemination procedure, as well as evidence of pregnancy by sonographic visualisation of a gestational sac beyond 5 weeks of gestation. Additional studies were extracted from the references in the full-text articles. Articles were restricted to English only, and we also considered published abstracts from conferences. Study selection and data extraction We selected studies that evaluated pregnancy outcomes in women with untreated unilateral tubal block proven by HSG. The primary outcome of interest was pregnancy rate defined as a positive fetal heartbeat visualised by first-trimester ultrasound. For studies to be eligible, outcome data of PR for both study and control groups were extracted in 2 9 2 tables. We also recorded cases of proximal and distal tubal block, mean female age, and spontaneous PR. Importantly, eligible studies needed to explicitly describe the diagnostic criteria for tubal block as well as have clear exclusion criteria for male factor infertility, which may confound IUI outcomes. Studies that evaluated pregnancy outcomes after treatment for tubal block, such as tubal recanalisation, were also excluded. Newcastle Ottawa quality assessment scales were used to evaluate the quality of the observational studies. 9 Two reviewers completed the quality assessment (JT and OT), and any disagreements about inclusion were resolved by consensus. Statistical analysis All analyses were carried out in R 3.4.1 (2017-06-30). 10 A random-effects meta-analysis was performed to calculate the estimated average odds ratios as implemented in the R package METAFOR. 11 In order to provide greater weight to larger studies, odds ratios were weighted by the inverse variance. The I 2 metric was calculated to assess study heterogeneity, and publication bias was assessed by visual inspection of funnel plots. The following comparisons were evaluated based on PR per IUI cycle and CPR: tubal block versus control, proximal tubal block versus control, distal tubal block versus control, and proximal versus distal tubal block. Subgroup analyses were also performed within the tubal block versus control comparison using different numbers of total cycles: specifically, we compared pregnancy outcomes after up to one, up to three, and up to six cumulative IUI cycles. Importantly, it should be noted that Yi 228
Effect of unilateral tubal block on IUI pregnancy outcomes et al. 7 did not specify the number of cycles, but it was noted to be more than one as the total number of cycles reported exceeded the total number of patients enrolled in the study. Results The search produced a total of 299 results: 62 from MED- LINE, 129 from EMBASE, four from Cochrane, and 44 from PUBMED. Following the removal of duplicates, 148 remained and each title and abstract was reviewed by two reviewers. Subsequently, 73 full texts were selected for full review and an additional 63 were excluded, leaving ten studies for quantitative analysis. 5 7,12 18 Reasons for exclusion included case reports, non-english articles, systematic reviews, and studies that failed to screen and exclude cases of male/female infertility, studies that did not specify the diagnostic method of diagnosing women with tubal block, and studies that did not report pregnancy outcomes. The PRISMA flow chart of the reviewed studies is shown in Figure S1. The main characteristics of the ten studies and the Newcastle Ottawa quality assessment are presented in Table 1. Overall, the studies scored well: six studies scored nine and four studies scored eight out of nine points (Table S1). Most importantly, all of the included studies provided diagnostic criteria for assessing tubal block and screened for appropriate male and female factors through detailed reproductive history and infertility evaluation. Males with abnormal semen profiles were excluded (Table S2). Unilateral tubal block versus control In terms of PR/cycle, the random-effects model showed no significant difference in the odds of pregnancy between women with unilateral tubal block and controls (odds ratio, OR = 0.88; 95% confidence interval, 95% CI = 0.69 1.12; P = 0.30; Figure 1A). There was also no substantial difference in estimated ORs among studies with a differing number of total cycles. Similarly, the random-effects model also showed no significant difference in the odds of cumulative pregnancy between women with any tubal block and controls (OR = 0.80, 95% CI = 0.62 1.04, P = 0.10; Figure 1B). No significant heterogeneity was observed, and the funnel plots displayed no evidence of publication bias (Figures S2 and S3). Proximal tubal block versus control The random-effects model showed no significant difference in the odds of pregnancy/cycle between women with a proximal tubal block and controls (OR = 1.06, 95% CI = 0.68 1.66, P = 0.80; Figure 2A). Similarly, the random-effects model showed no significant difference in the odds of cumulative pregnancy between women with a proximal block and controls (OR = 1.10, 95% CI = 0.75 1.62, P = 0.63; Figure 2B). No significant heterogeneity was observed, and the funnel plots displayed no evidence of publication bias. Distal tubal block versus control The random-effects model showed no significant difference in the odds of PR/cycle between women with a distal tubal block and controls (OR = 0.69, 95% CI = 0.22 2.23, P = 0.54; Figure 3A). Significant heterogeneity was observed [Q(3) = 12.13, P = 0.007; I 2 = 77.5%], however, and only four studies with small sample sizes were included; hence, these results may not be particularly robust. Of note, Eschliman et al. 13 is the only study that demonstrated a better PR/ cycle P value in the distal tubal block group compared with controls, although only 22 cycles were included. In terms of CPR, the random-effects model showed a significant difference in the odds of pregnancy between women with a distal block compared with controls (OR = 0.49, 95% CI = 0.25 0.97, P = 0.04; Figure 3B). No significant heterogeneity was observed (I 2 = 40.5%), and the funnel plot showed no evidence of publication bias. Hence, the estimated OR suggests that women with a distal block have lower odds of pregnancy than controls. Proximal versus distal tubal block The random-effects model showed no significant difference in the odds of PR/cycle between women with a proximal block compared with women with a distal block (OR = 1.99, 95% CI = 0.99 4.00, P = 0.54; Figure 4A). Similarly, the random-effects model showed a significant difference in the odds of cumulative pregnancy between women with a proximal block and women with a distal block (OR = 2.41, 95- %CI = 1.37 4.25, P = 0.002; Figure 4B). There was no significant heterogeneity, but Eschliman et al. 13 reported different results both in PR/cycle and CPR, compared with the other included studies. Once again, however, these results may not be particularly robust because only four studies with small sample sizes were included. The funnel plot showed no indication of publication bias (Figures S2 and S3). Discussion Main findings Based on the pooled results of 2965 patients across ten studies, our meta-analysis demonstrates that patients with unilateral tubal block diagnosed by HSG can expect similar pregnancy outcomes after COI-IUI compared with patients with bilateral tubal patency. Specifically, we found that both PR/cycle and CPR after one, three, and six IUI cycles are similar between infertile patients with bilateral patent tubes compared with patients with unilateral tubal block. Our subgroup analysis also demonstrates that similar 229
Tan et al. Table 1. PR/IUI cycle and cumulative PR for patients with unilateral tubal block versus bilateral patency with unexplained infertility Included studies Age (years) Study type Total patient (N) Cycles (N) PR/ cycle (%) P CPR/ patient (%) P One cycle Lin et al. (2013) 6 Exposure (UTO) 33.4 4.2 cohort 133 133 17.29 NS 17.3 NS Proximal 69 69 21.74 NS 21.7 N/A Distal 64 64 12.50 12.5 Control 32.9 3.6 570 570 18.95 18.9 Selchuk et al. (2016) 18 Exposure (UTO) 30.09 3.92 cohort 44 44 11.40 NS 11.4 NS Proximal N/A NS Distal Control 28.49 4.45 53 53 9.40 9.4 Yi et al. (2012) 7 Exposure (UTO) 32.6 3.2 cohort 37 52 17.31 NS 24.3 NS Proximal 13 16 20.31 N/A 30.7 NS Distal 24 36 9.27 20.8 Control 32.3 2.9 114 182 16.48 26.4 Up to three cycles Berker et al. (2014) 15 Exposure (UTO) 27.7 4.1 cohort 38 100 10.00 N/A 26.3 0.043 Proximal 21 51 15.69 N/A 38.1 0.06 Distal 17 49 4.08 11.7 0.01 (versus control) Control 28.1 4.3 123 301 18.27 44.7 Cochet et al. (2017) 12 Exposure (UTO) 34.6 3.9 cohort 23 52 7.69 <0.001 17.3 < 0.05 Proximal Distal N/A Control 34.3 4.3 717 1651 16.29 38 Ebrahmi et al. (2011) 17 Cross-sectional Exposure (UTO) 27.14 3.34 64 170 10.00 NS 26.56 0.87 Proximal 28.13 3.76 N/A N/A Distal Control 200 541 10.35 28 Eschliman et al. (2015) 13 Exposure (UTO) 32.2 4 cohort 24 36 16.67 0.10 31.58 0.56 Proximal 7 12 8.33 0.39 17 0.39 Distal 17 22 22.73 38 Control 33.4 2 87 275 7.64 24.14 Farhi et al. (2007) 5 Exposure (UTO) 29.9 4.9 cohort 55 30.9 0.142 Proximal 34 38.2 0.135 Distal 21 19 Control 29.2 4.4 101 42.6 0.044 (vs control) Yetkin Yildirim et al. (2017) 14 cohort Exposure (UTO) 30 4.41 59 165 5.45 NS 15.25 0.352 Proximal 32 N/A N/A N/A 21.87 0.183 Distal 27 N/A N/A 7.4 Control 29.4 4.29 178 490 7.55 20.79 Up to six cycles Yukiyo et al. (2012) 16 Exposure (UTO) 35.9 cohort 52 144 8.30 NS 38.2 NS Proximal 15 N/A N/A N/A 40 0.06 Distal 13 N/A N/A 7.69 Control 36.0 256 790 8.20 35.2 N.B. P < 0.05 denotes significance. 230
Effect of unilateral tubal block on IUI pregnancy outcomes Figure 1. Forest plot of unilateral tubal block versus control for PR/cycle (A) and CPR (B). The size of the boxes indicates the relative weighting of the studies. pregnancy outcomes can be expected in cases of proximal occlusion diagnosed by HSG, whereas patients with distal occlusion have significantly worse pregnancy outcomes compared with both proximal occlusion and bilateral tubal patency. Strengths and limitations To the best of our knowledge, this represents the first systematic review and meta-analysis to evaluate pregnancy outcomes after COH-IUI among patients with unilateral tubal occlusion diagnosed by HSG. Despite the large pooled cohort and lack of publication bias, all included studies were retrospective and hence susceptible to confounding. In addition, differences in screening/exclusion criteria and a lack of standardized IUI techniques between studies would also bias their comparability. Indeed, differences in sperm quality and processing, number of IUI cycles, cycle timing, and differences in ovarian stimulation 231
Tan et al. Figure 2. Forest plot of proximal tubal block versus control for PR/cycle (A) and CPR (B). The size of the boxes indicates the relative weighting of the studies. Figure 3. Forest plot of distal tubal block versus control for PR/cycle (A) and CPR (B). The size of the boxes indicates the relative weighting of the studies. have all been shown to affect IUI outcomes. 19 It is also important to note that the control group included couples with an independent condition, unexplained infertility, which may be associated with fertility-reducing factors that may bias these findings; however, given that all patients undergoing COH-IUI inevitably have some form of 232
Effect of unilateral tubal block on IUI pregnancy outcomes Figure 4. Forest plot of proximal versus distal tubal block for PR/cycle (A) and CPR (B). The size of the boxes indicates the relative weighting of the studies. infertility, it remains the most appropriate comparison group as all known and reversible causes of infertility have been screened and excluded. Future studies should prospectively evaluate the prognostic significance of unilateral tubal pathology on live birth rates and time-to-conception outcomes after COH-IUI. Furthermore, it would be useful in future studies to document whether the dominant follicle for each cycle developed on the side of the blocked tube and could indeed be correlated with the likelihood of a successful pregnancy. Finally, HSG remains the most widely available and accessible tool for evaluating tubal patency, yet sonohysterosalpingography (SIS) and hysterosalpingo-contrast sonography (HyCoSy) are other validated techniques to consider in future studies, owing to their potential benefits with respect to sensitivity and specificity. 20 Ultimately, HSG is a useful tool for evaluating tubal patency, but this does not necessarily equate to satisfactory tubal function; hence, more specific methods for evaluating the intricate physiological function of the fallopian tube may be warranted as the cost and availability of more advanced technology improves. Interpretation Overall, these results support the theory that obstruction of only one tube plays a limited role in subfertility. These findings contrast those of a large retrospective study that reported significantly higher PR/cycle and CPR among patients with bilateral tubal patency, compared with unilateral tubal occlusion (16 versus 9% and 38 versus 20%, respectively). 12 No significant difference in cumulative live birth rates was found once adjusted for age, body mass index (BMI), infertility duration, and number of IUI cycles, however. Furthermore, these results are consistent with several other studies that demonstrate no significant difference in pregnancy rates between patients with unilateral tubal occlusion compared with patients with normal HSG findings of bilateral tubal patency, 5,13 thereby suggesting that expectant management may also be appropriate for a certain period of time. 4,21 Among women who ultimately do pursue COH-IUI, our subgroup analysis suggests that the specific location of an obstruction along the tube may also influence the odds of successful pregnancy. Farhi et al. 5 first noted this apparent discrepancy in pregnancy outcomes, and several studies have since noted similar trends, 6,13 whereas others noted differences but were inadequately powered to detect a significant difference. 7,14 Conversely, Eschliman et al. 13 demonstrated improved CPR in cases of mid-distal occlusion (38%) compared with distal (23%) and proximal (17%) occlusion, although differences were not significantly different as only 24 cases of stands for unilateral tubal occlusion (UTO) were included. Furthermore, Cochet et al. 12 noted no significant difference in live birth rates 233
Tan et al. between distal and proximal occlusion (19 versus 22%), although cases of tubal occlusion by HSG were confirmed by laparoscopy; hence, these results may only reflect cases of true obstruction. In this way, the observed pregnancy outcomes between proximal and distal block may simply represent underlying limitations of diagnostic methods with HSG. Indeed, multiple studies have suggested that instances of proximal tubal occlusion may in fact represent falsepositive results caused by tubal spasm or the steal effect, and that HSG is better at diagnosing true distal occlusion compared with proximal occlusion. 3,6 In fact, Dessole et al. 22 noted that 60% of cases of proximal tubal occlusion will actually show bilateral tubal patency on repeat HSG. 18 Despite its limited sensitivity compared with alternative diagnostic methods such as sono-hsg, 23 HSG remains the most widely accepted first-line test to assess tubal patency owing to its low cost, minimal invasiveness, and high specificity, particularly among patients with no known risk factors for peritoneal disease. 24 In cases of proximal tubal obstruction, HSG has a significant false-positive rate, and although repeat HSG may improve diagnostic accuracy, our results demonstrate that management would not change as patients with unexplained infertility with proximal tubal occlusion should be treated with COH-IUI as if they were diagnosed with two patent fallopian tubes. Conversely, patients with distal tubal obstruction may warrant further evaluation to provide a more precise diagnosis of tubo-peritoneal factor, as it has been shown to influence treatment planning in a significant proportion of infertility cases. 25,26 With regards to current treatment trends, the surgical role in the treatment of unexplained infertility has been largely supplanted by in vitro fertilization (IVF); however, a variety of surgical options for optimising tubal function is available, including neosalpingostomy, traditional fimbrioplasty, and modified laparoscopic fimbrioplasty. These surgical options can be an alternative or predecessor to IVF, and are potential options for younger women. 27 Conversely, IVF/ICSI may be a more suitable option in cases of concurrent male factor infertility, advanced maternal age, low ovarian reserve, or extensive disease not amenable to surgery. 28 Conclusion Infertile patients with unilateral tubal block can expect similar pregnancy outcomes after COH-IUI compared with patients with bilateral tubal patency and unexplained infertility. Although women with proximal tubal block have similar odds of successful pregnancy, women with distal tubal block have lower odds of pregnancy compared with women with bilateral patent tubes undergoing COH- IUI. This observed difference between proximal and distal tubal occlusion may result from inherent diagnostic limitations of HSG or may reflect different underlying pathologies that differentially affect pregnancy outcomes. Furthermore, it is important to recognise that the effect of unexplained infertility in the control group may also mask the fertility-reducing effects of unilateral tubal occlusion. Notwithstanding these limitations, our results suggest that clinical work-up of unilateral tubal occlusion by HSG should focus on determining the specific location of the obstruction along the tube in order to better direct treatment. Among patients with proximal tubal occlusion diagnosed by HSG, COH-IUI is a suitable treatment option, whereas further prospective research is required to evaluate whether patients with distal occlusion may benefit from further tubal evaluation, or should be directed to IVF/ICSI sooner, depending on the specific patient s characteristics. Disclosure of interests None declared. Completed disclosure of interests forms are available to view online as supporting information. Contribution to authorship Study concept and design: JT, ST, and MB. Acquisition of data: JT, OT, and AK. Analysis and interpretation of data: JT, OT, and AA. Drafting the manuscript: JT, AA, and OT. Critical revision of the manuscript for important intellectual content: ST and MB. Details of ethics approval Not applicable. Funding Not applicable. Acknowledgements We would like to thank colleagues at the University of British Columbia and McGill University Health Centre. Supporting Information Additional supporting information may be found online in the Supporting Information section at the end of the article. Figure S1. PRISMA flow diagram of systematic literature search. Figure S2. Funnel plots of studies comparing PR/IUI cycle in: (A) unilateral tubal block versus control; (B) proximal tubal block versus control; (C) distal tubal block versus control; and (D) proximal versus distal tubal block. Figure S3. Funnel plots of studies comparing cumulative PR in: (A) unilateral tubal block versus control; (B) proximal tubal block versus control; (C) distal tubal block versus control; (D) proximal versus distal tubal block. 234
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