Ultrasound Obstet Gynecol 2019; 54: 172–181 Published online 26 June 2019 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.20238 Effectiveness on fertility outcome of tubal flushing with different contrast media: systematic review and network meta-analysis R. WANG1 , N. VAN WELIE2, J. VAN RIJSWIJK2,N.P.JOHNSON1,3,R.J.NORMAN1,4, K. DREYER2,V.MIJATOVIC2 andB.W.MOL1,5 1Robinson Research Institute and Adelaide Medical School, The University of Adelaide, North Adelaide, Australia; 2Department of Reproductive Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; 3Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand; 4Fertility SA, Adelaide, Australia; 5Department of Obstetrics and Gynaecology, Monash Medical Centre, Monash University and Monash Health, Clayton, Australia KEYWORDS: contrast media; Fallopian tube patency test; HSG; HyCoSy; hysterosalpingography; infertility; laparoscopy; systematic review; tubal flushing ABSTRACT low certainty of evidence, respectively) and compared with no intervention (OR, 2.28 (95% CI, 1.50–3.47), Objectives To compare, in women with infertility, moderate certainty of evidence; and OR, 2.85 (95% CI, the effectiveness and safety of tubal flushing using 1.41–5.74), low certainty of evidence, respectively). These oil-based contrast medium, water-based contrast medium results agreed with those of the pairwise meta-analysis. or their combination, and no tubal flushing, and to For clinical pregnancy within 6 months, there was evaluate the effectiveness of tubal flushing on fertility insufficient evidence of a difference between tubal flushing outcome over time. with water-based contrast medium and no intervention Methods We performed a systematic review and net- (OR, 1.36 (95% CI, 0.91–2.04), low certainty of work meta-analysis, searching the electronic databases evidence). For fertility outcomes after 6 months, there MEDLINE, EMBASE and Cochrane Central Register was insufficient evidence of a difference in any comparison of Controlled Trials, and trial registries, up to 25 Septem- (low to very low certainty of evidence). Compared with ber 2018. We included randomized controlled trials tubal flushing using water-based contrast medium, the use (RCTs) comparing the following interventions with each of oil-based contrast medium was associated with higher other or with no intervention in women with infertil- odds of asymptomatic intravasation (OR, 5.06 (95% CI, ity: tubal flushing using water-based contrast medium, 2.29–11.18), moderate certainty of evidence). tubal flushing using oil-based contrast medium or addi- Conclusions In women with infertility undergoing fertil- tional tubal flushing with oil-based medium following ity workup, tubal flushing using oil-based contrast med- diagnostic tubal flushing with water-based medium. The ium probably increases clinical pregnancy rates within outcomes included clinical pregnancy, live birth, ongoing 6 months after randomization and may increase subsequ- pregnancy, miscarriage, ectopic pregnancy and adverse ent live-birth rates, compared with tubal flushing using events. water-based contrast medium and compared with no inte- Results Of the 283 studies identified through the search, rvention. Evidence on fertility outcomes beyond 6 months 14 RCTs reporting on 3852 women with infertility is inadequate to draw firm conclusions. Copyright © 2019 were included. Network meta-analysis showed that tubal ISUOG. Published by John Wiley & Sons Ltd. flushing using oil-based contrast medium was associated with higher odds of clinical pregnancy within 6 months INTRODUCTION after randomization and more subsequent live births compared with tubal flushing using water-based medium Tubal flushing was initially introduced in reproductive (odds ratio (OR), 1.67 (95% CI, 1.38–2.03), moderate medicine as a diagnostic test to evaluate tubal patency. certainty of evidence; and OR, 2.18 (95% CI, 1.30–3.65), It constitutes an essential part of the fertility workup Correspondence to: Dr R. Wang, Robinson Research Institute, The University of Adelaide, 55 King William Road, North Adelaide, SA 5006, Australia (e-mail: [email protected]) Accepted: 6 February 2019 Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. SYSTEMATIC REVIEW Tubal flushing and fertility outcome 173 and is recommended in clinical guidelines1,2. Tubal and MEDLINE, as well as the trial registers ClinicalTrials flushing has been used in several different techniques .gov, International Clinical Trials Registry Platform and to visualize tubal patency, including hysterosal- Australian New Zealand Clinical Trials Registry, using pingography (HSG), hysterosalpingo-contrast sonog- combinations of relevant free words and/or index terms raphy (HyCoSy), hysterosalpingo-foam sonography (Appendix S1). The last electronic database search was (HyFoSy) and laparoscopy with dye testing. Water-based conducted on 25 September 2018. The reference lists of contrast media are widely used in all these procedures identified publications were searched manually to identify while oil-based contrast media are used mainly in HSG. additional relevant papers. A debate about the therapeutic effects of tubal 3,4 flushing started over six decades ago . Several potential Eligibility criteria mechanisms have been proposed to explain such therapeutic effects, including mechanical flushing out We intended to include studies in which the participants of the debris or mucus plugs in the Fallopian tubes5, were women wishing to conceive. We included RCTs enhancement of ciliary activity6 and immunobiological comparing at least two of the following treatment or actions on the endometrium or peritoneum7–11. control groups: (1) no tubal flushing; (2) tubal flushing In order to evaluate the effect of tubal flushing on with water-based contrast medium; (3) tubal flushing fertility outcomes, a number of studies have compared with oil-based contrast medium; or (4) an additional tubal flushing using different contrast media, alone tubal flushing procedure with oil-based contrast medium or in combination, with each other or with no after diagnostic tubal flushing with water-based contrast treatment. However, no large randomized controlled trial medium. Studies reporting on tubal flushing procedures (RCT) has compared all these different interventions, using any imaging technique, including HSG, HyCoSy, therefore a network meta-analysis incorporating both HyFoSy or laparoscopy (or hydrolaparoscopy), were direct and indirect evidence is required to determine the eligible for inclusion. Studies comparing different types most effective contrast medium in imaging techniques. of water-based, or different types of oil-based, contrast Moreover, considering the mechanisms proposed so far media were excluded. Quasi-RCTs were excluded. No to explain the beneficial effects of tubal flushing, it is likely language limitation was applied. that its effectiveness may not remain the same over time, and therefore it is also important to assess the trend of Outcomes fertility outcomes with different contrast media over time. Several meta-analyses on this topic have been The outcomes included clinical pregnancy, live birth, published12–14. These used only direct evidence in the ongoing pregnancy, miscarriage, ectopic pregnancy evidence synthesis and some evaluated water- vs oil-based and adverse events. We intended to use outcomes at the contrast in HSG only12,13, but did not consider women longest time of follow-up in each study for the primary who did not undergo tubal flushing or women with analysis. In order to show the trend over time, we also tubal flushing undergoing non-HSG techniques. More- planned a subgroup analysis to evaluate clinical pregnancy over, none of these meta-analyses considered fertility at different follow-up timepoints (i.e. at 3, 6, 9, 12 and 18 outcomes over time12–14. months) after randomization, if data were available. We conducted this systematic review and network All short-term outcomes related to tubal flushing, such meta-analysis to compare the effectiveness and safety as pelvic infection and intravasation, as well as long-term of tubal flushing according to the use of oil-based vs outcomes, such as birth defects, were reported on. water-based contrast medium vs their combination, or compared with no tubal flushing, in the outcome of women with infertility undergoing fertility workup. Our Study selection, data collection and quality assessment secondary objective was to evaluate the effectiveness of Two reviewers (R.W. and N.v.W.) independently eval- tubal flushing on fertility outcomes over time. uated study eligibility, extracted the data and assessed the quality of the included studies. Disagreements were METHODS solved by consensus or by discussion with a third reviewer (B.W.M.). The protocol of this systematic review was registered A predesigned form was used to collect the following on PROSPERO (CRD42017059832). We reported information: name of the first author, publication the systematic review according to the Preferred year, study population, participant characteristics, study Reporting Items for Systematic Reviews and Meta- funding, types of contrast medium evaluated, details Analysis (PRISMA) extension statement for network of interventions and co-interventions, sample size and meta-analysis15. outcomes. If outcome data were reported in published figures, DigitizeIt version 2.2 software (I. Bormann, Information sources and search strategy Braunschweig, Germany; https://www.digitizeit.de/)