Effectiveness on Fertility Outcome of Tubal Flushing with Different Contrast

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/) was used to reconstruct the data from the publications16. We searched the electronic databases EMBASE, Cochrane Risk of bias within individual studies was assessed using Central Register of Controlled Trials (CENTRAL) the Cochrane Collaboration tool17. The certainty of

Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2019; 54: 172–181. 174 Wang et al. evidence across the included studies was evaluated by We intended to perform subgroup analyses on age, considering study limitations (risk of bias), indirectness of duration of infertility, cause of infertility and outcomes evidence, inconsistency of results, imprecision of results at different timepoints after randomization if data were and risk of publication bias, using Conﬁdence in Network available. We planned a sensitivity analysis by including Meta-analysis (CINeMA)18. only studies with a low risk of bias. We also performed a post-hoc sensitivity analysis by excluding participants with missing outcome data17. Statistical analysis

We used network plots to show available head-to-head RESULTS comparisons in included RCTs and a contribution Characteristics of included studies matrix to illustrate the contribution of each head-to-head comparison to the overall body of evidence19,20. Of the 283 studies identified through the search, 14 RCTs We then tested global inconsistency using the (16 articles) reporting on 3852 women with infertility design-by-treatment interaction model21 and tested local were included25–40 (Figure 1). All studies reported on inconsistency using inconsistency plots22. When there women with infertility and the detailed causes of this was no significant inconsistency, we performed net- (including unexplained infertility) were provided in all work meta-analyses within multivariate random-effects but two studies32,34 (Table 1). Funding was reported in meta-analysis models23 as well as random-effects pairwise three studies28,29,31. Outcome data at different timepoints meta-analysis17. were extracted from the figures in seven studies by using We used the surface under the cumulative rank- DigitizeIt 2.2 software25,28,31,32,35,37,40. ing (SUCRA) to rank the treatments24, and applied Of the 14 included RCTs, the most frequent comparison comparison-adjusted funnel plots to assess small-study was tubal flushing using water-based vs oil-based contrast effects19. STATA version 15.0 (StataCorp., College Sta- medium (n = 6)26–28,32,35,36, followed by tubal flushing tion, TX, USA) was used to perform statistical analysis using water-based medium succeeded by oil-based and to illustrate the graphics23. contrast medium vs water-based contrast medium alone

Records identified through database search (n = 410): • MEDLINE (n = 96) Additional records identified • EMBASE (n = 235) through other sources n = • n = ( 2)

Identification CENTRAL ( 79)

Records after duplicates removed (n = 283)

Screening Records screened (n = 283) Records excluded (n = 256)

Full-text articles assessed for eligibility (n = 27) Full-text articles excluded (n = 11): • Duplicate study population (n = 5) Eligibility • Irrelevant intervention (n = 3) • Not RCT (n = 1) • Ongoing study (n = 1) Studies included in • Multiple reasons (n = 1) systematic review (n = 14 RCTs) (n = 16 articles)

Inclusion Studies included in network meta-analysis (n = 14 RCTs) (n = 16 articles)

Figure 1 Flowchart showing selection and inclusion of randomized controlled trials (RCTs) in systematic review and meta-analysis.

Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2019; 54: 172–181. Tubal flushing and fertility outcome 175 citrate (17.9%), IVF/ICSI (1.4%), ovulation induction (0.5%), laparoscopy (6.2%) or hysteroscopy (4.4%) citrate (14.8%), IVF/ICSI (1.3%), ovulation induction (0.5%), laparoscopy (6.2%) or hysteroscopy (4.2%) necessary necessary Co-intervention during/after tubal flushing Ovulation disorders treated with clomiphene According to prespecified indications: IUI Excision of endometriotic lesions when None None None Excision of endometriotic lesions when 15 mL) None (but four women had IVF) < (10–20 mL) Ioxitalamate) (5–10 mL) blue dye; lipiodol ethiodol (20 mL) diatrizoate (5–10 mL) Conray-60 (20 mL) blue dye; saline (10 mL) Method of tubal flushing Contrast medium oil Laparoscopy Dilute solution of methylene oil Laparoscopy Laparoscopic tubal testing; + + Intervention and control Water HSG Reno-M-60 (diatrizoate) Water HSG Telebrix Hystero (Meglumine Water HSG Iopamidol (10 mL)No flushing — Only hormonal therapy was used —No flushing —WaterNo flushing — HSG —No flushing — None Water Iotrolan (Isovist) (5–10 mL) — None HSG — Iohexol, Ioxaglate or None None None Water Laparoscopy Laparoscopic tubal testing; Water Laparoscopy Dilute solution of methylene (months) Follow-up ) n 88 12 Water 40 12 Water 131 6175 Oil 6 HSG Oil Lipiodol (10–20 mL) HSG158 Ovulation disorders treated Ethiodol with 6 (10 clomiphene mL) Oil334 Only hormonal therapy was HSG used 6 Water Lipiodol (10 mL) HyCoSy Echovist ( None 398 10 Oil HSG Lipiodol (5–10 mL) None size ( Sample 1119 6 Oil HSG Lipiodol (5–10 mL) According to prespecified indications: IUI endometriosis tubal factor (29%); endometriosis (8%); unexplained or mild male infertility (30%) male infertility male infertility (87%); tubal factor (8%); other cause (5%)* (61%); endometriosis (39%) (100%) male infertility (77%); tubal factor (23%) unexplained or mild male infertility (54%) Canada Unexplained infertility; Canada/USA Oligo-ovulation (33%); Netherlands Unexplained orNetherlands mild Unexplained or mild New Zealand Unexplained infertility USASweden Unexplained infertility Denmark Unexplained or mild UK NRJapanDenmark Unexplained infertility NR Tubal factor (46%); 34 242 6 9 Oil 302 Oil HSG 4 HSG Oil Lipiodol (mean, 5.8 mL) Lipiodol (5–10 mL) None HSG None Lipiodol, volume NR None 32 25 31 29 27 30 33 28 34 26 35 Characteristics of 14 randomized controlled trials included in systematic review (1991) Table 1 StudyAl-Fadhli (2006) Country Cause of infertility Continued over. Dreyer (2017) Letterie (1990) Lindequist (1994) Nugent (2002) Ogata (1993) Rasmussen Lindborg (2009) de Boer (1988) Johnson (2004) Alper (1986)

(n = 5)25,30,36–38. There were three studies comparing tubal flushing using oil-based contrast medium with no tubal flushing29,33,34, one comparing tubal flushing using water-based followed by oil-based contrast medium with the use of oil-based contrast medium only36, and one comparing tubal flushing with water-based contrast medium with no tubal flushing31 (Table 1). Clinical pregnancy within 6 months was the most commonly reported outcome (n = 12). The network plots for different outcomes are presented in Figure S1. Co-intervention during/after tubal flushing Ovulatory medication (53.3%) IUI (24.8%) None

Quality of evidence of individual studies With regard to selection bias, 64% (n = 9)25,26,28–31,36–38 of baseline data. ‡52.7% diatrizoate of included RCTs reported adequate methods of random perm injection; IUI, intrauterine insemination; sequence generation and 36% (n = 5)28,29,31,33,38 reported adequate methods of allocation concealment, while 7% (n = 1)37 had no concealment (Table 2). As blinding was not possible owing to the nature of the interventions, we scored the risk of performance bias as unclear in all ethiodol (10 mL) ethiodol (mean, 6.0 mL) lipiodol (5 mL) RCTs. Given that all the fertility outcomes are objective outcomes, it is unlikely that the non-blinded design would affect the outcome measurement, therefore, the risk of detection bias was low in all the included studies. Five RCTs25,26,30,32,34 had a high risk of attrition bias owing

Method of tubal flushing Contrast medium to the considerable proportion of missing outcome data. One RCT36 was scored at high risk of other bias because oil HSG Sinografin‡ (5–10 mL); oil HSG Sinografin‡ (mean, 8.2 mL); oil HSG Telebrix Hystero (10 mL); the age distribution was imbalanced in the groups. + + + The majority (> 70%) of the evidence for comparisons between tubal flushing using oil-based contrast medium vs Intervention and control Water HSG Sinografin‡ (5–10 mL) Ovulatory medication (61.5%) OilWater HSG HSG Sinografin‡ Ethiodol (mean, (mean, 9.4 8.6 mL) mL)Water IUI (24.8%) IUI (25.3%) HSG Telebrixno Hystero (10 mL) flushing, None water-based contrast medium vs no flushing and tubal flushing with oil- vs water-based contrast medium were at low risk of bias, but the evidence for the comparisons between the combination group (months) Follow-up (water-based followed by oil-based contrast medium) and )

n the other groups was prone to bias, as at least 25% of the

56 18 Water evidence was at high risk of bias (Figure S2). 666 12 Water 109 8 Water size ( Sample Network consistency and contribution When considering clinical pregnancy at the longest follow-up time in each study in the analysis, we found signiﬁcant global and local inconsistency (Table S1 and Figure S3). Therefore, we avoided pooling the outcomes at different timepoints21. Instead, we chose clinical pregnancy at the most commonly used timepoint (6 months) as an alternative main outcome, and presented outcomes at other timepoints in subgroup analyses. After

uterine-, peritoneal-, endocrine-, cervical-, immunologic- or drug-associated factor or unexplained infertility† endometriosis (12%); unexplained or mild male infertility (45%); tubal factor (3%) infertility (45%); anovulation (23%); endometriosis (8%); other factor (24%) separating outcomes at different timepoints, no signiﬁcant global or local inconsistency was observed (Table S1 and Figure S3). Therefore, time of outcome measurement is an important source of inconsistency in this network meta-analysis. The contribution of direct evidence to the USA Tubal-, male-, ovulatory-, age-, USA Ovulatory dysfunction (35%); China Unexplained or mild male network for different outcomes is presented in Figure S4.

37 Network and pairwise meta-analysis 36 fertilization; NR, not reported; oil, oil-based contrast medium; water, water-based contrast medium. 38

Continued Clinical pregnancy

in-vitro Twelve RCTs reported clinical pregnancy within 6 months meglumine and 26.8% iodipamide meglumine.IVF, HSG, hysterosalpingography; HyCoSy, hysterosalpingo-contrast sonography; ICSI, intracytoplasmic s Table 1 StudySpring (2000) Country Cause of infertility Only ﬁrst author of each study is given. *All patients had low risk of tubal pathology. †Detailed data were not available owing to incomplete reporting Yang (1989) Steiner (2003) in a total of 2884 women. The network meta-analysis

Table 2 Risk of bias in 14 randomized controlled trials included in systematic review

Performance Detection bias Attrition bias Selection bias Selection bias bias (blinding of (blinding of (incomplete Reporting Other bias (random sequence (allocation participants outcome outcome bias (selective (other sources Study generation) concealment) and personnel) assessment) data) reporting) of bias)

Al-Fadhli (2006)25 Low Unclear Unclear Low High Unclear Unclear Alper (1986)26 Low Unclear Unclear Low High Unclear Unclear de Boer (1988)27 Unclear Unclear Unclear Low Low Unclear Low Dreyer (2017)28 Low Low Unclear Low Low Low Low Johnson (2004)29 Low Low Unclear Low Low Low Low Letterie (1990)30 Low Unclear Unclear Low High Unclear Unclear Lindborg (2009)31 Low Low Unclear Low Low Low Low Lindequist (1994)32 Unclear Unclear Unclear Low High Unclear Low Nugent (2002)33 Unclear Low Unclear Low Low Low Low Ogata (1993)34 Unclear Unclear Unclear Low High Unclear Low Rasmussen (1991)35 Unclear Unclear Unclear Low Unclear Unclear Unclear Spring (2000)36 Low Unclear Unclear Low Low Low High Steiner (2003)37 Low High Unclear Low Low Unclear Low Yang (1989)38 Low Low Unclear Low Low Unclear Unclear

Only ﬁrst author of each study is given.

(Figure 2) showed that tubal flushing with oil-based Comparison Odds ratio (95% CI) contrast medium increased the odds of clinical preg- Water vs none (1 RCT, 334 women) nancy within 6 months after randomization compared Lindborg (2009)31 1.14 (0.71, 1.84) with no tubal flushing (odds ratio (OR), 2.28 (95% Overall 1.14 (0.71, 1.84) CI, 1.50–3.47); moderate certainty of evidence), while 1.36 (0.91, 2.04) there was insufficient evidence of a difference between Oil vs none (2 RCTs, 192 women) tubal flushing using water-based contrast medium and Johnson (2004)29 3.16 (1.50, 6.63) 33 no tubal flushing (OR, 1.36 (95% CI, 0.91–2.04); low Nugent (2002) 11.67 (0.58, 235.92) certainty of evidence). This suggests that, if the 6-month Overall 3.40 (1.65, 6.99) 2.28 (1.50, 3.47) clinical pregnancy rate following no tubal flushing is Both vs none (0 RCT) assumed to be 16%, the clinical pregnancy rates fol- Overall 2.30 (1.20, 4.41) lowing tubal flushing with oil-based contrast medium and water-based contrast medium would be 30% (95% Oil vs water (5 RCTs, 2065 women) CI, 22–40%) and 21% (95% CI, 15–28%), respec- Alper (1986)26 1.23 (0.54, 2.81) tively. Compared with water-based contrast medium, De Boer (1988)27 1.49 (0.78, 2.85) the use of oil-based medium resulted in a higher Dreyer (2017)28 1.64 (1.27, 2.11) OR for clinical pregnancy within 6 months (OR, 1.67 Lindequist (1994)32 1.40 (0.72, 2.70) (95% CI, 1.38–2.03); moderate certainty of evidence). Rasmussen (1991)35 2.11 (1.19, 3.72) This suggests that if the 6-month clinical pregnancy Overall 1.62 (1.33, 1.98) rate following tubal flushing with water-based contrast 1.67 (1.38, 2.03) Both vs water (4 RCTs, 293 women) medium is assumed to be 28%, the clinical pregnancy Al-Fadhli (2006)25 1.43 (0.58, 3.52) rate following tubal flushing with oil-based contrast Letterie (1990)30 3.86 (0.67, 22.11) medium would be 39% (95% CI, 35–44%). There Steiner (2003)37 2.16 (0.73, 6.36) was very low certainty of evidence for the compar- Yang (1989)38 1.41 (0.61, 3.22) ison between additional oil-based tubal flushing after Overall 1.69 (1.02, 2.81) water-based tubal flushing and the other interventions. 1.69 (1.02, 2.81) SUCRA values for tubal flushing with a combination Both vs oil (0 RCT) of water- and oil-based contrast media, oil-based con- Overall 1.01 (0.59, 1.74) trast medium alone, water-based contrast medium alone 0.5 1 2 5 and no tubal flushing were 83.0%, 82.0%, 31.7% Favors 2nd intervention Favors 1st intervention and 2.5%, respectively. The findings of the pairwise meta-analyses were similar to those of the network Figure 2 Forest plots of network and pairwise meta-analyses on meta-analyses for these comparisons (Figure 2). There clinical pregnancy within 6 months after randomization to tubal was no evidence of the existence of small-study effects flushing with oil-based contrast medium (oil), tubal flushing with (Figure S5). water-based contrast medium (water), additional tubal flushing Subgroup analysis of clinical pregnancy within 3 months with oil-based following flushing with water-based contrast medium (both) or no tubal flushing (none). Odds ratios and 95% showed similar findings to those for clinical pregnancy CIs of pairwise meta-analyses are illustrated by hollow diamonds within 6 months from randomization (Figure S6). With while those of network meta-analyses are illustrated by filled regard to clinical pregnancy within 9, 12 and 18 months, diamonds.

Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2019; 54: 172–181. 178 Wang et al. neither network meta-analysis nor pairwise meta-analysis with water-based contrast medium is assumed to be 22%, showed any statistically significant differences in most the live-birth rate following tubal flushing with oil-based comparisons. contrast medium would be 38% (95% CI, 27–51%). As the breakdown outcome data on women of different SUCRA values for tubal flushing with oil-based and ages or with different duration or cause of infertility were water-based contrast media and no tubal flushing were not available, no subgroup analyses on these variables 99.9%, 41.1% and 9.0%, respectively. The findings of were performed. Sensitivity analyses of studies with an the pairwise meta-analyses were consistent with those overall low risk of bias and after excluding participants of the network meta-analyses (Figure 3). The results for with missing outcome data showed findings consistent ongoing pregnancy resulting from pregnancy occurring with the main findings of the network meta-analysis for within 6 months following intervention (four RCTs, clinical pregnancy within 6 months (Figure S7). 1645 women) were consistent with those for live birth (Figure S6).

Live birth and ongoing pregnancy Miscarriage, ectopic pregnancy and adverse events Five studies reported on live birth resulting from pregnancy within 6 months in a total of 2043 women. The There was no conclusive evidence of a difference in any network meta-analysis (Figure 3) showed that tubal flush- of the comparisons for miscarriage or ectopic pregnancy ing using oil-based contrast medium resulted in higher (Figure S6). odds of live birth compared with no tubal flushing (OR, Five studies reported no short-term adverse events fol- 2.85 (95% CI, 1.41–5.74); low certainty of evidence), lowing tubal flushing. Pooled analysis of the three studies while there was insufficient evidence of a difference that reported on intravasation showed that, compared between tubal flushing using water-based medium and with water-based contrast medium, oil-based contrast no tubal flushing (OR, 1.31 (95% CI, 0.70–2.44); low medium was associated with higher odds of asymp- certainty of evidence). This suggests that, if the live-birth tomatic intravasation (OR, 5.06 (95% CI, 2.29–11.18); 2 = rate resulting from clinical pregnancy within 6 months three studies; I 0). No cases of pulmonary embolism following no tubal flushing is assumed to be 16%, the or death were reported. Three studies reported on live-birth rates following tubal flushing with oil-based pelvic infection, of which two compared tubal flushing contrast medium and water-based contrast medium with water-based vs oil-based contrast medium. Pooled would be 35% (95% CI, 21–52%) and 20% (95% CI, analysis showed that there was insufficient evidence of 12–32%), respectively. Tubal flushing using oil-based differences in the incidence of pelvic infection between contrast medium resulted in higher odds of live birth than these two interventions (OR, 0.23 (95% CI, 0.04–1.27); 2 = did the use of water-based contrast medium (OR, 2.18 two studies; I 0) (Figure S6). 28 (95% CI, 1.30–3.65); low certainty of evidence). This Only one study reported long-term adverse events, suggests that, if the live-birth rate following tubal flushing in which three newborns in the group of women who underwent tubal flushing with oil-based contrast medium had skeletal dysplasia, esophageal atresia and Comparison Odds ratio (95% CI) chromosomal mosaicism, respectively. No congenital Water vs none (1 RCT, 334 women) abnormalities were seen in neonates born to women who Lindborg (2009)31 1.13 (0.67, 1.91) underwent tubal flushing with water-based medium. Overall 1.13 (0.67, 1.91) 1.31 (0.70, 2.44) Oil vs none (2 RCTs, 192 women) DISCUSSION Johnson (2004)29 3.09 (1.39, 6.91) Nugent (2002)33 11.67 (0.58, 235.92) Summary of key findings Overall 3.38 (1.56, 7.34) 2.85 (1.41, 5.74) For the comparisons between tubal flushing using Oil vs water (2 RCTs, 1517 women) oil-based contrast medium vs water-based contrast Dreyer (2017)28 1.64 (1.27, 2.11) medium or no tubal flushing, the overall certainty of Rasmussen (1991)35 3.14 (1.66, 5.94) evidence was moderate for short-term clinical pregnancy, Overall 2.12 (1.14, 3.94) low for short-term live birth and low to very low 2.18 (1.30, 3.65) for outcomes beyond 6 months. Tubal flushing using 0.5 12 5 oil-based contrast medium probably increases short-term Favors 2nd intervention Favors 1st intervention (6 months) clinical pregnancy rate, and may increase subsequent live-birth rate compared with tubal flushing Figure 3 Forest plots of network and pairwise meta-analyses on with water-based contrast medium and no tubal flushing, live birth resulting from pregnancy within 6 months after but it is not certain whether this effect persists beyond randomization to tubal flushing with oil-based contrast medium 6 months. The evidence on the effectiveness of tubal (oil), tubal flushing with water-based contrast medium (water) or no tubal flushing (none). Odds ratios and 95% CIs of pairwise flushing using water-based contrast medium compared meta-analyses are illustrated by hollow diamonds while those of with no tubal flushing was insufficient (low certainty of network meta-analyses are illustrated by filled diamonds. evidence).

Strengths and limitations intravasation can potentially result in life-threating pulmonary embolism, we are unaware of any deaths reported The strengths of this systematic review include that since the 1960s49. This may be owing to fluoroscopy it incorporates evidence from both direct and indirect screening or the reduced use of HSG with oil-based con- comparisons, provides a hierarchy of rankings of effective- trast worldwide as HyCoSy and HyFoSy become more ness and uses multiple approaches for sensitivity analysis. popular. Secondly, any concerns about the thyroid func- Moreover, time from randomization was incorporated tion of mother and child are based on the effects of iod- into the outcome assessments and was identified as a inated contrast medium50,51 and a longer-persisting time source of inconsistency. Our current outcome-reporting of oil-based contrast in the pelvis52. Maternal hypothy- strategy not only reduced the heterogeneity in outcome roidism can occur after tubal flushing with oil-based reporting across trials but also illustrated the trend of contrast51, especially in women with subclinical hypothy- effectiveness of different interventions over time. roidism before HSG53. With regard to neonatal safety, On the other hand, several limitations of our a Japanese cohort showed that infants born to mothers meta-analysis should be addressed. Firstly, not all undergoing HSG using oil-based contrast before conceiv- trials reported live birth. Despite this, the agreement ing had a higher incidence of thyroid dysfunction (2.4%) between the results for live birth and those for clinical than did the unselected population (0.7%)50. Although pregnancy provided some reassurance for our main there is limited evidence on these safety issues, they should conclusion. Secondly, although the majority of the be fully discussed during clinical consultations. participants were broadly defined as having unexplained infertility, including endometriosis and mild male-factor infertility, the study population also included other Research implications causes of infertility; the heterogeneous nature of the study population may have resulted in selection bias. Future trials should evaluate long-term fertility outcomes Thirdly, some of the studies had a high risk of selection, after tubal flushing. The effectiveness needs to be tested attrition or other bias. This resulted in an overall low in trials addressing different populations, including quality of evidence in some comparisons, especially in women with advanced age, anovulation or tubal-factor the combination group of tubal flushing with oil-based infertility. Safety data on women and their offspring are medium following flushing with water-based contrast also needed to address the short- and long-term safety medium. Finally, the association between available concerns. evidence and competing interests of the manufacturer was The therapeutic effects of contrast media should unclear in most studies. Only three studies28,29,36 reported also be tested in techniques other than HSG, such as funding sources and all were from academic institutes or HyCoSy, HyFoSy and hydrolaparoscopy as well as societies, including one29 with additional support from laparoscopy, for instance by using tubal flushing with oil- industry. based contrast medium after confirming tubal patency with HyCoSy, or performing preovulatory tubal flushing without any imaging after confirmed tubal patency, fol- Clinical implications lowed by intrauterine insemination or timed intercourse, The effect of tubal flushing using oil-based contrast as suggested in some studies54,55. This would be an medium has not been evaluated outside HSG. HyCoSy interesting alternative treatment for in-vitro fertilization is an accurate test for diagnosing tubal occlusion in women with unexplained infertility. and performs similarly to HSG41. It prevents women from The mechanical effects of flushing on the Fallopian being exposed to radiation and, therefore, has replaced tubes seem to be the most reasonable theory to HSG in fertility workup in many settings. More recently, account for its therapeutic effects, as they persist after HyFoSy has become commonly used, and a trial on several menstrual cycles post tubal flushing, and such its diagnostic accuracy and cost-effectiveness in fertility effects have been observed following the use of both workup is underway42. oil-based and water-based contrast in a recent cohort The costs of HyCoSy with sonographic contrast and study56. With regard to the difference between different HSG with water-based contrast are considered similar43, contrast media, we hypothesize that for tubes with while HyFoSy may further reduce the cost42.InHSG, mucus plugs or debris, the higher viscosity of the oil-based contrast is more expensive than is water-based oil-based contrast causes a better flushing effect, maybe contrast, with an extra US$ 8198 for an additional owing to a higher pressure during the tubal flushing ongoing pregnancy in ovulatory women with infertility at procedure. A recent study found that the treatment effect low risk for tubal pathology44. Cost-effectiveness should of oil-based, as compared with water-based, contrast also be considered in shared decision-making. medium was higher in women suffering from severe Several safety concerns regarding tubal flushing have pain during tubal flushing57, possibly because the higher been raised. Firstly, venous intravasation occurs in intrauterine pressure associated with the dislodgement approximately 2–7% of cases undergoing HSG45–47 and of mucus plugs and debris might cause more pain. seems to occur more frequently when using oil-based con- However, we acknowledge that such a hypothesis is trast medium. Some reports on venous intravasation dur- difficult to test in animal models or humans. Hypotheses ing ultrasound show a higher incidence (13%)48. While related to other mechanisms, including the effects on

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SUPPORTING INFORMATION ON THE INTERNET

The following supporting information may be found in the online version of this article: Appendix S1 Search strategies Table S1 Results of global inconsistency assessment Figure S1 Network plots for clinical pregnancy within 3 months (a), 6 months (b), 9 months (c) and 12 months (d), and live birth resulting from pregnancy within 6 months (e), after randomization. Figure S2 Risk of bias contributions. Figure S3 Inconsistency plots for clinical pregnancy at the longest follow-up time (a), clinical pregnancy within 6 months (b), 3 months (c) and 12 months (d), and live birth resulting from pregnancy within 6 months (e), after randomization. Figure S4 Contribution plots for clinical pregnancy within 6 months (a), 3 months (b), 9 months (c) and 12 months (d), live birth resulting from pregnancy within 6 months (e) and miscarriage within 6 months (f) after randomization. Figure S5 Comparison-adjusted funnel plots for clinical pregnancy within 6 months (a) and 3 months (b) after randomization. Figure S6 Network and pairwise meta-analyses for clinical pregnancy at different timepoints (a), live birth at different timepoints (b), ongoing pregnancy resulting from pregnancy within 6 months after randomization (c), miscarriage (d) and ectopic pregnancy and adverse events (e). Figure S7 Sensitivity analysis for clinical pregnancy within 6 months when including only studies with low risk of bias (a) and when excluding participants with missing outcome data (b).

A video abstract of this article is available online

Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2019; 54: 172–181. Ultrasound Obstet Gynecol 2019; 54: 172–181 Published online 26 June 2019 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.20238

Eﬁcacia sobre el resultado de fertilidad del lavado de trompas con diferentes medios de contraste: revision´ sistematica´ y metaanalisis´ en red RESUMEN

Objetivos Comparar, en mujeres con infertilidad, la efectividad y seguridad del lavado de trompas con un medio de contraste a base de aceite, un medio de contraste a base de agua o una combinacion,´ y el no lavado de trompas, y evaluar la efectividad del lavado de trompas en el resultado de la fertilidad con el tiempo.

Metodos´ Se realizo´ una revision´ sistematica´ y un metaanalisis´ en red, mediante busquedas´ en las bases de datos electronicas´ MEDLINE, EMBASE y el Registro Central Cochrane de Ensayos Controlados, y en otros registros de ensayos, hasta el 25 de septiembre de 2018. Se incluyeron ensayos controlados aleatorizados (ECA) que compararon las siguientes intervenciones entre sı´ o con la no intervencion´ en mujeres con infertilidad: lavado de trompas con medio de contraste a base de agua, lavado de trompas con medio de contraste a base de aceite o lavado de trompas adicional con un medio a base de aceite despues´ de un lavado de trompas con un medio a base de agua. Los resultados incluyeron el embarazo conﬁrmado ecograﬁcamente,´ el nacimiento vivo, el embarazo en curso, el aborto espontaneo,´ el embarazo ectopico´ y los eventos adversos.

Resultados De los 283 estudios identificados mediante la busqueda,´ se incluyeron 14 ECA que informaron sobre 3852 mujeres con infertilidad. El metaanalisis´ en red mostro´ que el lavado de trompas con medio de contraste a base de aceite se asocio´ con mayores probabilidades de embarazo confirmado ecograficamente´ dentro de los seis meses posteriores a la aleatorizacion´ y mas´ nacimientos vivos posteriores en comparacion´ con el lavado de trompas con medio a base de agua (razon´ de momios [RM], 1,67; IC 95%: 1,38–2,03), certeza moderada de evidencia; y RM, 2,18 (IC 95%: 1,30–3,65), certeza baja de evidencia, respectivamente) y en comparacion´ con la no intervencion´ (RM, 2,28 (IC 95%: 1,50–3,47), certeza moderada de evidencia; y RM, 2,85 (IC 95%: 1,41–5,74), certeza baja de evidencia, respectivamente). Estos resultados coincidieron con los del metaanalisis´ por pares. No hubo evidencia suficiente de una diferencia entre el lavado de trompas con medio de contraste a base de agua y la no intervencion´ para el embarazo clınico´ dentro de los seis meses (RM, 1,36 (IC 95%: 0,91–2,04); certeza baja de evidencia). Para los resultados de fertilidad despues´ de los seis meses, no hubo evidencia suficiente de diferencias en cualquier comparacion´ (certeza de evidencia baja a muy baja). En comparacion´ con el lavado de trompas con un medio de contraste a base de agua, el uso de un medio de contraste a base de aceite se asocio´ con mayores probabilidades de intravasacion´ asintomatica´ (RM, 5,06 (IC 95%: 2,29–11,18), certeza moderada de evidencia).

Conclusiones En las mujeres con infertilidad que se someten a un examen de fertilidad, el lavado de trompas con medio de contraste a base de aceite aumenta la probabilidad de las tasas de embarazo clınico´ dentro de los 6 meses posteriores a la aleatorizacion´ y puede aumentar las tasas posteriores de nacimientos vivos, en comparacion´ con el lavado de trompas con medio de contraste a base de agua y en comparacion´ con la no intervencion.´ La evidencia sobre los resultados de fertilidad despues´ de los seis meses es inadecuada para establecer conclusiones ﬁrmes.