Background and rationale

Tubal factor infertility occurs when some pathology proximally at the uterotubal junction or more distally in the fallopian tube(s), caused by disease, obstruction, damage, scarring, congenital malformations or other factors, prevents oocyte pickup by the fimbriated ends of the tube or sperm access to the oocyte for fertilization in the tube, or impedes the fertilized egg and developing embryo from descending into the uterus, thereby preventing pregnancy or resulting in ectopic pregnancy. Of the different causes, the most prevalent is PID or salpingitis. In a large WHO multi-country study, bilateral tubal occlusion and acquired tubal abnormalities accounted for 17.7% and 11.6%, respectively, of all identifiable causes of female infertility (1, 2), although the distribution can vary between high-income, middle-income and low-income settings (see Annex 1. Distribution of the causes of infertility). Given the role of the fallopian tube in gamete and embryo transport (3), assessment of tubal disease, particularly tubal patency is important in the investigation of female infertility.

The two modalities for managing (or overcoming) tubal factor infertility, such as blockage, are IVF and tubal surgery. IVF is an ART procedure that involves combining eggs and sperm outside the body in a laboratory. The resulting embryos are transferred into the uterine cavity, without the need for open fallopian tubes. Surgical procedures include salpingostomy (formation of an opening at the distal end of an occluded fallopian tube), fimbrioplasty (removal of scar tissue around the distal end of the tube or reconstructing the fimbriae to approximate normal anatomy) and adhesiolysis (performed to remove scar tissue around the tube) (4).

Given that fecundity of women decreases with age (5), time to pregnancy is an important consideration when comparing surgery versus IVF. Apart from age, other important considerations include site and the extent of the tubal disease.

The Hull and Rutherford classification of tubal disease uses clinical descriptive characteristics, including tubal mucosal status, fibrosis and distension, and the extent of peritubal-ovarian adhesions; it groups patients (< 40 years old and excluding endometriosis) according to the prognosis for pregnancy (6). Classification according to severity is related to the prognosis for spontaneous (i.e. unassisted) pregnancy after surgery (indicated by the expected 3-year pregnancy rate). Grade I refers to minor disease (with favourable surgical prognosis of 85% clinical pregnancy rate [CPR] and 69% live birth rate [LBR]/3 years). Grade II indicates intermediate disease (with intermediate surgical prognosis of 72% CPR and 48% LBR/3 years), while grade III indicates severe disease (with unfavourable or poor surgical prognosis of 28% CPR and 9% LBR/3 years) (7). For these recommendations, the GDG addressed the question: should surgery versus IVF be used for women with infertility due to tubal disease? For these recommendations, surgical procedures for tubal disease exclude tubal re-anastomosis after sterilization (sterilization reversal). These recommendations assume that no significant male factor exists.

Balancing harms and benefits

A systematic review of the literature for randomized and non-randomized studies from 1990 to July 2019 was conducted. No RCTs comparing pregnancy rates after tubal surgery versus IVF were identified. Available evidence was identified from comparative non-randomized studies (8–10); the certainty of the evidence was very low because of potential confounding, low number of events and wide CIs, and the heterogeneity of surgical approaches. Studies providing data on tubal re-anastomosis were excluded. The balance of desirable and undesirable effects for tubal surgery or IVF was arrived at considering patient age and the severity of the disease.

The overall data showed that compared to IVF, surgery may result in more live births (212 more per 1000 [from 156 to 279 more]; RR: 3.36; 95% CI: 2.74–4.11) over a follow-up duration of at least 5 years and may also result in more clinical pregnancies over the same follow-up period (369 more per 1000 [from 300 to 447 more]; RR: 4.34; 95% CI: 3.72–5.05), suggesting the benefit of surgery in younger patients with a good prognosis based on the Hull and Rutherford classification, that is, grade I or II tubal disease. In addition, surgery may result in fewer miscarriages (10 fewer per 1000 [from 28 fewer to 18 more]; RR: 0.84; 95% CI: 0.54–1.30). Of note, the benefits from surgery were mainly from microsurgical techniques. The GDG judged these desirable effects to be large.

In terms of harms, the data showed that surgery may result in more ectopic pregnancies (120 more per 1000; risk difference (%): 12; 95% CI: 9–15). Data on multiple gestations and OHSS were not reported in the studies included. The GDG noted the absence of data on important outcomes such as bleeding, infection, injury to internal organs and blood vessels, risks of general anaesthesia, OHSS and high-order multiple pregnancy (HOMP). The GDG considered that there is very little risk, if any, of OHSS and HOMP with surgery but IVF may increase the risk of OHSS and HOMP; however, effective strategies to mitigate these risks of IVF, such as elective single embryo transfer, exist. However, the GDG noted that the greater risk of ectopic pregnancy, which may occur with surgery, may be more relevant in rural settings. However, in most cases these can be well managed by instituting heightened awareness and appropriate surveillance. The GDG considered that the outcomes of surgery are highly operator-dependent and may also be dependent on the extent and site of tubal disease. The GDG judged the undesirable effects to be small.

Although no evidence was found regarding values, the GDG agreed that women with infertility value pregnancy and live birth highly as the main outcomes of the intervention, as well as minimizing risks.

Based on these data, the GDG judged that the overall balance of effects probably does not favour either surgery or IVF. The GDG also noted that IVF outcomes and tubal surgery outcomes may vary in different settings depending on several factors, including the quality of the IVF laboratory and surgeon experience and expertise. In addition, the GDG considered the varying benefits of surgery for different subgroups, noting that the outcomes appear to be potentially influenced by several factors, including age and duration of follow-up. Cumulative pregnancy outcomes with surgery accrue over a longer duration of follow-up that ranges from 1 to 5 years, compared to IVF. Therefore, it is reasonable to offer surgery to younger patients (< 35 years) with mild and moderate disease (Hull and Rutherford grades I and II) because younger women may have time to explore other assisted reproduction options if pregnancy is not achieved after surgery. Given the resources expended in providing surgery, and the time required to achieve spontaneous (i.e. unassisted) pregnancy after surgery, it is recommended that health providers wait for a reasonable time (at least 1 year) after surgery before providing other interventions such as IVF. Most pregnancies occur within 1–2 years of surgical treatment of distal tubal disease (7, 11); therefore, waiting a minimum of 1 year may be reasonable. It should be noted that this recommendation does not apply to women desiring pregnancy after tubal ligation or sterilization.

For younger women aged < 35 years with severe disease (Hull and Rutherford grade III) the harms of surgery probably outweigh its benefits. Although younger women aged < 35 years may have time to explore other assisted reproduction options if pregnancy is not achieved after surgery, severe disease (Hull and Rutherford grade III) has poor prognosis; therefore, IVF is recommended over surgery for these women.

Given concerns related to age-related fertility decline, IVF is also suggested over surgery in women aged ≥ 35 years regardless of the severity of tubal disease. For older women (≥ 35 years) the additional time required to undergo surgery and wait for spontaneous (i.e. unassisted) pregnancy means that women would be much older before exploring other options such as IVF, should pregnancy not be achieved after surgery; therefore, they would have a much lower chance of achieving pregnancy. For older women, the benefits of IVF probably outweigh the harms compared to surgery. For women who are older, women with severe tubal disease and couples with male-factor infertility, IVF could be offered. The overall certainty of evidence was judged to be very low; all studies included were observational.

Other considerations

Performing tubal reconstructive surgery with good results requires a well-equipped health system and a high level of expertise or training. Although it is probably feasible to train health professionals to provide surgery (12), the resource requirements are often not available or met in many low-resource settings. Thus, the GDG judged that large resources are required for surgery and that compared to IVF, surgery would probably have no or limited effect on equity as IVF also involves high costs to be set up and operate.

Tubal surgery is often a one-time procedure that may be conducted as a minimally invasive outpatient procedure. It is more invasive than IVF. Given the impact of both age and severity of disease on pregnancies and live births, surgery is probably acceptable in younger patients with Hull and Rutherford grade I or II tubal disease, while in severe tubal disease (Hull and Rutherford grade III), IVF would probably be acceptable.

Implementation considerations

→ Health care providers should counsel patients, communicate the prognosis, clearly discuss the options and costs of surgery and IVF, and consider patient preferences. In settings where the infrastructure for tubal surgery or IVF does not exist, patient referrals to adequately equipped centres should be considered. Health care providers should be trained to adequately monitor, mitigate and manage the undesirable effects of surgery (such as ectopic pregnancy) and IVF (such as OHSS and HOMP).

→ In implementing this recommendation, health care providers should consider whether patients have hydrosalpinges which may have a negative effect on pregnancy and IVF success rates (13). If hydrosalpinx is present in women planning to undergo IVF, health care providers should implement recommendations related to treatment of hydrosalpinx before IVF, as described in the next section. In addition, these recommendations assume that no significant male factor exists.

Research gaps and future guideline update

Ovarian reserve may be an additional factor to consider; however, data were not available on the subgroup of women with decreased ovarian reserve, which should be addressed in future studies. Future studies should also assess important outcomes such as bleeding, infection, injury to internal organs and vessels, risks of general anaesthesia, OHSS and HOMP, and patients’ values, including attitudes towards surgery or IVF, and preferences related to time to pregnancy and desired family size.

Background and rationale

In cases of tubal disease or blockage, women may develop hydrosalpinx, a condition where fluid accumulates inside the fallopian tubes. The presence of hydrosalpinx may have a negative effect on successful embryo implantation and affect IVF outcomes (1). Therefore, the GDG agreed that guidance is needed regarding the management of hydrosalpinx in patients who are scheduled to undergo IVF.

Treatment of hydrosalpinx is aimed at preventing the hydrosalpingeal fluid from reaching the uterine cavity (2). Options for hydrosalpinx treatment include surgically resecting and removing the affected fallopian tubes (salpingectomy), isolating the hydrosalpinx from the uterine cavity using laparoscopic or hysteroscopic tubal occlusion, transvaginal aspiration of hydrosalpingeal fluid under ultrasound guidance or draining the hydrosalpingeal fluid by means of salpingostomy (3).

For this recommendation, the GDG addressed the question: should salpingectomy or tubal occlusion versus none be used to treat tubal disease due to hydrosalpinx in women due to undergo IVF?

Balancing harms and benefits

A systematic review published in 2020 was identified, with a search date from inception of the databases up to January 2020 (3). From this systematic review, four RCTs published between 1998 and 2006 provided data for the outcomes (4–7).

The results showed that compared to no treatment, conducting salpingectomy or tubal occlusion before IVF may result in slightly greater pregnancies and no difference in ectopic pregnancy and miscarriage. There were 151 more pregnancies (from 58 to 287 more) per 1000 (RR: 2.01; 95% CI: 1.39–2.91), three fewer miscarriages (from 32 fewer to 71 more) per 1000 (RR: 0.94; 95% CI: 0.36–2.41) and nine fewer ectopic pregnancies (from 14 fewer to 15 more) per 1000 (RR: 0.39; 95% CI: 0.08–1.97). Live births and quality of life outcomes were not reported. Compared to no treatment before IVF, conducting salpingectomy or tubal occlusion before IVF may result in 10 more conversions to laparotomy (RD: 0.01; 95% CI: −0.02 to 0.03) and 10 more pelvic infections per 1000 (RD: 0.01; 95% CI: −0.02 to 0.03). Although not measured, the GDG noted that the risk of other potential complications, such as visceral injuries, injury to blood vessels and bleeding, may exist with salpingectomy or tubal occlusion conducted before IVF. The GDG agreed that there were moderate benefits, but small harms, based on the very low certainty of the evidence because of few events or participants. Therefore, the GDG judged that the balance of effects probably favours surgery over no treatment before IVF.

Other considerations

No studies documented patient values; however, the GDG agreed that most couples would place higher value on maximizing pregnancy and birth outcomes and minimizing harms. The GDG agreed that the resources for surgery (e.g. equipment) and personnel training would result in moderate costs, although some cost variations between countries is expected.

No evidence was found on cost-effectiveness. The GDG noted that because of the costs, treatment with salpingectomy or tubal occlusion before IVF would probably reduce equity in settings with limited public health financing of infertility treatment. The GDG judged that surgery is probably acceptable, noting that while most couples would prefer to avoid invasive treatment, someone with confirmed hydrosalpinx who understands the impact of the condition on their IVF outcome would probably opt for treatment with salpingectomy or tubal occlusion to optimize the chance of success with subsequent IVF. The GDG judged that salpingectomy and tubal occlusion are probably feasible but require surgical facilities and training.

Implementation considerations

→ Caution should be taken during salpingectomy for hydrosalpinx conducted before IVF to avoid compromising the vascular supply to the ovaries, which could potentially result in suboptimal ovarian stimulation. Health care providers may consider several factors to determine whether to offer salpingectomy or tubal occlusion before IVF, for example, the presence of dense adhesions and patient preferences. Health care providers should monitor patients for potential complications after salpingectomy or tubal occlusion.

Research gaps and future guideline update

Future studies should report outcomes related to live birth rates, complications and quality of life, and should compare the different techniques of salpingectomy or tubal occlusion. Future guidance will be required on subgroups that may benefit optimally, for example, based on whether the hydrosalpinx is communicating or not. Future guidance will be required regarding the optimal timing of salpingectomy or tubal occlusion in relation to ovarian stimulation and egg retrieval.

References

1.

Strandell A, Waldenström U, Nilsson L, Hamberger L. Hydrosalpinx reduces in-vitro fertilization/embryo transfer pregnancy rates. Hum Reprod. 1994;9(5):861–3 (10.1093/oxfordjournals.humrep.a138606). [PubMed: 7929732] [CrossRef]

2.

Palagiano A, Cozzolino M, Ubaldi FM, Palagiano C, Coccia ME. Effects of hydrosalpinx on endometrial implantation failures: evaluating salpingectomy in women undergoing in vitro fertilization. Rev Bras Ginecol Obstet. 2021;43(4):304–10 (10.1055/s-0040-1722155). [PMC free article: PMC10183881] [PubMed: 33601465] [CrossRef]

3.

Melo P, Georgiou EX, Johnson N, Voorst SF, Strandell A, Mol BWJ et al. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database Syst Rev. 2020;(10):CD002125 (10.1002/14651858.CD002125.pub4). [PMC free article: PMC8094448] [PubMed: 33091963] [CrossRef]

4.

Strandell A, Lindhard A, Waldenström U, Thorburn J, Janson P, Hamberger L. Hydrosalpinx and IVF outcome: a prospective, randomized multicentre trial in Scandinavia on salpingectomy prior to IVF. Hum Reprod. 1999;14(11):2762–9 (10.1093/humrep/14.11.2762). [PubMed: 10548619] [CrossRef]

5.

Kontoravdis A, Makrakis E, Pantos K, Botsis D, Deligeoroglou E, Creatsas G. Proximal tubal occlusion and salpingectomy result in similar improvement in in vitro fertilization outcome in patients with hydrosalpinx. Fertil Steril. 2006;86(6):1642–9 (10.1016/j.fertnstert.2006.05.032). [PubMed: 17069813] [CrossRef]

6.

Déchaud H, Daurès JP, Arnal F, Humeau C, Hédon B. Does previous salpingectomy improve implantation and pregnancy rates in patients with severe tubal factor infertility who are undergoing in vitro fertilization? A pilot prospective randomized study. Fertil Steril. 1998;69(6):1020–5 (10.1016/s0015-0282(98)00077-6). [PubMed: 9627287] [CrossRef]

7.

Moshin V, Hotineanu A. Reproductive outcome of the proximal tubal occlusion prior to IVF in patients with hydrosalpinx. Abstracts of the 22nd Annual Meeting of ESHRE. Hum Reprod. 2006;21 (Suppl 1):i189–i193 (10.1093/oxfordjournals.humrep.a002507). [CrossRef]

Background and rationale

Options for hydrosalpinx treatment include surgically resecting and removing the affected fallopian tubes (salpingectomy), isolating the hydrosalpinx from the uterine cavity using laparoscopic or hysteroscopic tubal occlusion, transvaginal aspiration of hydrosalpingeal fluid under ultrasound guidance or draining the hydrosalpingeal fluid by means of salpingostomy (1). For this recommendation, the GDG addressed the question: should transvaginal aspiration of hydrosalpingeal fluid versus no treatment be used in tubal disease in women with hydrosalpinx who are due to undergo IVF?

Balancing harms and benefits

A systematic review published in 2020 was identified, with a search date from inception of the databases up to January 2020 (1). From this systematic review, three RCTs published between 2008 and 2015 provided data for the outcomes (2–4).

The results showed that transvaginal aspiration before IVF may result in a small increase in pregnancies and no differences in ectopic pregnancy or miscarriage compared to no treatment before IVF. There may be 96 more clinical pregnancies (from 12 to 226 more) per 1000 with transvaginal aspiration (RR: 1.64; 95% CI: 1.08–2.51), 12 more miscarriages (from 27 fewer to 118 more) per 1000 (RR: 1.24; 95% CI: 0.46–3.36) and five fewer ectopic pregnancies (from 13 fewer to 54 more) per 1000 (RR: 0.69; 95% CI: 0.10–4.62).

Live births and quality of life outcomes were not reported. In addition, there may be no difference in pelvic infection, but a slight increase in multiple pregnancy, which is likely attributable to IVF treatment: transvaginal aspiration may result in zero fewer pelvic infections per 1000 (RD: 0; 95% CI: −0.03 to 0.03) and 53 more multiple pregnancies (from 19 fewer to 373 more) per 1000 (RR: 2.33; 95% CI: 0.52–10.32). There may also be an important proportion of women with recurrence after transvaginal aspiration; the number of other major or minor complications is low. Overall, recurrence with or without sclerotherapy occurred in 27% (18–39%). More specifically, without sclerotherapy, recurrence was 53% (46–60%); with sclerotherapy, it was 14% (8–22%). Major complications occurred in 10 out of 1297 (0.7%) and minor complications (e.g. pain, extravasation, ruptured cyst, flush reactions and gastrointestinal discomfort) in 80 out of 1297 (6%). Based on these data, the GDG judged that there may be small desirable and undesirable effects of transvaginal aspiration compared to no treatment before IVF.

The certainty of evidence was judged to be very low because of inconsistent blinding of participants and outcome assessors, loss to follow-up and few events or participants; some studies were not comparative. Although the GDG agreed that most people would place higher value on pregnancy and birth outcomes, while wanting to minimize harms, they judged that the balance of effects probably does not favour either transvaginal aspiration or no treatment.

Other considerations

The GDG agreed that the resources for transvaginal aspiration would result in moderate costs. No data were found on cost-effectiveness; however, the GDG considered that transvaginal aspiration would probably not be cost-effective because of the moderate costs, small benefits and small harms. No studies of the impact on health equity were available; however, the GDG judged that in women receiving IVF, the addition of transvaginal aspiration of hydrosalpingeal fluid before IVF would probably reduce equity because of additional costs.

No data were identified on acceptability; however, the GDG judged that transvaginal aspiration would probably not be acceptable given that most people would like to avoid an invasive procedure when there may be little benefit compared to harm. Nevertheless, the GDG judged that transvaginal aspiration is probably feasible, noting that ultrasound is available in most settings as a basic tool for gynaecological assessment; training of health care providers is required to perform transvaginal aspiration safely.

Implementation considerations

→ Health care providers should monitor patients for potential complications after treatment of hydrosalpinx, including post-aspiration infection, recurrence of fluid accumulation and accumulation of fluid in the endometrial cavity. Health care providers should note that transvaginal aspiration may only be offered if salpingectomy and tubal occlusion are not available or feasible.

Research gaps and future guideline update

Future guidance comparing transvaginal aspiration with salpingectomy or tubal occlusion should report outcomes related to live birth rates and surgical complications, optimal timing of procedures in relation to ovarian stimulation and oocyte retrieval or embryo transfer, and quality of life. Further guidance will be required regarding whether antibiotic prophylaxis should be used routinely if transvaginal aspiration is provided before IVF.

References

1.

Melo P, Georgiou EX, Johnson N, Voorst SF, Strandell A, Mol BWJ et al. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database Syst Rev. 2020;(10):CD002125 (10.1002/14651858.CD002125.pub4). [PMC free article: PMC8094448] [PubMed: 33091963] [CrossRef]

2.

An J, Ni Y, Liu X, Gao X, Wang Y. Effects of transvaginal aspiration of hydrosalpinx combined auricular point sticking on IVF-ET outcomes [article in Chinese]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2015;35(6):682–5 (in Chinese). [PubMed: 26242119]

3.

Hammadieh N, Coomarasamy A, Ola B, Papaioannou S, Afnan M, Sharif K. Ultrasound-guided hydrosalpinx aspiration during oocyte collection improves pregnancy outcome in IVF: a randomized controlled trial. Hum Reprod. 2008;23(5):1113–7 (10.1093/humrep/den071). [PubMed: 18343810] [CrossRef]

4.

Fouda UM, Sayed AM. Effect of ultrasound-guided aspiration of hydrosalpingeal fluid during oocyte retrieval on the outcomes of in vitro fertilisation-embryo transfer: a randomised controlled trial (NCT01040351). Gynecol Endocrinol. 2011;27(8):562–7 (10.3109/09513590.2010.507290). [PubMed: 20672903] [CrossRef]