Follicular flushing during oocyte retrieval in assisted reproductive techniques.

BACKGROUND: Follicular aspiration under transvaginal ultrasound guidance is routinely performed as part of assisted reproductive technology (ART) to retrieve oocytes for in vitro fertilisation (IVF). The process involves aspiration of the follicular fluid followed by the introduction of flush, typically culture media, back into the follicle followed by re-aspiration. However, there is a degree of controversy as to whether this intervention yields a larger number of oocytes and is hence associated with greater potential for pregnancy than aspiration only. OBJECTIVES: To assess the safety and efficacy of follicular flushing as compared with aspiration only performed in women undergoing ART. SEARCH METHODS: We searched the following electronic databases up to 13 July 2021: the Cochrane Gynaecology and Fertility Specialised Register of Controlled Trials, CENTRAL (containing output from two trial registries and CINAHL), MEDLINE, Embase, and PsycINFO. We also searched LILACS, Google Scholar, and Epistemonikos. We reviewed the reference lists of relevant papers and contacted experts in the field to identify further relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared follicular aspiration and flushing with aspiration alone in women undergoing ART using their own gametes. Primary outcomes were live birth rate and miscarriage rate per woman randomised. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies identified by search against the inclusion criteria, extracted data, and assessed risk of bias. A third review author was consulted if required. We contacted study authors as needed. We analysed dichotomous outcomes using Mantel-Haenszel odds ratios (ORs), 95% confidence intervals (CIs), and a fixed-effect model, and we analysed continuous outcomes using mean differences (MDs) between groups presented with 95% CIs. We examined the heterogeneity of studies via the I2 statistic. We assessed the certainty of evidence using the GRADE approach. MAIN RESULTS: We included 15 studies with a total of 1643 women. Fourteen studies reported outcomes per woman randomised, and one study reported outcomes per ovary. No studies were at low risk of bias across all domains; the main limitation was lack of blinding. The certainty of the evidence ranged from moderate to very low, and was downgraded for risk of bias, imprecision, and inconsistency. We are uncertain of the effect of follicular flushing on live birth rate compared to aspiration alone (OR 0.93, 95% CI 0.59 to 1.46; 4 RCTs; n = 467; I2 = 0%; moderate-certainty evidence). This suggests that with a live birth rate of approximately 30% with aspiration alone, the equivalent live birth rate with follicular flushing lies between 20% and 39%.  We are uncertain of the effect of follicular flushing on miscarriage rate compared to aspiration alone (OR 1.98, 95% CI 0.18 to 22.22; 1 RCT; n = 164; low-certainty evidence). This suggests that with a miscarriage rate of approximately 1% with aspiration alone, the equivalent miscarriage rate with follicular flushing lies between 0% and 22%. We are uncertain of the effect of follicular flushing on oocyte yield (MD -0.47 oocytes, 95% CI -0.72 to -0.22; 9 RCTs; n = 1239; I2 = 61%; very low-certainty evidence); total number of embryos (MD -0.10 embryos, 95% CI -0.34 to 0.15; 2 RCTs; n = 160; I2 = 58%; low-certainty evidence); and clinical pregnancy rate (OR 1.12, 95% CI 0.85 to 1.51; 7 RCTs; n = 939; I2 = 46%; low-certainty evidence). The duration of the retrieval process may be longer with flushing (MD 175.44 seconds, 95% CI 152.57 to 198.30; 7 RCTs; n = 785; I2 = 87%; low-certainty evidence). It was not possible to perform a meta-analysis for adverse events, although individual studies reported on outcomes ranging from depression and anxiety to pain and pelvic organ injury. AUTHORS' CONCLUSIONS: The effect of follicular flushing on both live birth and miscarriage rates compared with aspiration alone is uncertain. Although the evidence does not permit any firm conclusions on the impact of follicular flushing on oocyte yield, total number of embryos, number of cryopreserved embryos, or clinical pregnancy rate, it may be that the procedure itself takes longer than aspiration alone. The evidence was insufficient to permit any firm conclusions with respect to adverse events or safety.

Surgical treatment for tubal disease in women due to undergo in vitro fertilisation.

BACKGROUND: Tubal disease accounts for 20% of infertility cases. Hydrosalpinx, caused by distal tubal occlusion leading to fluid accumulation in the tube(s), is a particularly severe form of tubal disease negatively affecting the outcomes of assisted reproductive technology (ART). It is thought that tubal surgery may improve the outcome of ART in women with hydrosalpinges. OBJECTIVES: To assess the effectiveness and safety of tubal surgery in women with hydrosalpinges prior to undergoing conventional in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, DARE, and two trial registers on 8 January 2020, together with reference checking and contact with study authors and experts in the field to identify additional trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing surgical treatment versus no surgical treatment, or comparing surgical interventions head-to-head, in women with tubal disease prior to undergoing IVF. DATA COLLECTION AND ANALYSIS: We used Cochrane's standard methodological procedures. The primary outcomes were live birth rate (LBR) and surgical complication rate per woman randomised. Secondary outcomes included clinical, multiple and ectopic pregnancy rates, miscarriage rates and mean numbers of oocytes retrieved and of embryos obtained. MAIN RESULTS: We included 11 parallel-design RCTs, involving a total of 1386 participants. The included trials compared different types of tubal surgery (salpingectomy, tubal occlusion or transvaginal aspiration of hydrosalpingeal fluid) to no tubal surgery, or individual interventions to one another. We assessed no studies as being at low risk of bias across all domains, with the main limitations being lack of blinding, wide confidence intervals and low event and sample sizes. We used GRADE methodology to rate the quality of the evidence. Apart from one moderate-quality result in one review comparison, the evidence provided by these 11 trials ranged between very low- to low-quality. Salpingectomy versus no tubal surgery No included study reported on LBR for this comparison. We are uncertain of the effect of salpingectomy on surgical complications such as the rate of conversion to laparotomy (Peto odds ratio (OR) 5.80, 95% confidence interval (CI) 0.11 to 303.69; one RCT; n = 204; very low-quality evidence) and pelvic infection (Peto OR 5.80, 95% CI 0.11 to 303.69; one RCT; n = 204; very low-quality evidence). Salpingectomy probably increases clinical pregnancy rate (CPR) versus no surgery (risk ratio (RR) 2.02, 95% CI 1.44 to 2.82; four RCTs; n = 455; I2 = 42.5%; moderate-quality evidence). This suggests that in women with a CPR of approximately 19% without tubal surgery, the rate with salpingectomy lies between 27% and 52%. Proximal tubal occlusion versus no surgery No study reported on LBR and surgical complication rate for this comparison. Tubal occlusion may increase CPR compared to no tubal surgery (RR 3.21, 95% CI 1.72 to 5.99; two RCTs; n = 209; I2 = 0%; low-quality evidence). This suggests that with a CPR of approximately 12% without tubal surgery, the rate with tubal occlusion lies between 21% and 74%. Transvaginal aspiration of hydrosalpingeal fluid versus no surgery No study reported on LBR for this comparison, and there was insufficient evidence to identify a difference in surgical complication rate between groups (Peto OR not estimable; one RCT; n = 176). We are uncertain whether transvaginal aspiration of hydrosalpingeal fluid increases CPR compared to no tubal surgery (RR 1.67, 95% CI 1.10 to 2.55; three RCTs; n = 311; I2 = 0%; very low-quality evidence). Laparoscopic proximal tubal occlusion versus laparoscopic salpingectomy We are uncertain of the effect of laparoscopic proximal tubal occlusion versus laparoscopic salpingectomy on LBR (RR 1.21, 95% CI 0.76 to 1.95; one RCT; n = 165; very low-quality evidence) and CPR (RR 0.81, 95% CI 0.62 to 1.07; three RCTs; n = 347; I2 = 77%; very low-quality evidence). No study reported on surgical complication rate for this comparison. Transvaginal aspiration of hydrosalpingeal fluid versus laparoscopic salpingectomy No study reported on LBR for this comparison, and there was insufficient evidence to identify a difference in surgical complication rate between groups (Peto OR not estimable; one RCT; n = 160). We are uncertain of the effect of transvaginal aspiration of hydrosalpingeal fluid versus laparoscopic salpingectomy on CPR (RR 0.69, 95% CI 0.44 to 1.07; one RCT; n = 160; very low-quality evidence). AUTHORS' CONCLUSIONS: We found moderate-quality evidence that salpingectomy prior to ART probably increases the CPR compared to no surgery in women with hydrosalpinges. When comparing tubal occlusion to no intervention, we found that tubal occlusion may increase CPR, although the evidence was of low quality. We found insufficient evidence of any effect on procedure- or pregnancy-related adverse events when comparing tubal surgery to no intervention. Importantly, none of the studies reported on long term fertility outcomes. Further high-quality trials are required to definitely determine the impact of tubal surgery on IVF and pregnancy outcomes of women with hydrosalpinges, particularly for LBR and surgical complications; and to investigate the relative efficacy and safety of the different surgical modalities in the treatment of hydrosalpinges prior to ART.

Long-term GnRH agonist therapy before in vitro fertilisation (IVF) for improving fertility outcomes in women with endometriosis.

BACKGROUND: Endometriosis is known to have an impact on fertility and it is common for women affected by endometriosis to require fertility treatments, including in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI), to improve the chance of pregnancy. It has been postulated that long-term gonadotrophin-releasing hormone (GnRH) agonist therapy prior to IVF or ICSI can improve pregnancy outcomes. This systematic review supersedes the previous Cochrane Review on this topic (Sallam 2006). OBJECTIVES: To determine the effectiveness and safety of long-term gonadotrophin-releasing hormone (GnRH) agonist therapy (minimum 3 months) versus no pretreatment or other pretreatment modalities, such as long-term continuous combined oral contraception (COC) or surgical therapy of endometrioma, before standard in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) in women with endometriosis. SEARCH METHODS: We searched the following electronic databases from their inception to 8 January 2019: Cochrane Gynaecology and Fertility Specialised Register of Controlled Trials, CENTRAL via the Cochrane CENTRAL Register of Studies ONLINE (CRSO), MEDLINE, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL). We searched trial registries to identify unpublished and ongoing trials. We also searched DARE (Database of Abstracts of Reviews of Effects), Web of Knowledge, OpenGrey, Latin American and Caribbean Health Science Information Database (LILACS), PubMed, Google and reference lists from relevant papers for any other relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) involving women with surgically diagnosed endometriosis that compared use of any type of GnRH agonist for at least three months before an IVF/ICSI protocol to no pretreatment or other pretreatment modalities, specifically use of long-term continuous COC (minimum of 6 weeks) or surgical excision of endometrioma within six months prior to standard IVF/ICSI. The primary outcomes were live birth rate and complication rate per woman randomised. DATA COLLECTION AND ANALYSIS: Two independent review authors assessed studies against the inclusion criteria, extracted data and assessed risk of bias. A third review author was consulted, if required. We contacted the study authors, as required. We analysed dichotomous outcomes using Mantel-Haenszel risk ratios (RRs), 95% confidence intervals (CIs) and a fixed-effect model. For small numbers of events, we used a Peto odds ratio (OR) with 95% CI instead. We analysed continuous outcomes using the mean difference (MD) between groups and presented with 95% CIs. We studied heterogeneity of the studies via the I2 statistic. We assessed the quality of evidence using GRADE criteria. MAIN RESULTS: We included eight parallel-design RCTs, involving a total of 640 participants. We did not assess any of the studies as being at low risk of bias across all domains, with the main limitation being lack of blinding. Using GRADE methodology, the quality of the evidence ranged from very low to low quality. Long-term GnRH agonist therapy versus no pretreatment We are uncertain whether long-term GnRH agonist therapy affects the live birth rate (RR 0.48, 95% CI 0.26 to 0.87; 1 RCT, n = 147; I2 not calculable; very low-quality evidence) or the overall complication rate (Peto OR 1.23, 95% CI 0.37; to 4.14; 3 RCTs, n = 318; I2 = 73%; very low-quality evidence) compared to standard IVF/ICSI. Further, we are uncertain whether this intervention affects the clinical pregnancy rate (RR 1.13, 95% CI 0.91 to 1.41; 6 RCTs, n = 552, I2 = 66%; very low-quality evidence), multiple pregnancy rate (Peto OR 0.14, 95% CI 0.03 to 0.56; 2 RCTs, n = 208, I2 = 0%; very low-quality evidence), miscarriage rate (Peto OR 0.45, 95% CI 0.10 to 2.00; 2 RCTs, n = 208; I2 = 0%; very low-quality evidence), mean number of oocytes (MD 0.72, 95% CI 0.06 to 1.38; 4 RCTs, n = 385; I2 = 81%; very low-quality evidence) or mean number of embryos (MD -0.76, 95% CI -1.33 to -0.19; 2 RCTs, n = 267; I2 = 0%; very low-quality evidence). Long-term GnRH agonist therapy versus long-term continuous COC No studies reported on this comparison. Long-term GnRH agonist therapy versus surgical therapy of endometrioma No studies reported on this comparison. AUTHORS' CONCLUSIONS: This review raises important questions regarding the merit of long-term GnRH agonist therapy compared to no pretreatment prior to standard IVF/ICSI in women with endometriosis. Contrary to previous findings, we are uncertain as to whether long-term GnRH agonist therapy impacts on the live birth rate or indeed the complication rate compared to standard IVF/ICSI. Further, we are uncertain whether this intervention impacts on the clinical pregnancy rate, multiple pregnancy rate, miscarriage rate, mean number of oocytes and mean number of embryos. In light of the paucity and very low quality of existing data, particularly for the primary outcomes examined, further high-quality trials are required to definitively determine the impact of long-term GnRH agonist therapy on IVF/ICSI outcomes, not only compared to no pretreatment, but also compared to other proposed alternatives to endometriosis management.

Follicular flushing during oocyte retrieval in assisted reproductive techniques.

BACKGROUND: Follicular aspiration under transvaginal ultrasound guidance is routinely performed as part of assisted reproductive technology (ART) to retrieve oocytes for in vitro fertilisation (IVF). However, controversy as to whether follicular flushing following aspiration yields a larger number of oocytes and hence is associated with greater potential for pregnancy than aspiration only is ongoing. OBJECTIVES: To assess the safety and efficacy of follicular flushing as compared with aspiration only performed in women undergoing ART. SEARCH METHODS: We searched the following electronic databases up to 18 July 2017: Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, the CENTRAL Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We also searched the trial registries ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform to identify ongoing and registered trials up to 4 July 2017. We reviewed the reference lists of reviews and retrieved studies to identify further potentially relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared follicular aspiration and flushing with aspiration alone in women undergoing ART using their own gametes. Primary outcomes were live birth rate and miscarriage rate per woman randomised. DATA COLLECTION AND ANALYSIS: Two independent review authors assessed studies against the inclusion criteria, extracted data, and assessed risk of bias. A third review author was consulted if required. We contacted study authors as required. We analysed dichotomous outcomes using Mantel-Haenszel odds ratios (ORs), 95% confidence intervals (CIs), and a fixed-effect model, and we analysed continuous outcomes using mean differences (MDs) between groups presented with 95% CIs. We examined the heterogeneity of studies via the I2 statistic. We assessed the quality of evidence by using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) criteria. MAIN RESULTS: We included ten studies, with a total of 928 women. All included studies reported outcomes per woman randomised. We assessed no studies as being at low risk of bias across all domains and found that the main limitation was lack of blinding. Using the GRADE method, we determined that the quality of the evidence ranged from moderate to very low, and we identified issues arising from risk of bias, imprecision, and inconsistency.Comparing follicular flushing to aspiration alone revealed probably little or no difference in the live birth rate (OR 0.95, 95% CI 0.58 to 1.56; three RCTs; n = 303; I2 = 30%; moderate-quality evidence). This suggests that with a live birth rate of approximately 41% with aspiration alone, the equivalent live birth rate with follicular flushing is likely to lie between 29% and 52%. None of the included studies reported on the primary outcome of miscarriage rate.Data show probably little or no difference in oocyte yield (MD -0.28 oocytes, 95% CI -0.64 to 0.09; six RCTs; n = 708; I2 = 0%; moderate-quality evidence). Very low-quality evidence suggests that the duration of oocyte retrieval was longer in the follicular flushing group than in the aspiration only group (MD 166.01 seconds, 95% CI 141.96 to 190.06; six RCTs; n = 714; I2 = 88%). We found no evidence of a difference in the total number of embryos per woman randomised (MD -0.10 embryos, 95% CI -0.34 to 0.15; two RCTs; n = 160; I2 = 58%; low-quality evidence) and no evidence of a difference in the number of embryos cryopreserved (meta-analysis not possible). Data show probably little or no difference in the clinical pregnancy rate (OR 1.07, 95% CI 0.78 to 1.46; five RCTs; n = 704; I2 = 49%; moderate-quality evidence). Only two studies reported on adverse outcomes: One reported no differences in patient-reported adverse outcomes (depression, anxiety, and stress), and the other reported no differences in needle blockage, vomiting, and hypotension. No studies reported on safety. AUTHORS' CONCLUSIONS: This review suggests that follicular flushing probably has little or no effect on live birth rates compared with aspiration alone. None of the included trials reported on effects of follicular aspiration and flushing on the miscarriage rate. Data suggest little or no difference between follicular flushing and aspiration alone with respect to oocyte yield, total embryo number, or number of cryopreserved embryos. In addition, follicular flushing probably makes little or no difference in the clinical pregnancy rate. Evidence was insufficient to allow any firm conclusions with respect to adverse events or safety.

Human chorionic gonadotrophin priming for fertility treatment with in vitro maturation.

BACKGROUND: In vitro maturation (IVM) is a fertility treatment that involves the transvaginal retrieval of immature oocytes, and their subsequent maturation and fertilisation. Although the live birth rate is lower than conventional in vitro fertilisation (IVF) with ovarian stimulation, it is a useful treatment, as it avoids the risk of ovarian hyperstimulation syndrome (OHSS). Women with polycystic ovaries (PCO) or polycystic ovarian syndrome (PCOS) are at an increased risk of OHSS. Thus, IVM may be a more useful treatment in this patient group.Strategies to maximise the maturation rates of the immature oocytes are important. This review focuses on the administration of human chorionic gonadotrophin (hCG) prior to immature oocyte retrieval. OBJECTIVES: To determine the effectiveness and safety of hCG priming in subfertile women who are undergoing IVM treatment in the context of assisted reproduction. SEARCH METHODS: We searched the following electronic databases up to 29 August 2016: Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, PsycINFO, and CINAHL. We also searched the trial registries ClinicalTrials.gov and WHO ICTPR to identify ongoing and registered trials. We sought recently published papers not yet indexed in the major databases, and reviewed the reference lists of reviews and retrieved studies as sources of potentially relevant studies. There were no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared hCG priming with placebo or no priming in women undergoing IVM. We also included RCTs that compared different doses of hCG, or the timing of oocyte retrieval. The primary outcomes were live birth rate and miscarriage rate per woman randomised. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, and with a third author, assessed risk of bias and extracted data. We contacted the original authors where data were missing. For dichotomous outcomes, we used the Mantel-Haenszel method to calculate odds ratios (OR). For continuous outcomes, we calculated the mean differences (MD) between treatment groups. We assessed statistical heterogeneity using the I² statistic. We assessed the overall quality of the evidence using GRADE methods. MAIN RESULTS: We included four studies, with a total of 522 women, in the review. One of these studies did not report outcomes per woman randomised, and so was not included in formal analysis. Three studies investigated 10,000 units hCG priming compared to no priming. One study investigated 20,000 units hCG compared to 10,000 units hCG priming. Three studies only included women with PCOS (N = 122), while this was an exclusion criteria in the fourth study (N = 400).We rated all four studies as having an unclear risk of bias in more than one of the seven domains assessed. The quality of the evidence was low, the main limitations being lack of blinding and imprecision.When 10,000 units hCG priming was compared to no priming, we found no evidence of a difference in the live birth rates per woman randomised (OR 0.65, 95% confidence intervals (CI) 0.24 to 1.74; one RCT; N = 82; low quality evidence); miscarriage rate (OR 0.60, 95% CI 0.21 to 1.72; two RCTs; N = 282; I² statistic = 21%; low quality evidence), or clinical pregnancy rate (OR 0.52, 95% CI 0.26 to 1.03; two RCTs, N = 282, I² statistic = 0%, low quality evidence). Though inconclusive, our findings suggested that hCG may be associated with a reduction in clinical pregnancy rates; 22% of women who received no priming achieved pregnancy, while between 7% and 23% of women who received hCG priming did so.The study comparing 20,000 units hCG with 10,000 units hCG did not report sufficient data to enable us to calculate odds ratios.No studies reported on adverse events (other than miscarriage) or drug reactions. AUTHORS' CONCLUSIONS: This review found no conclusive evidence that hCG priming had an effect on live birth, pregnancy, or miscarriage rates in IVM. There was low quality evidence that suggested that hCG priming may reduce clinical pregnancy rates, however, these findings were limited by the small number of data included. As no data were available on adverse events (other than miscarriage) or on drug reactions, we could not adequately assess the safety of hCG priming. We need further evidence from well-designed RCTs before we can come to definitive conclusions about the role of hCG priming, and the optimal dose and timing.