Interventions to optimize embryo transfer in women undergoing assisted conception: a comprehensive systematic review and meta-analyses

Abstract

Background: Several interventions and techniques are suggested to improve the outcome of embryo transfer (ET) in assisted conception. However, there remains no consensus on the optimal practice, with high variations among fertility specialists.

Objective and rationale: We conducted a comprehensive systematic review and meta-analyses of randomized controlled trials (RCTs) aiming to identify effective interventions that could be introduced around the time of ET to improve reproductive outcomes.

Search methods: We searched the electronic databases (MEDLINE, EMBASE and Cochrane CENTRAL) from inception until March 2021 using a multi-stage search strategy of MeSH terms and keywords, and included all RCTs that evaluated an intervention in the 24-h period before/after ET in women undergoing IVF/ICSI. Our primary outcome was clinical pregnancy rate post-ET confirmed as viable pregnancy on ultrasound scan. We assessed the risk of bias in included trials and extracted data in duplicate. We pooled data using a random-effect meta-analysis and reported using risk ratio (RR) with 95% CI. We explored publication bias and effect modifiers using subgroup analyses.

Outcomes: Our search yielded 3685 citations of which we included 188 RCTs (38 interventions, 59 530 participants) with a median sample size of 200 (range 26-1761). The quality of included RCTs was moderate with most showing a low risk of bias for randomization (118/188, 62.8%) and attrition (105/188, 55.8%) but there was a significant risk of publication bias (Egger's test P = 0.001). Performing ET with ultrasound guidance versus clinical touch (n = 24, RR 1.265, 95% CI 1.151-1.391, I2 = 38.53%), hyaluronic acid versus routine care (n = 9, RR 1.457, 95% CI 1.197-1.261, I2 = 46.48%) and the use of a soft versus hard catheter (n = 27, RR 1.122, 95% CI 1.028-1.224, I2 = 57.66%) led to higher clinical pregnancy rates. Other pharmacological add-ons also showed a beneficial effect including granulocyte colony-stimulating factor (G-CSF: n = 4, RR 1.774, 95% CI 1.252-2.512, I2 = 0), Atosiban (n = 7, RR 1.493, 95% CI 1.184-1.882, I2 = 68.27%) and hCG (n = 17, RR 1.232, 95% CI 1.099-1.382, I2 = 57.76%). Bed rest following ET was associated with a reduction in clinical pregnancy (n = 6, RR 0.857, 95% CI 0.741-0.991, I2 = 0.01%). Other commonly used interventions, such as non-steroidal anti-inflammatory drugs, prophylactic antibiotics, acupuncture and cervical mucus removal, did not show a significant benefit on reproductive outcomes. Our effect estimates for other important outcomes, including miscarriage and live birth, were limited by the varied reporting across included RCTs.

Wider implications: Using ultrasound guidance, soft catheters and hyaluronic acid at the time of ET appears to increase clinical pregnancy rates. The use of Atosiban, G-CSF and hCG showed a trend towards increased clinical pregnancy rate, but larger trials are required before adopting these interventions in clinical practice. Bed rest post-ET was associated with a reduction in clinical pregnancy and should not be recommended.

Keywords: ICSI; IVF; assisted conception; embryo transfer; meta-analysis; systematic review.

Figure 1.

Selection and inclusion process for randomized controlled trials evaluating interventions at the time of embryo transfer in women undergoing assisted reproduction.

Figure 2.

Risk of bias in included randomized controlled trials evaluating interventions at the time of embryo transfer in women undergoing assisted reproduction.

Figure 3.

Funnel plot evaluating the risk of publication bias in randomized controlled trials evaluating interventions at the time of embryo transfer in women undergoing assisted reproduction.

Figure 4.

Summary forest plots of effect estimates of evaluated interventions at the time of embryo transfer on the reproductive outcomes in women undergoing assisted reproduction. G-CSF, granulocyte colony-stimulating factor; TA, transabdominal; TV, transvaginal; CT, computerized tomography; NSAID, non-steroidal anti-inflammatory drug; RCT, randomized controlled trial; HA, hyaluronic acid.