Improving the outcome of embryo transfer

Published 13 April 2022

A substantial meta-analysis of 38 interventions evaluated in 188 eligible trials found that three – the use of ultrasound guidance, soft catheters and hyaluronic acid at the time of ET – appeared to improve pregnancy rates; bed rest post-ET was associated with a reduction and ‘should not be recommended’.

Optimising embryo transfer (ET) – both fresh and frozen – is fundamental to the success of fertility treatment. Yet a lack of consensus over best practice has left clinics with the dilemma of how to choose from the numerous competing (and ever-growing) interventions available.
The most recent published ET guideline was in 2016 from the ASRM, while one from ESHRE on the number of embryos to transfer is expected soon.(1,2) Since then more than a dozen ‘add-on’ therapies have emerged, further complicating the safety and efficacy debate.

Now, a thoroughly comprehensive systematic review and meta-analysis of the most up-to-date evidence on ET techniques and interventions has sought to provide clarity.(3) Based on data relating to 59,530 women undergoing IVF/ICSI and studies of 38 interventions, the main outcomes show clinical pregnancy rates appear to be increased at the time of ET by several commonly adopted techniques, namely ultrasound (versus clinical touch), soft (vs hard) catheters, and addition of hyaluronic acid as an ‘adherence’ agent to the transfer medium (vs routine care).

The UK-based research group say three other approaches appear to have similar benefits, but warrant larger RCTs before adoption in everyday practice. These are atosiban, granulocyte colony-stimulating factor (G-CSF), and hCG supplementation (found to be the most commonly evaluated pharmacological intervention).

Conversely, bedrest (vs no rest or immediate ambulation) was the only intervention that significantly reduced pregnancy rates (RR 0.857) and is not recommended post ET, consistent with the ASRM guidance. Indeed, the review identified ‘a substantial number’ of unnecessary interventions which lack sufficient evidence to support their effectiveness and safety. ‘Such interventions should not be routinely recommended in clinical practice’ until assessed in future RCTs,’ the authors conclude.

A total of 188 RCTs were selected for the systematic review/meta-analysis, although the authors highlight significant concerns around the methodology and high risk of publication bias (45% of trials). Described as of moderate and low quality, the RCT data limited their ability to estimate other important outcomes, such as miscarriage and live birth, and factors such as number of embryos transferred, transfer of fresh vs frozen, and patient characteristics (BMI for example) which might have affected ET transfer outcomes.

Nevertheless, the authors say the widespread use of ultrasound guidance and soft ET catheters was supported by a large body of good quality evidence, and their findings fill a knowledge gap in an area where suboptimal practice is often linked to the failure of treatment cycles and to reduced pregnancy rates.

A total of 38 interventions were featured among the RCTs assessed by the authors, who selected them from a search of MEDLINE, EMBASE and Cochrane CENTRAL from inception until March 2021. Most RCTs featured fresh ET (51%), and 11% frozen or fresh; studies excluded from the analysis included those reporting IUI treatments or ovulation induction. Otherwise, the study evaluated any intervention introduced 24 hours before/after ET following any treatment aiming to improve implantation rates in couples. The primary outcome was clinical pregnancy rate post ET, which was confirmed as a viable pregnancy on ultrasound.

The findings for procedures whch appeared to improve pregnancy rates were as follows: ultrasound (versus clinical touch) (RR 1.265), soft (vs hard) catheters (RR 1.122), and use of hyaluronic acid (vs routine care) (RR 1.457). For those pharmacological agents with apparent promise, the results were as follows: atosiban to promote uterine relaxation (RR 1.493), the growth factor G-CSF at the time of ET (RR 1.774), and hCG supplementation at the time of ET, the most commonly evaluated intervention (RR 1.232). Uterine relaxation is a mechanism common to these interventions. The authors say this could be a possible explanation for an apparent improvement in pregnancy rates through maximising this effect at the time of ET and optimising endometrial receptivity.

A major implication for clinical practice from this systematic review is the substantial number of interventions which do not meaningfully enhance reproductive outcomes. The list includes relaxation interventions such as acupuncture and massage therapy, as well as other commonly used approaches such as non-steroidal anti-inflammatory drugs or prophylactic antibiotics. The authors say there is a ‘lack sufficient evidence in support of their effectiveness and safety’ and so far cannot be recommended.

The current ASRM guideline recommend cervical mucus removal, yet this latest review found no benefit based on evidence from five RCTs. The message from this, say the authors, is that professional societies need to ‘champion’ reviews based on the most current evidence in order to regularly update clinical practice guidelines.
Given the many interventions suggested to patients, including those that count as experimental, the overall conclusion – as ever - is that robust evidence in the form of larger well-conducted RCTs is vital. The authors say this would protect women undergoing ET from harmful or unnecessary treatments, and these trials should involve patient input.

1 Penzias A, Bendikson K, Butts S, et al. Performing embryo transfer: a committee opinion. Fertil Steril 2017; 107: 882-896. doi: 10.1016/j.fertnstert.2017.01.025.
2. See https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Guidelines-in-development
3. Tyler B, Walford H, Tamblyn J, et al. Interventions to optimize embryo transfer in women undergoing assisted conception: a comprehensive systematic review and meta-analyses. Hum Reprod Update 2022; doi.org/10.1093/humupd/dmac009

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