No benefit from laser-assisted hatching for subfertile couples

Assisted hatching

Published 02 November 2023

Fertility clinics should tell patients that there is no evidence that assisted hatching works, nor any guarantee that the add-on treatment is risk-free. This information should be provided before offering couples this adjuvant technique.

This is the message from the authors of a double-blinded, multicentre randomised controlled trial (RCT) (1) that also suggests that fertility providers should offer assisted hatching at no extra cost, and preferably only provide assisted hatching within a clinical trial setting.

Based on more than 500 couples with recurrent implantation failure (RIF), the findings cast yet more doubt on the benefits of adjuvant fertility treatments which have been criticised by regulators for being costly and ineffective.

The study failed to find any statistically significant evidence that assisted hatching – a procedure developed more than 30 years ago to facilitate sperm penetration – improves live birth rates (LBR) among subfertile RIF patients.

Moreover, the Dutch team who carried out the RCT write that they cannot ‘exclude the possibility that assisted hatching decreases the live birth rates.’

Such is the controversy around add-ons that more than 200 comments were received by a (now closed) stakeholder review of the first ESHRE guidance (2) on adjuvants. The ESHRE Add-ons working group reviewed 27 treatments and none are recommended for routine clinical practice in the final good practice document published recently in Human Reproduction.

In the case of assisted hatching, some meta-analyses have suggested that poor prognosis women, especially RIF patients, might benefit most from this technique. However, the committee who drew up ESHRE’s recently published recommendations on RIF (3) state that the phenomenon has become associated with poor and even exploitative practice, and advises against ‘uncontrolled use’ of add-ons.

The ESHRE RIF guidance was not available when this RCT was carried out in the Netherlands. But the authors do reference the knowledge gap around assisted hatching with a recent Cochrane review concluding the quality of evidence is very low to low.

As such, the study designed the RCT to show if assisted hatching does/does not increase the cumulative LBR in subfertile couples who experience RIF.

The study was performed at the laboratory sites of three tertiary referral hospitals and two university medical centres in the Netherlands. Participants were eligible for inclusion after having had either at least two consecutive fresh IVF or ICSI embryo transfers.

This included transfer of frozen and thawed embryos originating from those fresh cycles, and which did not result in a pregnancy; or at least one fresh IVF or ICSI transfer and at least two frozen embryo transfers with embryos originating from that fresh cycle which did not result in a pregnancy.

Participants were included and randomised from November 2012 until November 2017. A total of 297 subfertile couples were allocated to the assisted hatching and 295 to the control to demonstrate a statistically significant absolute increase in live birth rate of 10% after assisted hatching.

Block randomisation (n=20 participants per block) was applied and randomisation was concealed from participants, treating physicians, and laboratory staff involved in the embryo transfer procedure.

Ovarian hyperstimulation, oocyte retrieval, laboratory procedures, embryo selection for transfer and cryopreservation, the transfer itself, and luteal support were performed according to local protocols.

Procedures were identical in both the intervention and control arm of the study with the exception of the assisted hatching, which was only performed in the intervention group. Laboratory staff performing the assisted hatching were not involved in the embryo transfer itself.

Results showed that the cumulative LBR per started cycle, including the transfer of fresh and subsequent frozen/thawed embryos if applicable, resulted in 77 live births in the assisted hatching group (n=297, 25.9%) and 68 live births in the control group (n=295, 23.1%). This did not prove to be statistically significant (relative risk: 1.125, 95% CI: 0.847 to 1.494, P=0.416).

Miscarriage rates were shown to decrease after assisted hatching, a finding that was statistically significant. However, the authors suggest this may be down to chance and caution that this should not be used as an indication for offering the add-on.

The authors acknowledge that a small cohort of subfertile couples who did not achieve an ongoing pregnancy still had cryopreserved embryos in storage at the endpoint of the trial (1 year after the last randomisation).

Hence, they cannot exclude that future transfer of these frozen/thawed embryos will increase the cumulative LBR in either/both study arms.

In addition, the authors write that they cannot rule out that assisted hatching might be effective in higher order RIF because there was no international consensus on the definition of RIF when they started the study.

1 Max H J M Curfs, Ben J Cohlen, Els J Slappendel, Dick C Schoot, Josien G Derhaag et al. A multicentre double-blinded randomized controlled trial on the efficacy of laser-assisted hatching in patients with repeated implantation failure undergoing IVF or ICSI. Hum Reprod 2023;

2 ESHRE Add-ons working group: K. Lundin, J.G. Bentzen, G. Bozdag, T. Ebner, J. Harper , N. Le Clef, A. Moffett, S. Norcross, N.P. Polyzos, S. Rautakallio-Hokkanen, I. Sfontouris , K. Sermon , N. Vermeulen, and A. Pinborg. Good practice recommendations on add-ons in reproductive medicine. Human Reproduction 2023 (0), 1–43

3 ESHRE Working Group on Recurrent Implantation Failure, D Cimadomo, M J de los Santos, G Griesinger, G Lainas, N Le Clef, D J McLernon, D Montjean, B Toth, N Vermeulen, N Macklon. ESHRE good practice recommendations on recurrent implantation failure. Hum Reprod Open 2023 (3)

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