Sex selection without embryo selection for non-medical reasons

Published 28 March 2023

A new study from the USA introduces a method of sex selection using self-selected sperm for ICSI based on a density gradient approach. The technique avoids ‘embryo wastage’, says the report, which fails to address the wider controversies of non-medical sex selection.

Both ESHRE and the ASRM have expressed opinions on the ethics of sex selection without a medical indication, the latter more recently than the former.(1,2) Both organisations recognised the practice as ‘controversial’, made increasingly so by the wider application of PGT. However, neither seemed categorically in favour of proscription. ESHRE, a decade ago, recognised that there were scenarios in which a ‘responsible’ use of sex selection might be acceptable for family-balancing, where ‘at least one or at least more than one child of the non-requested sex’ was found in the household. ASRM reaffirmed that ‘sex selection should not be encouraged for nonmedical indications’, though adding that clinics ‘are under no ethical obligation’ to provide or refuse to provide non-medically indicated sex selection. As in ESHRE’s opinion of ten years earlier, the arguments for and against are still many and varied, patient autonomy and ‘reproductive liberty’ being the most common in favour.

The emerging techniques of PGT 30 years ago made it clear that PGT can identify the sex of an embryo. Indeed, the very first reported case of PGT in 1990 performed by Alan Handyside and colleagues was to avoid the transmission of an X-linked disease in at-risk couples with the transfer of an affected male embryo. Sex selection by PGT, of course, implies the deselection of embryos, which became an increasing source of controversy and why several sperm selection techniques were developed and introduced - though none with lasting advantages and reliability. Approaches have included swim-up techniques, in which sperm cells are allowed to swim through a layer of culture medium such that concentrations of male or female cells will be richer at higher or lower levels, electrophoresis, and flow cytometry in which sperm cells are exposed to fluorescent dyes which label their genetic material. However, none of them seems attractive, with fears expressed that exposing sperm cells to fluorescent dyes or electrical charges might contribute to DNA damage.

Yet the search goes on, and now the group of Rosenwaks at Weill Cornell in New York report their development of a ‘novel’ sperm sex selection technique which, they say, appears to be ‘consistently safe and effective’.(3) ‘Our sex selection method does not increase the proportion of additional aneuploid embryos,’ they explain. ‘Therefore, it can be regarded as extremely safe as well as efficient, inexpensive, and ethically palatable.’ The method was tested in a non-randomised study, which aimed to support a method which might ‘skew the proportion of embryos’ towards a couple’s desired sex without encouraging embryo wastage. Samples were analysed by FISH to determine the proportion of X- and Y-bearing cells prior to sperm processing.

And the method? Described as an ’in-house protocol’, the technique comprises a four-layer density gradient in which the medium is layered in four concentrations (20%, 40%, 60% and 90%) with the sperm pellet layered at the top (in the weakest medium concentration) and allowed to ‘self-select’ for 90 minutes. Y-bearing sperm cells were retrieved from the upper 20% layer, and the heavier X-bearing cells retrieved from the bottom 90% layer. The sample’s final concentration and motility were assessed, before being used for ICSI.

The study comprised 1317 ICSI patients, of whom 1212 were allocated to a control group and 105 to the study group. All were scheduled for PGT-A after fertilisation, the control group for aneuploidy assessment, and the study group for sex selection and confirmation of sperm selection results. FISH determined an even proportion of X- and Y-bearing sperm in the ICSI/PGT-A control group, while for those couples selecting for female sex the sperm selection method yielded an increased proportion of X-bearing spermatozoa (P<0.0001). Similarly, the technique yielded a greater proportion of Y-bearing sperm cells for couples selecting a male sex (P<0.0001).

Specifically, PGT-A results in the control group indicated a euploidy rate of 73.1% for female and 72.4% for male embryos. These couples achieved a 65.2% clinical pregnancy rate, with 551 deliveries (48.5% female, 51.5% male). All 105 men in the study group had sperm samples with an equal sex distribution at baseline. However, after sperm selection 59 men who desired female offspring obtained an 81.6% enrichment of X-chromosome cells, which after ICSI resulted in 79.1% female embryos and 16 singleton deliveries of the desired female sex. Similarly, 46 couples hoping for male offspring obtained an 80.8% sperm sex enrichment, which after ICSI led to 79.6% male embryos, with 13 singleton deliveries of healthy male offspring.

As a measure of safety, the study compared embryo aneuploidy rates between the two groups and found no significant increase in embryo aneuploidy between them, ‘indicating that our method can be safely used to increase the proportion of embryos for a specific sex’. Sperm aneuploidy rates in the treatment group were also unaffected.

The authors concede that sex selection is still ‘ethically debatable’, but propose that this method - while not guaranteeing a baby of the desired sex - may bypass concerns about embryo selection in its enriched sperm selection approach. However, they do not address the wider debate of sex selection other than to note that the desire to choose an offspring’s sex has been ‘particularly present’ since the 1970s and to itemise the several reasons behind the desire (social, family, financial - as well as health-related).

In many countries (Australia, Europe, Canada, though not the USA) sex selection for non-medical purposes is prohibited by law - or became so after a distortion of the gender balance, particularly so in some Asian and north African countries where there had been a heavy male imbalance (eg, India, China). The strongest arguments against its use come from the UN and WHO, who have both argued that non-medical sex selection may distort the natural gender balance and encourage discriminatory attitudes. The former is a variation on the ‘designer baby’ argument, making headlines more recently in the CRISPR-Cas9 baby scandal or in the more widespread proposals that embryo selection might be made on the basis of parents’ genomic data.

Sex selection seems more governed by law than by ethical argument, so the ‘novel’ sperm selection technique now reported from New York may well be more of academic interest than practical. In the UK, for example, the regulator reaffirms that any licensed clinic found to be offering sex selection for non-medical reasons ‘would automatically be in breach of the law’. However, most countries do offer sex selection for medical indications only, suggesting that the demarcation lies in the intention rather than the technique. The internet is littered with ads from clinics offering sex selection (mainly from the USA), so one assumes the demand exists, but this does not resolve the ethical debate

1. Dondorp W, De Wert G, Pennings G, et al. ESHRE Task Force on Ethics and Law 20: sex selection for non-medical reasons. Hum Reprod 2013; 28: 1448-1454.
2. Ethics Committee of the American Society for Reproductive Medicine. Use of reproductive technology for
sex selection for nonmedical reasons: an Ethics Committee opinion. Fertil Steril 2022; 117: 720-725.
3. Cheung S, Elias R, Xie P, Rosenwaks Z, Palermo GD. A non-randomized clinical trial to determine the safety and efficacy of a novel sperm sex selection technique. PLoS ONE 18(3): e0282216. pone.0282216

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