Impact of pre-implantation genetic testing for aneuploidy on obstetrical practice

Liona Poon
Co-Chair, Reproductive Screening SIG

The risk of miscarriage is significantly increased in women of advanced age, predominantly relating to the increased risk of aneuploidy. Preimplantation genetic testing for aneuploidy (PGT-A), a technology that screens for chromosome aneuploidy or major chromosome structural rearrangement in embryos before implantation, aims to select euploid embryos with the best potential for survival. It has been shown to reduce the negative effect of increasing maternal age on in vitro fertilization (IVF) outcomes, including low implantation rate, low clinical pregnancy rates and miscarriage [1-3].

Multiple pregnancy after fertility treatment is a major challenge in obstetric practice, with an increased risk of a range of pregnancy complications. With the improvement in implantation rate following PGT-A and appropriate counselling by fertility specialists, women might be more willing to accept single embryo transfer after IVF treatment, which could significantly reduce the chance of multiple pregnancy and the related complications [4].

Clinical approach of prenatal diagnostic testing after implantation of PGT-A determined euploid embryos

PGT-A by various platforms such as chromosomal microarray (CMA), single-nucleotide polymorphism (SNP) array or next-generation sequencing (NGS) could be done to examine the chromosome complement of the biopsied cells. The reported error rates of PGT-A are 1-4%, depending on the genetic testing techniques [5-8]. Laboratories usually specify the methodologies and limitations in the report. Managing clinicians should routinely review the PGT-A report in the first trimester of pregnancy when prenatal testing is considered for the most appropriate management and women should be advised to undergo routine screening during the antenatal period according to local guidelines. Aneuploidy screening options include first trimester combined test with fetal nuchal translucency thickness and serum biochemistry, and cell-free DNA testing. Women are also advised to undergo a routine morphology scan at mid-gestation for the evaluation of fetal structural anomaly.

Implications of mosaic aneuploid embryos after PGT-A

PGT-A at the blastocyst-stage can be considered a very early chorionic villus sampling (CVS). Mosaicism detected in the placental cells could represent true fetal mosaicism or confined placental mosaicism. It is therefore possible for a mosaic aneuploid embryo to result in a fetus with normal chromosome complement. Genome-wide approaches used in PGT-A have increased the chance of detecting mosaicism. The reported rates of identification of mosaic embryos are 4% and 21% from CMA and NGS, respectively [9,10]. Furthermore, the clinical utility of the detected degree of mosaicism is unknown as it might only reflect the technical bias due to random sampling of a restricted trophoblastic area and therefore it should be used with caution for prioritizing embyros [11].

Successful pregnancies have been reported following the transfer of mosaic euploid-aneuploid embryos in women for whom IVF has resulted in no euploid embryos [9]. However, follow up data on these pregnancies is lacking. Women who have limited ovarian reserve and no euploid embryo available after several cycles of IVF-PGT-A may consider transferring mosaic aneuploid embryo after genetic counseling. They must be informed that long-term follow up data are not available for review at present.

The Preimplantation Genetic Diagnosis International Society (PGDIS) has published a position statement to guide the choice of mosaic aneuploid embryos for transfer [12]. The statement recommends that autosomal monosomies should be selected over trisomies because monosomic cell lines are not viable except monosomy X. An evidence-based scoring system for prioritizing mosaic aneuploid embryos after PGT-A has been developed to guide clinician on choosing mosaic aneuploid embryos for transfer based on a risk score assessment [11]. A risk score for each chromosome is assigned based on (i) the likelihood that the mosaicism detected in the trophoblast is also present in the fetus; (ii) the incidence of clinically significant fetal uniparental disomy (UPD) resulting from the mosaic aneuploidy; and (iii) the likelihood of miscarriage based on the incidence of each individual mosaic aneuploidy identified in product of conception. Based on the scoring system, the authors have suggested that mosaic trisomies 1, 3, 10, 12 and 19 have the lowest composite score of 0 and have the highest priority for transfer, whilst mosaic aneuploidies including trisomies 13, 14, 16, 18, 21 and 45,X should be avoided due to the high possibility of aneuploidy livebirth.

Clinical approach of prenatal diagnostic testing after implantation of mosaic aneuploid embryos

Due to the increased risk of fetal aneuploidy, prenatal diagnostic testing is recommended for ongoing pregnancies after the transfer of mosaic aneuploid embryos. Amniocentesis should be recommended as first line prenatal diagnostic testing as amniotic fluid cells (or amniocytes) are more representative of fetal tissues. However, clinicians and patients must understand that amniocytes are derived from the embryonic ectoderm and amnion, and therefore a normal cytogenetic result cannot exclude the possibility of fetal mosaicism in other tissue cell line [13].

Regarding the choice of chromosome analysis, fetal karyotype with counting of 50 or more cells should be performed when aneuploid mosaicism is suspected according to the Clinical Laboratory Improvement Amendments standards [6]. If mosaic partial aneuploidy or partial aneuploidy is suspected, prenatal CMA should be performed for copy number variations. However, low-level mosaicism may not be detected by prenatal CMA. In some circumstances, fluorescent in situ hybridization for specific regions may be required for the detection of low-level mosaicism.

For mosaic aneuploid embryos involving chromosomes 6, 7, 11, 14, 15 and 16, UPD testing should be performed due to the increased risk of clinically significant UPD syndromes. For mosaic aneuploid embryos involving chromosomes 2, 7, 16 and 22, regular fetal surveillance for growth assessment is recommended due to the increased risk of intrauterine growth restriction and fetal demise.

Single transfer of a mosaic aneuploid embryo should be advised to minimize the chance of multiple pregnancies. There are several considerations. Prenatal invasive procedure in multiple pregnancies of possible discordant aneuploidies would increase the procedure related risks, as the fetuses have to be individually sampled. The pregnancy management would become more challenging when one fetus is subsequently confirmed to be affected and the other is euploid. Selective embryo reduction of the aneuploid fetus increases the risk of fetal demise in the euploid co-twin. 


PGT-A could potentially reduce the negative effect of increasing maternal age on IVF pregnancy outcomes. Recent advances in technology of PGT-A increase the possibility of encountering mosaic embryos, which might lead to an increased risk of miscarriage, fetal mosaic aneuploidy and UPD, etc. Obstetricians need to be familiar with the prenatal diagnostic testing approach after transfer of mosaic aneuploid embryos. At present, there is a lack of long-term outcome data after mosaic aneuploid embryo transfer.



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