Aneuploidy, PGT-A, and what those grades mean

Pre-implantation genetic testing for aneuploidy, abbreviated PGT-A, screens IVF embryos for the correct number of chromosomes before transfer. The single biggest predictor of aneuploidy rate is maternal age. At 31, roughly 30% of blastocysts are aneuploid. By 38, the rate climbs above 50%. By 42, above 70%. Rather than a paternal effect, the dominant mechanism is meiosis-I nondisjunction in the oocyte, where a chromosome fails to separate cleanly during the first meiotic division.

Which aneuploidies survive

• Trisomy 16: the most common autosomal trisomy at conception, and universally lethal pre- or peri-implantation. Almost never compatible with live birth.
• Trisomy 21 (Down syndrome): the only common autosomal trisomy compatible with live birth, although affected individuals carry developmental and medical implications.
• Trisomies 13 and 18 (Patau and Edwards syndromes): occasionally compatible with birth, with severe outcomes and short life expectancy.
• 45,X (Turner syndrome): a single X chromosome rather than two. About 99% miscarry in the first trimester, but the 1% who survive develop with the syndrome.
• XXY (Klinefelter), XYY, XXX: usually compatible with live birth and life expectancy near typical, with milder developmental implications.

Reading a Gardner grade

Blastocyst grades use a three-part code in the Gardner system. The first character is a number from 1 to 6 describing the expansion stage, where higher numbers reflect more advanced expansion (5 is hatching, 6 is hatched). The second and third characters are letters from A (highest quality) to C (lowest) describing the inner cell mass and the trophectoderm respectively. A grade of 5AA is a hatching blastocyst with top-quality inner cell mass and trophectoderm. A grade of 3BB is a fully expanded blastocyst with mid-tier ICM and TE.

Grade correlates with implantation potential but does not perfectly predict it. A 4BB euploid embryo often outperforms a 5AA mosaic, and the chromosomal status reported by PGT-A is the stronger predictor of live birth in published data.

Why the maternal age effect is so steep

Oocytes are produced once, in fetal development, and then sit arrested in prophase I until ovulation occasionally lifts one out of the reserve, decades later. The cohesin complexes that hold homologous chromosomes paired during meiosis I degrade slowly over those decades, and the older the oocyte the more likely the cohesin loss leads to nondisjunction at meiosis I. The mechanism is well-characterised in mouse models and human IVF cohorts: roughly 70% of meiotic-origin aneuploidies trace to maternal meiosis I nondisjunction, with the remainder split between maternal meiosis II and (rarely) paternal nondisjunction. Premature sister chromatid separation is a related mechanism that becomes more common with age and shows up as fragmented PGT-A signal across many chromosomes simultaneously.

Aneuploidy rate by maternal age, in detail

Pooled PGT-A data across major reproductive centres show the following euploid rates per blastocyst, with substantial inter-centre variation:

• Under age 30: roughly 65% euploid (35% aneuploid).
• Age 30 to 34: roughly 55% euploid (45% aneuploid).
• Age 35 to 37: roughly 45% euploid (55% aneuploid).
• Age 38 to 40: roughly 35% euploid (65% aneuploid).
• Age 41 to 42: roughly 25% euploid (75% aneuploid).
• Age 43 and older: roughly 15% euploid (85% aneuploid).

These figures dominate the entire IVF success curve. Many couples who do not reach a live birth on their first cycle find that the proximate cause is "too few euploid blastocysts retrieved", not "the euploid blastocyst we transferred failed to implant". This is why pre-IVF AMH testing, antagonist protocol selection, and number-of-cycles planning matter more than minor improvements in any single embryo's grade.

PGT-A platforms

Three platforms dominate clinical PGT-A. Next-generation sequencing (NGS) is the current standard at most US and European centres: it sequences a few million reads per embryo across the whole genome at very low coverage and infers chromosome copy number from the read distribution. NGS gives the best resolution for sub-chromosomal events and partial aneuploidies, and it can quantify mosaicism (the fraction of biopsy cells carrying the aneuploidy) within roughly 5% accuracy. SNP arrays (Illumina Karyomap is the dominant product) are the platform of choice for PGT-M because they can simultaneously detect a known pathogenic variant alongside aneuploidy. aCGH (array comparative genomic hybridisation) was the standard before NGS and is mostly historical now, retained for backward compatibility at some centres.

Trophectoderm biopsy and what it does and does not tell you

A blastocyst at day 5 or 6 has two cell populations: the inner cell mass (which will become the foetus) and the trophectoderm (which will become the placenta). PGT-A biopsies 5 to 7 cells from the trophectoderm, which is selected because its loss is recoverable for the embryo and because it sits on the outside of the blastocyst where biopsy is mechanically straightforward. The clinical assumption is that the trophectoderm sample reflects the inner cell mass's chromosomal status with high concordance; concordance studies (Capalbo 2017, Greco 2015) put the agreement at roughly 95% for fully aneuploid versus fully euploid calls but lower (around 60 to 70%) for mosaic calls, which is why mosaic transfer remains contested. A few centres now perform double biopsy (TE plus a separate ICM-targeted aspiration) for high-stakes cases; this is not standard.