Pre-Implantation Genetic Testing (PGT): PGT-A, PGT-M and PGT-SR Explained — Cost, Top Hospitals & Success Rates | MyMedicPlus

Pre-implantation genetic testing (PGT) is a group of molecular diagnostic procedures performed on embryos produced by in vitro fertilisation (IVF) before transfer to the uterus. The goal is to identify chromosomal abnormalities or inherited gene mutations so that only unaffected embryos with the highest developmental potential are selected for transfer.

PGT has replaced the older term pre-implantation genetic diagnosis (PGD) and is now classified by indication:

• PGT-A (aneuploidy): Screens all 24 chromosomes for copy-number abnormalities such as trisomies, monosomies, and polyploidy — the leading cause of IVF failure and miscarriage.
• PGT-M (monogenic disorders): Tests for a specific single-gene disease in families known to carry a pathogenic variant — for example, cystic fibrosis (CFTR), spinal muscular atrophy (SMN1), Huntington disease (HTT), or BRCA1/2.
• PGT-SR (structural rearrangements): Identifies unbalanced chromosomal products in embryos from carriers of balanced translocations (reciprocal or Robertsonian) or inversions.

Embryo biopsy is performed at the blastocyst stage (day 5 or 6), removing 5-10 trophectoderm cells from the outer cell layer while leaving the inner cell mass intact. The embryo is then vitrified (flash-frozen) pending genetic results, which typically take 2-7 days. Only chromosomally normal or disease-unaffected euploid embryos are warmed and transferred in a subsequent frozen embryo transfer (FET) cycle.

PGT is governed internationally by the European Society of Human Reproduction and Embryology (ESHRE) guidelines (last updated 2023), the PGDIS position statements, and national regulatory frameworks which vary considerably between countries.

PGT can detect a wide spectrum of genetic conditions before pregnancy is established:

Chromosomal aneuploidies (PGT-A):

• Trisomies 13, 18, and 21 (Patau, Edwards, Down syndrome)
• Sex chromosome aneuploidies (Turner 45,X; Klinefelter 47,XXY)
• Polyploidy (triploidy, tetraploidy)
• Segmental aneuploidies detectable at >10 Mb resolution by NGS

Monogenic disorders (PGT-M) — selected examples:

• Autosomal recessive: Cystic fibrosis, spinal muscular atrophy (SMA), sickle cell disease, beta-thalassaemia, phenylketonuria, Gaucher disease, Tay-Sachs disease
• Autosomal dominant: Huntington disease, myotonic dystrophy type 1 (DM1), BRCA1/BRCA2 hereditary breast-ovarian cancer, familial adenomatous polyposis (APC), Marfan syndrome (FBN1)
• X-linked: Duchenne muscular dystrophy (DMD), Fragile X syndrome (FMR1 expansion), haemophilia A and B
• Mitochondrial diseases: Selected mtDNA variants (with caveats regarding heteroplasmy)

Structural rearrangements (PGT-SR):

• Reciprocal translocations — risk of unbalanced offspring is 30-50% per spontaneous conception
• Robertsonian translocations involving chromosomes 13, 14, 15, 21, 22
• Chromosomal inversions (paracentric and pericentric)

PGT-A is also offered in recurrent implantation failure (RIF, defined as ≥3 failed transfers), recurrent pregnancy loss (RPL, ≥2 clinical miscarriages), and advanced maternal age (≥35-38 years depending on guideline).

Candidacy for PGT is assessed jointly by a reproductive endocrinologist and a clinical geneticist. Eligibility criteria differ by PGT subtype:

PGT-A candidates:

• Women aged ≥35 years (advanced maternal age increases embryonic aneuploidy rate)
• Recurrent implantation failure (≥3 failed euploid transfers)
• Recurrent pregnancy loss (≥2 clinically confirmed miscarriages)
• Previous aneuploid pregnancy (e.g., prior trisomy 21)
• Severe male factor infertility (non-obstructive azoospermia, high sperm DNA fragmentation)

PGT-M candidates:

• Couples where both partners carry autosomal recessive pathogenic variants for the same disease (25% offspring risk)
• One partner carries an autosomal dominant pathogenic variant (50% offspring risk)
• Female carrier of X-linked disease (50% affected males)
• Couples with a previously affected child who wish to avoid recurrence
• Single-gene disorders with severe, early-onset, untreatable phenotypes are prioritised

PGT-SR candidates:

• One or both partners carry a balanced chromosomal rearrangement identified by karyotype
• History of multiple miscarriages or failed IVF in the context of translocation

Pre-cycle requirements: Couples must complete a dedicated PGT workup cycle, which includes ovarian stimulation yielding ideally ≥3-5 blastocysts to maximise the probability of having at least one euploid embryo available for transfer. Couples with diminished ovarian reserve (AMH <1.0 pmol/L, AFC <5) or expected poor response may be counselled that the chance of obtaining a suitable embryo is low. Genetic counselling prior to testing is mandatory under ESHRE and most national guidelines.

Modern PGT uses molecular platforms chosen according to the clinical indication, laboratory capability, and cost considerations:

Biopsy approaches:

• Trophectoderm (TE) biopsy at day 5-6: The current gold standard. Removes 5-10 trophectoderm cells from the blastocyst using laser-assisted zona opening and cell aspiration. Provides adequate DNA for reliable analysis and does not compromise the inner cell mass.
• Polar body biopsy: Tests maternal genome only; used in countries where embryo biopsy is legally restricted (e.g., Austria, Germany historically). Cannot detect paternally-derived or de novo mutations.
• Day 3 cleavage-stage biopsy: Now largely abandoned due to lower accuracy (single-cell amplification errors), higher embryo damage rates, and the need for fresh transfer which limits turnaround time.

Genetic platforms:

• Next-generation sequencing (NGS / whole-genome sequencing): Current preferred platform for PGT-A and PGT-SR. Delivers >99.5% sensitivity for whole-chromosome aneuploidies and detects segmental imbalances >10 Mb. Bioinformatics pipelines differentiate true aneuploidy from mosaicism (20-80% abnormal reads).
• SNP array (Karyomapping): Uses single nucleotide polymorphism (SNP) microarrays to simultaneously perform PGT-A and PGT-M via haplotype linkage analysis. Requires parental and DNA samples from an affected reference person. Detects uniparental disomy (UPD) which NGS cannot distinguish.
• PCR-based custom probes: Historically used for PGT-M for specific point mutations (CFTR, HTT CAG repeat). Now often combined with NGS for concurrent aneuploidy screening.
• FISH (fluorescence in situ hybridisation): The original PGT platform, limited to 5-9 chromosomal probes on cleavage-stage cells. Sensitivity <70%; now superseded by NGS for most indications.

Mosaic embryo transfer: NGS identifies embryos with mosaic patterns (20-80% aneuploid cells). International guidelines (PGDIS 2021, ESHRE 2023) permit transfer of low-grade mosaics (<50% abnormal) after detailed counselling about residual risk of chromosomally abnormal offspring. Ongoing prenatal testing (cfDNA or amniocentesis) is strongly recommended for all mosaic transfers.

PGT offers significant reproductive and health advantages for carefully selected patients:

Improved IVF success rates (PGT-A):

• Euploid single embryo transfer (eSET) achieves live birth rates of 50-70% per transfer in women under 38, compared to 25-45% for untested embryos of similar morphological grade.
• Transfer of a single euploid blastocyst eliminates the risk of multiple pregnancy, which carries elevated maternal and neonatal morbidity.
• Cumulative live birth rates over a full IVF cohort are not significantly increased by PGT-A in good-prognosis patients, but per-transfer efficiency and time to live birth are improved.

Prevention of inherited disease (PGT-M):

• PGT-M provides up to 98-99% accuracy in avoiding transmission of severe monogenic diseases — effectively eliminating the need for prenatal diagnosis and potential termination of an affected pregnancy.
• Couples with a previously affected child describe significant psychological benefit from proceeding to pregnancy knowing the embryo has been tested.
• For conditions with late-onset penetrance (BRCA1/2, Huntington), PGT-M allows prospective parents who have not undergone predictive testing themselves to avoid passing on the variant without learning their own carrier status.

Reduced miscarriage risk: Transferring euploid embryos reduces early miscarriage rates from approximately 20-25% (untested) to 5-10% per euploid transfer, substantially reducing the emotional and physical burden on patients.

Benefits in translocation carriers (PGT-SR): Translocation carriers who conceive naturally face 30-70% miscarriage risk. PGT-SR reduces this to <10% per transfer by selecting only balanced or normal embryos.

PGT is a highly specialised procedure with important technical and clinical limitations that must be discussed during pre-test counselling:

Technical limitations:

• Allelic dropout (ADO): Failure of one allele to amplify in PCR-based PGT-M can cause misdiagnosis. Modern protocols using whole-genome amplification (WGA) and haplotype analysis have reduced ADO rates to <2%.
• Diagnostic error rate: Overall misdiagnosis rates for PGT-M are approximately 0.1-0.3%. Confirmatory prenatal testing (chorionic villus sampling or amniocentesis) is recommended for all PGT-M pregnancies.
• Confined placental mosaicism (CPM): Trophectoderm biopsy samples the placental precursor cells. Chromosomal mosaicism may be present in the placenta but not in the fetus (CPM), potentially leading to unnecessary embryo discard. Conversely, true fetal mosaicism may not be detected in TE cells.

Clinical and ethical considerations:

• Mosaic embryo uncertainty: The clinical significance of different mosaic levels remains under active investigation. Transferring mosaic embryos carries a small but real risk of chromosomally abnormal offspring, premature delivery, or placental insufficiency.
• Embryo attrition: Not all stimulated follicles yield mature eggs, not all eggs fertilise, and not all embryos reach blastocyst stage or survive biopsy and vitrification. Couples with few embryos may find no suitable embryo for transfer after PGT.
• No guarantee of normal child: PGT tests only for the specific condition(s) requested. It does not exclude all genetic or structural anomalies.
• Ethical considerations: Testing for adult-onset conditions, sex selection for non-medical purposes, and HLA matching for saviour sibling donation are governed by national law and vary significantly between jurisdictions.

After a euploid (or disease-unaffected) embryo transfer, follow-up encompasses both obstetric monitoring and, in many cases, confirmatory genetic testing:

Immediate post-transfer period:

• Serum beta-hCG measurement 10-12 days after transfer to confirm biochemical pregnancy
• Repeat hCG 48 hours later to confirm doubling (exponential rise indicates viable intrauterine pregnancy)
• Transvaginal ultrasound at 6-7 weeks gestation to confirm fetal cardiac activity and exclude ectopic pregnancy or blighted ovum

Prenatal confirmatory testing:

• For PGT-M: Chorionic villus sampling (CVS) at 11-13 weeks or amniocentesis at 15-17 weeks is recommended by ESHRE guidelines to confirm the PGT result, given the 0.1-0.3% misdiagnosis rate.
• For mosaic embryo transfers: Invasive prenatal diagnosis (amniocentesis preferred over CVS to avoid CPM artefact) is strongly recommended to assess true fetal karyotype.
• Cell-free fetal DNA (cfDNA/NIPT) from 10 weeks gestation is often offered as an interim non-invasive screen but does not replace invasive testing for monogenic conditions.

Ongoing embryo storage: Surplus vitrified euploid embryos should be catalogued and stored at the treating laboratory or a licensed storage facility. Couples should clarify storage duration, consent for future transfers, and the disposition of embryos in the event of relationship breakdown or death — requirements specified by national legislation.

Psychological support: PGT cycles are emotionally intensive, particularly when no euploid embryo is available for transfer ("complete aneuploidy"). Referral to fertility counsellors experienced with PGT outcomes is recommended, especially when cumulative PGT cycles fail to achieve a live birth.

PGT adds a substantial cost premium over standard IVF. The total investment varies by country, platform, number of embryos biopsied, and the specific PGT type requested:

Component costs:

• IVF stimulation cycle: USD 3,000-15,000 depending on country and clinic (medications, monitoring, egg retrieval, fertilisation, and embryo culture to blastocyst)
• Biopsy fee: USD 800-2,000 per cycle for TE biopsy of all viable blastocysts
• NGS / chromosomal analysis (PGT-A/SR): USD 200-400 per embryo tested, or USD 1,500-3,500 as a per-cycle batch fee
• PGT-M custom probe development: USD 1,500-5,000 as a one-time design fee per family (required to create the bespoke linkage haplotyping assay before the first cycle)
• Vitrification and storage: USD 500-1,500 per year per storage period
• Frozen embryo transfer (FET) cycle: USD 1,000-4,000 additional

Geographic cost variation:

• Czech Republic, Greece, Spain, and India offer PGT cycles at 30-60% of US/UK prices with equivalent ESHRE-compliant protocols
• India and Thailand provide particularly competitive PGT-M pricing due to lower genetic laboratory operating costs

Insurance coverage: Coverage varies widely. Several US states mandate IVF coverage but not PGT. In the UK, NHS funding for PGT is available for specific serious monogenic conditions through a clinical commissioning group pathway. Couples should confirm coverage before commencing a cycle.

For couples who cannot access, afford, or ethically accept PGT, several alternative reproductive and diagnostic strategies exist:

• Standard IVF without PGT: Embryo selection based on morphological grading (Gardner score for blastocysts) and time-lapse imaging (morphokinetics). Does not provide chromosomal or genetic certainty but is considerably less expensive. Appropriate for good-prognosis patients without known genetic risk.
• Prenatal diagnosis after natural conception: CVS at 11-13 weeks or amniocentesis at 15-17 weeks tests the established pregnancy for chromosomal abnormalities or specific monogenic conditions. Provides definitive diagnosis but requires the difficult option of termination if an affected pregnancy is confirmed.
• Cell-free fetal DNA (cfDNA / NIPT): Non-invasive maternal blood test from 10 weeks for common aneuploidies. Highly sensitive and specific for trisomies 21, 18, 13, and sex chromosome anomalies but cannot test for most monogenic conditions. A screening (not diagnostic) test — positive results require invasive confirmation.
• Donor gametes: Using donor eggs (oocyte donation) from young, screened donors substantially reduces aneuploidy rates. Sperm or egg donation from an unaffected donor eliminates the risk of transmitting inherited monogenic disease in certain scenarios.
• Adoption or child-free living: Legitimate choices that some couples make after careful consideration, particularly when PGT cycles have repeatedly failed or the genetic condition is incompatible with the couple's values and circumstances.

The choice between PGT and alternatives is deeply personal and should be supported by non-directive genetic and psychosocial counselling.