A pregnancy achieved through in vitro fertilization (IVF) following preimplantation genetic testing for aneuploidy (PGT-A) offers high reassurance regarding the embryo’s chromosomal health. Despite this, many patients are still offered Non-Invasive Prenatal Testing (NIPT) once pregnancy is established. This raises questions about the necessity of sequential screening, given the embryo was already screened for chromosomal errors. Both PGT-A and NIPT are screening tools used at different stages, and each has distinct mechanisms and limitations explaining why one does not fully replace the other.
Understanding Preimplantation Genetic Testing for Aneuploidy
Preimplantation Genetic Testing for Aneuploidy (PGT-A) is performed during an IVF cycle to screen embryos for whole chromosomal errors. The test identifies euploid embryos (correct number of chromosomes) from aneuploid embryos (abnormal number). PGT-A is used to select embryos most likely to result in a successful live birth, as aneuploidy is a common cause of implantation failure and miscarriage.
Testing is performed on a blastocyst, typically five to seven days old, by removing a small cluster of cells from the outer layer, called the trophectoderm. The trophectoderm will eventually form the placenta. The inner cell mass, which develops into the fetus, is not sampled. The trophectoderm cells are sent for genetic analysis, and the embryo is frozen while awaiting results.
An embryo is classified as euploid if it possesses the normal count of 46 chromosomes. An aneuploid embryo has missing or extra chromosomes, such as Trisomy 21 or Monosomy X. PGT-A helps specialists prioritize euploid embryo transfer, increasing the chance of pregnancy and reducing the risk of miscarriage.
The Mechanism of Non-Invasive Prenatal Testing
Non-Invasive Prenatal Testing (NIPT) is a screening test performed during pregnancy, typically starting around ten weeks. It requires only a simple blood draw from the pregnant person, making it non-invasive and safe. The blood sample contains fragments of cell-free DNA (cfDNA) circulating in the maternal bloodstream.
The cfDNA originates from the mother and the placenta, with placental DNA acting as a proxy for the fetal genetic material. NIPT analyzes these fragments to assess the risk of common chromosomal conditions. Primary targets include Trisomy 21, Trisomy 18, and Trisomy 13, as well as certain sex chromosome aneuploidies.
The test measures the proportion of cfDNA fragments from specific chromosomes. An increased or decreased proportion indicates the presence of an extra or missing chromosome in the fetus. NIPT is a screening tool, meaning a high-risk result requires confirmation through an invasive procedure like amniocentesis.
Why PGT-A Does Not Guarantee a Euploid Pregnancy
Despite PGT-A’s high accuracy, a euploid result does not guarantee a chromosomally normal pregnancy. The main reason lies in the biological difference between the sampled trophectoderm cells and the inner cell mass that forms the fetus. This difference introduces uncertainty that NIPT is designed to address.
One significant factor is Confined Placental Mosaicism (CPM), where chromosomal abnormalities are restricted to the placental tissue. Since PGT-A only analyzes the trophectoderm, a euploid result might be inaccurate if the abnormality is present only in the inner cell mass, though this is rare. Conversely, an abnormal PGT-A result could reflect a condition confined only to the trophectoderm, potentially resulting in a healthy baby.
Technical limitations and biological events occurring after the PGT-A biopsy also introduce uncertainty. The initial PGT-A result is based on a small sample of five to ten trophectoderm cells, which may not perfectly represent the entire embryo. Sampling error can occur, leading to a false-negative PGT-A result if aneuploid cells were missed during the biopsy.
Furthermore, new genetic errors, known as de novo mutations, can arise after the biopsy and embryo transfer. These post-implantation errors can lead to a chromosomal abnormality in the fetus or placenta not present in the original biopsied cells. NIPT screens the ongoing pregnancy using placental DNA, serving as a check for these late-occurring or unsampled abnormalities.
Current Clinical Guidance on Sequential Testing
Medical organizations generally recommend that NIPT still be offered to patients who conceived using a PGT-A-screened embryo. The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) recommend offering prenatal genetic screening to all patients, regardless of PGT-A status. This consensus stems from the understanding that PGT-A and NIPT screen for different aspects of chromosomal health at different times.
PGT-A is an embryo selection tool, while NIPT is a prenatal screening test for the established pregnancy. NIPT provides an additional safety measure by detecting errors like confined placental mosaicism or de novo mutations. Although the risk of a true aneuploid pregnancy is significantly lower after a euploid PGT-A transfer, NIPT offers a highly sensitive method to detect the most common trisomies.
The decision to proceed with NIPT is ultimately personal, influenced by factors like patient anxiety, cost, and the availability of expanded NIPT panels. Patients should discuss their individual history and risk profile with a genetic counselor or maternal-fetal medicine specialist. These experts can interpret the data, discuss the limitations of both tests, and help the patient make an informed choice that balances reassurance with the low residual risk.