Continued Advances in NIPT Drives Updated Recommendations

Our 2020 blog, Evolution of non-invasive prenatal testing (NIPT), discussed the testing’s history and capabilities and offered guidance on its use. Since then, the field has continued to evolve with several notable developments driven by the acceleration of screening capabilities, improvements in the affordability of next-generation sequencing techniques, and updates in professional recommendations.

NIPT guidelines advance in 2023

The American College of Obstetricians and Gynecologists (ACOG) recently released updated recommendations for NIPT, also known as non-invasive prenatal screening (NIPS). They state that prenatal genetic screening and diagnostic testing options should be discussed and offered to all pregnant patients, regardless of age or risk of chromosomal abnormality.¹ Several diagnostic tests, including chorionic villus sampling or amniocentesis, and serum (with or without nuchal translucency ultrasound) or cell-free DNA (cfDNA) for screening are recommended. cfDNA is highlighted as the most sensitive and specific screening tool available for common fetal aneuploidies and is continued to be defined as the leading screening method. These updated recommendations distinguish between genetic screening testing and diagnostic testing. 

New guidelines issued by the American College of Medical Genetics and Genomics (ACMG) strongly recommend NIPS over traditional methods to screen for fetal trisomies 21, 18, and 13 in all pregnant patients. The guidelines are based on a systematic review of evidence that consistently demonstrated the improved accuracy of NIPS compared to traditional methods for trisomies 21, 18, and 13 in both singleton and twin gestations.² ACMG also recommends offering NIPS to all pregnant patients to screen for fetal sex chromosomal aneuploidies (SCAs).

An April 2023 International Society for Prenatal Diagnosis (ISPD) position paper updates its 2015 statement regarding technologies, clinical experience, and implementation. The paper describes NIPT as “the most accurate screening test for the common autosomal aneuploidies (trisomies 21, 18, and 13) in unselected singleton populations.” ¹² The authors note that NIPT detects genome-wide chromosome imbalances, segmental imbalances, and microdeletion/microduplications. 

NIPT use varies globally

Healthcare systems in Belgium, the Netherlands, Denmark, and the UK include NIPT in their national screening programs. NIPT is covered by state and private health insurance in the United States, while it is patient-funded in many other countries. Recommendations vary between countries and regions. For instance, most European countries provide NIPT only for high-risk women after first-trimester screening.^{3, 4} Regulating new reproductive technologies, including NIPT, can face challenges. China and India are two examples where providing information about fetal sex to potential parents is forbidden.¹²  

Expanding NIPT field

The NIPT market has expanded beyond testing for common aneuploidy of chromosomes 21, 18, and 13 to include other sub-chromosomal copy number variants (CNVs), SCAs, and rare autosomal trisomies (RATs). This expanded NIPT field was created through screening technology advancements that broadened the testing offering to cover more conditions, overcoming the limitations of traditional screening methods. For example, the development of high throughput molecular counting methods with single base pair resolution from companies such as BilliontoOne and Medicover Genetics has enabled the clinical implementation of NIPT for monogenic disorders such as sickle cell disease, cystic fibrosis, hemoglobinopathies, and spinal muscular atrophy.⁵

Unlike carrier screening, single-gene NIPT does not require paternal DNA samples,⁶ which previously hindered testing sensitivity due to poor uptake.⁷ In addition, long-read sequencing platforms have allowed researchers to explore long cfDNA molecules which monogenic diseases and detection/monitoring of pregnancy-associated disorders such as preeclampsia.⁸ More recently, researchers have combined cfDNA screening with artificial intelligence to widen the scope of disease testing, helping detect epigenetic aberrations, such as fetal congenital heart defects.⁹

Despite these technological advances, there is still considerable controversy around the use of expanded NIPT for investigating conditions other than fetal trisomies 21, 18, and 13. This is mainly due to several studies demonstrating its relatively low accuracy for SCAs, RATs, microdeletions, and CNVs,^10,11 combined with the ethical concerns of providing appropriate information and counseling for parents. More research and guidance are undoubtedly needed for further clinical implementation of expanded NIPT. 

How can LGC help?

NIPT continues to be a quickly evolving and popular area of interest in fetal and maternal care, and it is important for laboratories and healthcare providers to stay on top of new technologies and clinical recommendations and ensure the accuracy of their tests. LGC Clinical Diagnostics offers a comprehensive range of NIPT reference materials, including T21, T18, T13, Sex Chromosomes Aneuploidies, 22q11 microdeletion and euploid (negative); to help laboratories develop and validate their NIPT assays with high-quality performance criteria and to monitor assay performance.

To learn more, or to reach out to a representative, Contact Us.

References

1. ACOG. NIPT Summary of Recommendations. (2023). Available at https://www.acog.org/advocacy/policy-priorities/non-invasive-prenatal-testing/current-acog-guidance. Accessed 11th April 2023.
2. Dungan, J, S. et al. and ACMG Board of Directors. Noninvasive prenatal screening (NIPS) for fetal chromosome abnormalities in a general-risk population: An evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine 25, 2 (2023): 100336.
3. Gadsbøll, K., et al. Current use of noninvasive prenatal testing in Europe, Australia and the USA: A graphical presentation. Acta obstetricia et gynecologica Scandinavica, 99, 6 (2020): 722–730. https://doi.org/10.1111/aogs.13841
4. Perrot, A., Horn, R. The ethical landscape(s) of non-invasive prenatal testing in England, France and Germany: findings from a comparative literature review. Eur J Hum Genet 30, 676–681 (2022). https://doi.org/10.1038/s41431-021-00970-2
5. Westin, E. R., et al. Validation of single-gene noninvasive prenatal testing for sickle cell disease. American journal of hematology 97, 7 (2022): E270-E273.
6. Hoskovec, J. et al. Maternal carrier screening with single-gene NIPS provides accurate fetal risk assessments for recessive conditions. Genetics in Medicine 25, 2 (2023): 100334.
7. Choates, M, G. et al. It takes two: uptake of carrier screening among male reproductive partners. Prenatal diagnosis 40, 3 (2020): 311-316.
8. Yu, S,C,Y. et al. Single-molecule sequencing reveals a large population of long cell-free DNA molecules in maternal plasma. Proceedings of the National Academy of Sciences 118, 50 (2021): e2114937118.
9. Bahado-Singh, R, et al. Cell-free DNA in maternal blood and artificial intelligence: accurate prenatal detection of fetal congenital heart defects. American journal of obstetrics and gynecology 228, 1 (2023): 76-e1.
10. Hu, Y, et al. Clinical utility of expanded NIPT for chromosomal abnormalities and etiology analysis of cytogenetic discrepancies cases. Journal of Assisted Reproduction and Genetics (2022): 1-13.
11. Ge, Y, et al. Expanded noninvasive prenatal testing for fetal aneuploidy and copy number variations and parental willingness for invasive diagnosis in a cohort of 18,516 cases. BMC medical genomics 14 (2021): 1-12.
12. Hui, L. et al. and the ISPD Board of Directors. Position statement from ISPD on the use of non-invasive prenatal testing for the detection of fetal chromosomal conditions in singleton pregnancies (2023) https://doi.org/10.1002/pd.6357