New Algorithms in Prenatal Diagnosis

New Algorithms in Prenatal Diagnosis

INTRODUCTION

The approach in prenatal diagnosis has been revolutionized by advances in prenatal molecular diagnostics. New algorithms in prenatal diagnosis are evolving and becoming increasingly complicated (Figure 1). The goal is to maximize the prenatal information for pregnant women and the families to make choices for the next generations.

Down syndrome screening has been the focus in prenatal diagnosis for a long time. However, many other chromosomal and structural foetal abnormalities were diagnosed incidentally during the  screening programme for Down syndrome, coupled with the 18–22 weeks foetal anomaly ultrasound. Combined screening at 11–13 weeks by maternal age, foetal nuchal translucency (NT) thickness by ultrasound, maternal serum pregnancy-associated plasma protein A (PAPP-A) and free beta-human chorionic gonadotropin (β-hCG) can identify 90% of foetuses with trisomy 21 (Down syndrome) and other common aneuploidies (trisomies 18 and 13) at a false-positive rate (FPR) of 5%.1

The performance is highly reproducible worldwide and has also been demonstrated in the Hospital Authority universal Down syndrome screening programme in Hong Kong from 2010.2 Additional ultrasound and maternal serum markers with different contingent screening tests have been studied to further improve the detection rates and to reduce the FPR.

An important breakthrough in prenatal screening using maternal plasma cell-free foetal DNA as a noninvasive prenatal testing (NIPT) for foetal chromosomal abnormalities was discovered by Professor Dennis Lo from Hong Kong.3 The detection rate for Down syndrome using NIPT is >99% with an FPR of as low as 0.1%. NIPT can be performed using maternal blood sample from 10 weeks’ gestation onwards. NIPT is currently available as a secondary screening tool for pregnancies with positive conventional Down screening as well as for primary screening for Down syndrome.4-6

For prenatal diagnosis in the 21st century, traditional karyotyping is no longer adequate. Advances in prenatal molecular diagnostics including polymerase chain reaction (PCR) as rapid aneuploidy test, and chromosomal microarray (CMA) as molecular karyotyping including the detection of microdeletions and microduplications, are going to replace traditional karyotyping sooner or later.7 There are also new modalities being developed such as whole exome sequencing, WES (sequencing all the protein-coding genes in the genome) or whole genome sequencing, WGS (sequencing the entire genome). WES or WGS will not be discussed in this review article.

Despite the rapid ongoing development in prenatal molecular diagnostics, ultrasound maintains a pivotal role in the new algorithms (Figure 1), being the link between the various tests inside the algorithms. In modern prenatal diagnosis, continued utility of ultrasound (with corresponding counselling) could offer career sustainability for foetal medicine specialists.

This review article is focused on the new algorithms in prenatal diagnosis (Figure 1) from a clinical service/clinical pathway point of view. The current situation in Hong Kong will be referred to from time to time for illustration. It is beyond the author’s capacity to go in-depth into the laboratory aspects.