Aneuploidy and Structural Fetal Abnormalities

Aneuploidy and structural fetal abnormalities are the two broad categories of fetal conditions targeted by prenatal screening and diagnosis. Aneuploidy refers to an abnormal number of chromosomes, such as the trisomies of chromosomes 21, 18, and 13, while structural abnormalities are malformations of fetal anatomy. Both are detected through a combination of ultrasound, biochemical and cell-free DNA screening, and confirmatory diagnostic testing.

Definition

Aneuploidy is the presence of an abnormal chromosome number in the fetus, most commonly the autosomal trisomies 21, 18, and 13 and the sex-chromosome aneuploidies; structural fetal abnormalities are congenital malformations of fetal anatomy detectable by imaging. Both are the targets of prenatal screening and confirmatory diagnosis.

Scope

This topic covers the principal chromosomal aneuploidies and structural malformations identified in pregnancy, the screening and diagnostic methods used to detect them, and how screening risk relates to diagnostic confirmation. It is a reference description of these conditions and the methods that detect them, and is non-prescriptive about individual management.

Core questions

• What are the common fetal aneuploidies and structural abnormalities?
• How does ultrasound detect structural anomalies and aneuploidy markers?
• How do cell-free DNA and combined screening estimate aneuploidy risk?
• How is a positive screen confirmed by diagnostic testing?

Key concepts

• Trisomy 21, 18, and 13
• Sex-chromosome aneuploidy
• Nuchal translucency
• Soft markers and structural anomalies
• Cell-free DNA (cfDNA) screening
• Positive predictive value
• Diagnostic confirmation by CVS or amniocentesis

Mechanisms

Aneuploidy arises mainly from errors of chromosome segregation, the frequency of which rises with maternal age for several trisomies. Screening estimates aneuploidy risk through maternal age, ultrasound markers such as increased nuchal translucency, serum biochemistry, and analysis of cell-free DNA derived largely from the placenta (Snijders, 1998; Bianchi, 2014; Norton, 2015). Structural abnormalities are detected by systematic anatomical survey on ultrasound, with detection depending on the organ system, gestational age, and image quality (Salomon, 2022). Because all of these are screening methods that quantify probability, a high-risk result is confirmed by diagnostic testing of fetal cells obtained through chorionic villus sampling or amniocentesis (ACOG, 2020).

Clinical relevance

Understanding these conditions and how they are detected clarifies the meaning of screening results, including why a positive screen is a probability rather than a diagnosis and why confirmatory testing is offered. This entry describes the conditions and their detection at a population level and is not a basis for individual diagnostic or treatment decisions.

Epidemiology

The autosomal trisomies are the most common clinically significant aneuploidies detected prenatally, and their birth prevalence rises with maternal age. Cell-free DNA screening has high sensitivity and specificity for trisomy 21, with lower positive predictive value in lower-risk populations, which is why confirmatory diagnosis remains necessary (Bianchi, 2014; Norton, 2015; ACOG, 2020).

History

Prenatal detection of aneuploidy progressed from maternal-age-based offers of amniocentesis, through nuchal translucency and combined biochemical screening in the 1990s, to cell-free DNA screening after 2011. In parallel, improvements in ultrasound resolution expanded the antenatal detection of structural malformations.

Debates

Should cell-free DNA screening replace traditional screening for all pregnancies?

Cell-free DNA has higher detection for common trisomies, but its positive predictive value varies with prior risk, it does not assess all conditions detected by ultrasound or serum screening, and cost and access differ; guidelines therefore frame it as one option requiring confirmatory diagnosis rather than a universal replacement.

Key figures

• Kypros Nicolaides
• Diana Bianchi
• Mary Norton
• Ronald Wapner

Seminal works

• snijders-1998-nt
• bianchi-2014-next
• norton-2015

Frequently asked questions

Why does a positive cell-free DNA screen still require diagnostic testing?

Cell-free DNA screening estimates probability rather than confirming a diagnosis, and its positive predictive value depends on the prior risk in the population, so a positive result is confirmed by diagnostic testing of fetal cells before any decisions are based on it.

What is the difference between aneuploidy and a structural abnormality?

Aneuploidy is an abnormal number of chromosomes, whereas a structural abnormality is a malformation of fetal anatomy; the two can occur together or independently and are detected by partly different methods.