Maternal Serum Screening and Biomarkers

Maternal serum screening measures analytes in the pregnant person's blood that vary with fetal and placental physiology, combining them with maternal and ultrasound information to estimate the risk of conditions such as Down syndrome and open neural tube defects. It is a non-invasive risk-estimation method that long preceded cell-free DNA screening and remains in use in many programmes.

Definition

Maternal serum screening is the measurement of biochemical markers in maternal blood—such as alpha-fetoprotein, human chorionic gonadotropin, unconjugated estriol, inhibin A, and pregnancy-associated plasma protein A—interpreted as multiples of the median and combined into risk estimates for fetal aneuploidy and open neural tube defects.

Scope

This topic covers the principal serum biomarkers used in pregnancy, the first- and second-trimester screening combinations, and how marker levels are converted into adjusted risk estimates. It frames serum screening as risk stratification, not diagnosis, and is non-prescriptive about individual care.

Core questions

• Which maternal serum biomarkers are used in pregnancy screening?
• How are first-trimester and second-trimester screening tests combined?
• How are marker levels converted into a risk estimate?
• How does serum screening relate to cell-free DNA screening?

Key concepts

• Alpha-fetoprotein (AFP)
• Human chorionic gonadotropin (hCG)
• Unconjugated estriol
• Inhibin A
• Pregnancy-associated plasma protein A (PAPP-A)
• Multiple of the median (MoM)
• Combined and integrated screening
• Detection and false-positive rates

Mechanisms

Concentrations of placental and fetal analytes in maternal blood deviate in characteristic directions when the fetus is affected by certain conditions. Each marker is expressed as a multiple of the median for gestational age and adjusted for maternal factors, then combined with prior risk to yield an individualized probability. First-trimester combined screening uses pregnancy-associated plasma protein A and human chorionic gonadotropin together with nuchal translucency; second-trimester screening uses the triple or quadruple marker panel; integrated approaches combine markers across trimesters to raise detection at a given false-positive rate (Wald, 1988; Malone, 2005). Elevated alpha-fetoprotein also screens for open neural tube defects (Wald, 1977).

Clinical relevance

Serum screening illustrates how biochemical markers are translated into population-level risk estimates and how detection and false-positive rates trade off across screening strategies. This entry describes the method and its performance and is not a basis for individual diagnostic or treatment decisions.

Epidemiology

Detection rates for Down syndrome rise across screening strategies, with combined and integrated approaches outperforming single second-trimester panels at comparable false-positive rates; the FASTER trial provided direct comparative estimates among these strategies (Malone, 2005; ACOG, 2020).

History

Maternal serum alpha-fetoprotein screening for neural tube defects was established in the 1970s, followed in the late 1980s by serum marker screening for Down syndrome and the development of the triple and quadruple tests. First-trimester combined screening and integrated strategies followed, and large comparative trials clarified their relative performance before cell-free DNA screening was introduced.

Key figures

• Nicholas Wald
• Howard Cuckle
• Fergal Malone

Seminal works

• wald-1988
• malone-2005-faster
• wald-1977-afp

Frequently asked questions

What is a multiple of the median in serum screening?

It expresses a marker level relative to the median value for the same gestational age, allowing results to be standardized and combined into a risk estimate regardless of the absolute concentration.

Has serum screening been replaced by cell-free DNA testing?

Cell-free DNA screening has higher detection rates for the common trisomies, but maternal serum screening remains in use in many programmes and still contributes to screening for open neural tube defects and to first-trimester risk assessment.