B·R·A·H·M·S Biomarkers: Understanding Birth Defects

What you should know about birth defects

Birth defects affect 6% of babies worldwide.1 Chromosomal abnormalities happen during the fertilization process and are caused by a change in the number or structure of the chromosomes. Among chromosomal abnormalities, trisomy is originated from a cell containing three copies of chromosomes instead of the normal two. Trisomies are the main chromosomal abnormalities affecting the fetus during pregnancy and lead to organ and body anomalies, cardiac dysfunction and severe intellectual disability.1 Risk of trisomy increases with advanced maternal age and therefore trisomies are more prevalent in developed countries.

 

The most common trisomies are trisomy 21, trisomy 18 and trisomy 13, as described below.2

 

Table listing the frequencies of trisomies. Trisomy 21 (Down syndrome) has a frequency of 1 in 1,000 births, trisomy 28 (Edwards syndrome) has a frequency of 1 in 10,000 births, and trisomy 13 (Patau syndrome) has a frequency of 1 in 20,000 births.

Neural tube defects are congenital defects that occur if the developing neural tube fails to close properly during the third or fourth week of embryonic development.3 The incidence of NTD is 1.9 per 1000 births.4 

How to identify fetal abnormalities early in pregnancy

The development of screening for fetal abnormalities has greatly improved prenatal care in many countries. Prenatal screening helps to identify pregnant woman at risk of having an affected fetus during the first or the second trimester of pregnancy.

 

A combination of biomarkers, ultrasound markers and maternal characteristics offers an early and reliable screening strategy in the first and second trimesters of pregnancy.5

 

Combined screening in first trimester, as described below:6

 

Chart illustrating combined screening, including maternal age and history, ultrasound markers, fetal nuchal translucency thickness (NT), and biomarkers (Free βhCG, PAPP-A, and PIGF). With combined screening including biomarkers, the detection rate for T21 at 5% false positive rate is 90%, the detection rate for T18 at 0.5% fase positive rate is 97%, and the detection rate for T13 at 0.5% fasse positive rate is 84%.

When ultrasound is not available, the quadruple test in first trimester can be proposed, as described below:7

 

Chart showing the quadruple test, including maternal age history and biomarkers (Free βhCG, PAPP-A, PIGF, and AFP). This test has a detection rate for T21 of 88% and a false positive rate of 13%.

In second trimester, with no need of ultrasound, biomarkers can be combined to provide an efficient risk assessment, as described below:8

 

Chart showing second trimester screening, including maternal age history and biomarkers (Free βhCG/hCG + β and AFP for a double test, +uE3 for a triple test, and +inhibin A for a qualdruple test). This quad test has a detection rate of 65-75% and a false positive rate of 5%.

AFP value measured in weeks 15-20 of gestation can indicate a risk for neural tube defects, which should be confirmed via an ultrasound.3

Maximizing screening benefits: The power of contingent screening

Diagram illustrating contingent screening

To achieve the best possible performance in prenatal screening, the Fetal Medicine Foundation UK and expert clinicians strongly advocate for the adoption of a contingent screening approach.9 In the realm of prenatal screening, contingent screening proves to be a superior approach when compared to relying solely on noninvasive prenatal testing (NIPT). By combining biomarkers as a first line screening tool and reserving NIPT for women in the intermediate risk group, clinicians and laboratory managers can unlock a multitude of benefits, including improved accuracy, cost savings, and minimized invasive procedures.

 

References

1.    World Health Organization. (n.d.). Congenital disorders. World Health Organization. https://www.who.int/health-topics/congenital-                        anomalies 

2.     Loane M et al. Eur J Hum Genet 2013; 21(1):27-33

3.     McRae AR and Canick JA. Handbook of Clinical Laboratory Testing during pregnancy 2004;71-137

4.     Kancherla V Childs Nerv Syst.2023;39(7):1703-1710

5.     Wald NJ J Med Screen 1997;4:181-246

6.     Kagan et al. Human reproduction 2008 ;23(9):1968-1975

7.     Caron L et al. Clin Chem Lab Med 2023 ;61(9) :1630-1635

8.     Nicolaides et al. Prenat Diagn 2011 ; 31 :7-15

9.     Nicolaides et al. Ultrasound Obstet Gynecol 2013 ;42 :41-50

10.   Strauss TS et al. The Journal of Maternal-Fetal & Neonatal Medicine 2022; 35:25, 9907-9912

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