Down syndrome (DS) is the most common human disease caused by a structural chromosome defect, with an occurrence rate of about 1 in 700 (Shaw 2008). The original screening test for DS was maternal age or a history of a previously affected infant. Women who are 35 years or older account for approximately 30% of DS, which can be diagnosed mostly by amniocentesis.
A screening test
Screening is a systemic application of a test or enquiry to identify subjects at sufficient risk of a specific disorder so that they can benefit from further investigation or direct preventive action (Wald, 1994). There is no universally accepted definition of medical screening, but there is a general agreement that it should contain three elements: (i) It should identify those individuals who are at sufficient high risk of a specific disorder, preliminary to a diagnostic test and, if required, preventive action. (ii) It should be offered systematically to people with no signs or symptoms of the disease for which screening is being conducted. (iii) It should be beneficial to the individuals being screened.
The three elements of screening apply also to DS where screening is offered systematically to every pregnant woman and selection is for high-risk pregnancies, which are then offered an invasive diagnostic test, that is, chorionic villus sampling (CVS) or amniocentesis. The advantages include ability to choose whether to discontinue an affected pregnancy and the ability to prepare for a delivery of a DS baby for those who choose to continue the pregnancy.
Second trimester screening
Screening for DS using maternal age as a criteria started 30 years ago. Women who aged 35 years or more were offered amniocentesis to exclude this condition. However, the detection rate using this method resulted in a low 30%.
Currently, second-trimester screening is generally offered between 14th and 20th week of gestation, using a combination of maternal serum analysis and age.
The double test, consists of serum alpha fetoprotein and hCG gives detection rate of 57% to 63% with a false-positive rate of between 5.3% and 6.5%. Wald et al (2004) suggested that the double test is no longer justified as a routine screening tool for DS on the basis of the relatively low detection rates and poor cost effectiveness.
The “triple test”, which is commonly used in many other countries has an overall detection rate of 69% with the same false positive rate (ACOG 2007). With an addition of serum inhibin to the triple test, the quadruple test has an enhanced detection rate to 81% with a false positive of 5% (Malone 2005). This test is currently the most popular second-trimester screening test in the USA.
The second trimester test performance
Detection rate False positive OAPR
Double test 71% 13% 1 in 68
Triple test 69-77% 9-14% 1 in 49
Quadruple test 81-83% 6-7% 1 in 32-37
OAPR: the ratio of the number of affected to unaffected individuals with positive results
(Adapted from: Weisz et al., H. Reprod Update 2006)
First trimester screening
First-trimester screening is typically conducted between the 11th and 14th week of gestation. This screening involves either ultrasonography measurement of nuchal translucency (NT) with or without blood test (free β-hCG and PAPP-A).
The performance of NT screening in terms of success varies among studies, with the detection rate ranging from 64% to 70% with a 5% false-positive rate depending on the study (Malone 2004).
A combination of NT measurement with the above two serum biochemical markers in the first trimester comprises the “combined test” (Wald 1997). The detection rate for this test is between 82% and 87% with a false-positive rate of 5%, which is even better than quadruple test in the second trimester. The advantage of the combined test is the early availability of the results, which allows karyotyping by chorionic villus sampling and early surgical termination of pregnancy when this is indicated.
The first-trimester combined test was the most cost-effective screening tool. However, the relatively high abortion rate with the above invasive procedure and the possibility of operator error with sonography should be informed to patients.
Pregnant women now have a choice in terms of DS screening, namely first- or second-trimester screening. The cost of first-trimester DS screening is about twice that of second-trimester DS screening. A better screening tool in the second trimester, namely triple or quadruple test should be offered when the opportunity for first-trimester combined test is missed.
Although, there is no national guidelines on DS screening in Malaysia, most pregnant mothers are offered the triple test as it is most affordable.
ACOG Practice Bulletin No. 77. Obstet Gynecol 2007
Malone FD. N Engl J Med 2005
Shaw SW. J Hum Genet 2008
Wald NJ. BJOG 2004
Wald NJ. Prenat Diagn 1997
Weisz et al., H. Reprod Update 2006