Combined first trimester screen or noninvasive prenatal testing or both

In Singapore, Down syndrome screening is routinely offered to all pregnant women regardless of age.(1) The most common test offered is the combined first trimester screen (FTS) if the patient presents before 14 weeks of gestation. The combined FTS comprises detailed ultrasonography (USG) measuring the crown rump length (CRL) and the nuchal translucency (NT) of the fetus at 11–13 weeks of gestation, combined with serum screening of free beta-human chorionic gonadotrophin (bhCG) and pregnancy-associated plasma protein A (PAPP-A) at between 8–13 weeks of gestation. While the combined FTS detection rate of 90% is excellent, the main problem is its relatively high false positive rate, where 1 in 20 (5%) patients screened would be unnecessarily worried.(2) Another problem is ensuring the quality of the USG component due to the operator-dependent nature of USG. Hence, good USG machines are required, and well-trained sonographers need to be accredited and regularly audited, to avoid potential disputes when Down syndrome cases are missed. Noninvasive prenatal testing (NIPT) via the analysis of cell-free fetal DNA (cffDNA) from the plasma of pregnant women has recently become commercially available. There are many companies now that offer this test with different patented algorithms. These screening tests have demonstrated detections rates > 98% for Down syndrome (trisomy 21) and Edward syndrome (trisomy 18), and > 90% for Patau syndrome (trisomy 13), with very low false positive rates of 0.1%–0.5% in high-risk populations (i.e. those who have been screened positive by advanced maternal age, past or family history, combined FTS, second trimester serum screening or second trimester USG),(3-7) which reduces unnecessary worry and the need for invasive prenatal procedures such as chorionic villus sampling (CVS) or amniocentesis in patients. Indeed, various guidelines, including the December 2012 guideline of the American College of Obstetricians and Gynecologists, state that NIPT should not be offered to low-risk women or women with multiple gestations, in view of the limited data in these groups at the time.(8) As more data showing very high detection rates for Down syndrome is being accumulated for low-risk women(9-11) and multiple gestations,(12) it is likely that these guidelines will change soon. Bianchi et al have demonstrated a lower false positive rate for cffDNA compared to standard screening (0.3% vs. 3.6%) with 100% detection rates using both methods, albeit with a limited number of Down syndrome fetuses in the study.(9) It is important, however, to note that the positive predictive value of a positive cffDNA for fetal Down syndrome in low-risk populations is only about 45%,(9) and hence, it is critical to perform an invasive diagnostic test before termination of such fetuses, as one in two fetuses could be normal despite a positive test. This test can be taken as early as ten weeks into the pregnancy and requires one to two weeks for a result to be reported. The Achilles heel of this test is the non-report rate of 1%–5% for various reasons, including low fraction of the cffDNA due to early gestation or maternal characteristics such as increased body mass index. It is also very expensive at the time of writing, with the cheapest test costing just under S$1,000. Local practices pursue different strategies with regard to integrating NIPT in the Down syndrome screening protocols. Some offer NIPT to all, others offer to none, while others may offer it as a contingency test to women who are found to be at intermediate risk at FTS.