Prediction of Down's Syndrome in Second Trimester by Screening

A Cochrane review [Abstract] 4 included 22 studies with a total of 228 615 pregnancies (including 1067 with Down's syndrome). 32 different test combinations were evaluated formed from combinations of 8 different tests and maternal age; first trimester nuchal translucency (NT) and the serum markers AFP, uE3, total hCG, free βhCG, Inhibin A, PAPP-A and ADAM 12. Meta-analysis of the 6 most frequently evaluated test combinations showed that a test strategy involving maternal age and a combination of first trimester NT and PAPP-A, and second trimester total hCG, uE3, AFP and Inhibin A significantly outperformed other test combinations that involved only one serum marker or NT in the first trimester, detecting about nine out of every 10 Down's syndrome pregnancies at a 5% false positive rate.

A Cochrane review [Abstract] 3 included 59 studies with a total of 341 262 pregnancies (including 1 994 with Down's syndrome) screened. 17 studies made direct comparisons between tests. 54 test combinations were evaluated formed from combinations of 12 different tests and maternal age; alpha-fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic gonadotrophin (hCG), free beta human chorionic gonadotrophin (βhCG), free alpha human chorionic gonadotrophin (αhCG), Inhibin A, SP2, CA125, troponin, pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PGF) and proform of eosinophil major basic protein (ProMBP).Meta-analysis of 12 best performing or frequently evaluated test combinations showed double and triple tests (involving AFP, uE3, total hCG, free βhCG) significantly outperform individual markers, detecting 6 to 7 out of every 10 Down's syndrome pregnancies at a 5% false positive rate. Tests additionally involving inhibin performed best (8 out of every 10 Down's syndrome pregnancies) but were not shown to be significantly better than standard triple tests in direct comparisons. Significantly lower sensitivity occurred in women over the age of 35 years.

A systematic review 1 included 16 studies with a total of 223 631 women screened. Collective screening performance for the triple analyte trials gave Down's syndrome detection rates of 57, 64 and 69% at amniocentesis referral rates of 3, 5 and 7% respectively. Four of the five studies using two analytes performed less well individually than the three analyte studies overall.

Another systematic review 2 including 22 cohort studies with a total of 194 326 participants was abstracted in DARE. The proportion of women with positive results that accepted prenatal testing ranged between 67% and 92%. The results according to the number of Down's syndrome cases were as follows: Cutoff 1: 190 to 200, >= 35 years: sensitivity 89%, false-positive rate 25%, screen positive rate 25%. All ages: sensitivity 67%, false-positive rate 4%, screen positive rate 4%. Cutoff 1: 250 to 295: >= 35 years: sensitivity 80%, false-positive rate 21%, screen positive rate 20.9%. < 35 years: sensitivity 57%, false-positive rate 4%, screen positive rate 4.4%. All ages: sensitivity 71%, false-positive rate 6%, screen positive rate 5.9%. Cutoff 1: 350 to 380: All ages: sensitivity 73%, false positive rate 8%, screen positive rate 8.2%.

References

• Palomaki GE, Neveux LM, Haddow JE. Can reliable Down's syndrome detection rates be determined from prenatal screening intervention trials? J Med Screen 1996;3(1):12-7. [PubMed]
• Conde-Agudelo A, Kafury-Goeta AC. Triple-marker test as screening for Down syndrome: a meta-analysis. Obstet Gynecol Surv 1998 Jun;53(6):369-76. [PubMed][DARE]
• Alldred SK, Deeks JJ, Guo B et al. Second trimester serum tests for Down's Syndrome screening. Cochrane Database Syst Rev 2012;6:CD009925. [PubMed]
• Alldred SK, Takwoingi Y, Guo B et al. First and second trimester serum tests with and without first trimester ultrasound tests for Down's syndrome screening. Cochrane Database Syst Rev 2017;(3):CD012599. [PubMed]