Screening, whether in the first or second trimester, is an effective means of selecting women for chorionic-villus sampling or amniocentesis when Down syndrome is a possibility. At present, however, at least 5 percent of screened women have to undergo amniocentesis for 60 to 80 percent of affected fetuses to be detected. The present study was an effort to integrate measurements made during both trimesters to yield a single risk estimate. Data were taken from published studies of first-trimester screening (for serum pregnancy-associated plasma protein A in 77 affected and 383 unaffected pregnancies; for nuchal translucency on ultrasound in 326 affected and 95,476 unaffected pregnancies). In the second trimester, varying combinations of serum &agr;-fetoprotein (AFP), unconjugated estriol, human chorionic gonadotropin (hCG), and inhibin A tests were available for 77 affected and 385 unaffected pregnancies. The test regimens compared included the following: 1) a double test, second-trimester measurements of serum AFP and hCG; 2) a triple test, second-trimester measurements of serum AFP, unconjugated estriol, and hCG; 3) a quadruple test, second-trimester measurements of the same parameters plus inhibin A; 4) a combined test, first-trimester measurements of pregnancy-associated plasma protein A, free &bgr; subunit of hCG, and nuchal translucency; and 5) an integrated test, first-trimester tests of pregnancy-associated plasma protein A and nuchal translucency and second-trimester measurements of serum AFP, unconjugated estriol, hCG, and inhibin A.At a false-positive rate of 5 percent, the integrated test detected 94 percent of cases, compared with 76 percent for the most effective second-trimester test (quadruple test) and 85 percent for the combined first-trimester tests. At a 1 percent false-positive rate, the integrated test detected 85 percent of cases, compared with 46 percent for the triple test. With the integrated test, only 1 percent of screened women would require an invasive procedure and karyotyping for 80 percent of affected pregnancies to be detected (Fig. 1). The corresponding figure for the double test was 22 percent. The reduced false-positive rate using the integrated test is especially evident for women aged 35 years and older.Fig. 1. Percentage of screened women who would need to undergo amniocentesis or chorionic-villus sampling in order for 80 percent of the pregnancies affected by Down syndrome to be detected, according to type of screening test. The double test includes measurements of serum &agr;-fetoprotein and human chorionic gonadotropin in the second trimester. The triple test includes measurements of serum &agr;-fetoprotein, unconjugated estriol, and human chorionic gonadotropin in the second trimester. The quadruple test includes measurements of serum &agr;-fetoprotein, unconjugated estriol, human chorionic gonadotropin, and inhibin A. The combined test includes measurements of serum pregnancy-associated plasma protein A, the free &bgr; subunit of human chorionic gonadotropin, and nuchal translucency in the first trimester. The integrated test includes measurements of serum pregnancy-associated plasma protein A and nuchal translucency in the first trimester and serum &agr;-fetoprotein, unconjugated estriol, human chorionic gonadotropin, and inhibin A in the second trimester. Used with permission from N Engl J Med 1999;341:461–467. © 1999 Massachusetts Medical Society.It is estimated that in the United States, using the integrated test rather than the triple test to detect Down syndrome prenatally would yield approximately 800 more affected pregnancies. It also would keep about 1400 unaffected fetuses from being lost as a result of amniocentesis or chorionic-villus sampling if all high-risk women were to have either of these procedures.N Engl J Med 1999;341:461–467