Summary of findings 1. Performance of first trimester serum test strategies with or without maternal age.
| Review Question | What is the accuracy of serum‐based markers for Down's syndrome screening in the first trimester? | ||||
| Population | Pregnant women at less than 14 weeks' gestation confirmed by ultrasound, who had not undergone previous testing for Down’s syndrome. Most studies were undertaken in women identified to be high risk based on maternal age | ||||
| Settings | All settings | ||||
| Numbers of studies, pregnancies and Down's syndrome cases | 56 studies (68 publications) involving 204,759 pregnancies of which 2113 were Down's syndrome pregnancies. | ||||
| Index tests | 18 serum markers (ADAM12, AFP, inhibin, PAPP‐A, ITA, free βhCG, PlGF, SP1, total hCG, progesterone, uE3, GHBP, PGH, hyperglycosylated hCG, ProMBP, hPL, free αhCG, and free ßhCG to AFP ratio) singly or in combination with or without maternal age. | ||||
| Reference standards | Chromosomal verification (amniocentesis and CVS undertaken during pregnancy, and postnatal karyotyping) and postnatal macroscopic inspection. | ||||
| Study limitations | 35 studies used selective chromosomal verification during pregnancy, and were at risk of under‐ascertainment of Down's syndrome cases due loss of the pregnancy to miscarriage between the serum test and the reference standard. | ||||
| Tests with at least 70% sensitivity and at least 95% specificity | |||||
| Test strategy | Studies | Women (cases) | Sensitivity (95% CI) | Specificity (95% CI) | Test* |
| Test strategies (with or without maternal age) evaluated by a single study | |||||
| Without maternal age | |||||
| Double tests | |||||
| PAPP‐A and AFP | 1 | 96 (16) | 81 (54 to 96) | 95 (88 to 99) | |
| PAPP‐A and ITA | 1 | 344 (24) | 71 (49 to 87) | 95 (92 to 97) | |
| Triple tests | |||||
| PAPP‐A, free ßhCG and ITA | 1 | 344 (24) | 75 (53 to 90) | 95 (92 to 97) | |
| PlGF, PAPP‐A and free ßhCG | 1 | 699 (90) | 72 (62 to 81) | 95 (93 to 97) | |
| With maternal age | |||||
| Double tests | |||||
| Free ßhCG and SP1 | 1 | 60 (14) | 71 (42 to 92) | 96 (85 to 99) | |
| PAPP‐A and Hyperglycosylated hCG | 1 | 10775 (23) | 74 (52 to 90) | 95 (95 to 95) | |
| Triple tests | |||||
| PAPP‐A, free ßhCG and Inhibin | 1 | 1110 (85) | 74 (63 to 83) | 95 (94 to 96) | |
| PAPP‐A, SP1 and ProMBP | 1 | 192 (15) | 73 (45 to 92) | 95 (91 to 98) | |
| hPL, PAPP‐A and free ßhCG (1:250 risk) | 1 | 183 (47) | 77 (62 to 88) | 95 (90 to 98) | |
| Quadruple tests | |||||
| GHBP, PGH, PAPP‐A and free ßhCG (1:250 risk) | 1 | 335 (74) | 76 (64 to 85) | 95 (91 to 97) | |
| Quintuple tests | |||||
| PAPP‐A, free ßhCG, AFP, uE3 and Inhibin | 1 | 1110 (85) | 78 (67 to 86) | 95 (94 to 96) | |
| PAPP‐A, total hCG, AFP, uE3 and Inhibin | 1 | 1110 (85) | 73 (62 to 82) | 95 (94 to 96) | |
| Test strategies (with or without maternal age) evaluated by at least two studies | |||||
| Free ßhCG | 4 | 4280 (390) | 25 (18 to 34) | 95 (94 to 96) | P < 0.001 |
| PAPP‐A | 4 | 2837 (325) | 52 (39 to 65) | 95 (94 to 96) | |
| Age, free ßhCG | 7 | 5893 (460) | 42 (36 to 48) | 95 (94 to 96) | |
| Age, PAPP‐A | 5 | 3491 (359) | 55 (46 to 63) | 95 (94 to 96) | |
| Age, free ßhCG and AFP | 3 | 2992 (157) | 49 (39 to 60) | 95 (94 to 96) | |
| Age, PAPP‐A and free ßhCG | 17 | 49827 (1037) | 68 (65 to 71) | 95 (95 to 95) | |
| Age, PAPP‐A, free ßhCG and AFP | 2 | 2705 (116) | 74 (65 to 81) | 95 (94 to 96) | |
| Age, ADAM 12, PAPP‐A and free ßhCG | 2 | 1222 (74) | 74 (63 to 83) | 95 (94 to 96) | |
| Age, PlGF, PAPP‐A and free ßhCG | 2 | 1144 (160) | 76 (69 to 82) | 95 (93 to 96) | |
*Likelihood ratio test for the difference in sensitivity between the nine test strategies that were formally compared in a single meta‐analytic model. ADAM12: a disintegrin and metalloprotease; AFP: alpha‐fetoprotein; αhCG: alpha human chorionic gonadotrophin; ßhCG: beta human chorionic gonadotrophin; CI: confidence interval; CVS: chorionic villus sampling; GHBP: growth hormone binding protein; hCG: human chorionic gonadotrophin; hPL: human placental lactogen; ITA: invasive trophoblast antigen; PAPP‐A: pregnancy‐associated plasma protein A; PGH: placental growth hormone; PIGF: placental growth factor; PROMBP: proform of eosinophil major basic protein; SPI: Schwangerschafts protein 1; uE3: unconjugated oestriol