Screening for trisomy 21 by maternal age, fetal nuchal translucency thickness, free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A.

OBJECTIVES: To derive a model and examine the performance of first-trimester combined screening by maternal age, fetal nuchal translucency (NT) thickness and maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A).

METHODS: Prospective combined screening for trisomy 21 was carried out at 11 + 0 to 13 + 6 weeks in 56,771 singleton pregnancies, including 56,376 cases with a normal karyotype or delivery of a phenotypically normal baby (unaffected group) and 395 cases with trisomy 21. The blood test and ultrasound scan were carried out in the same visit. In each case the maternal age-related risk for trisomy 21 at term was calculated and adjusted according to the gestational age at the time of screening to derive the a-priori risk. The measured NT was transformed into a likelihood ratio using the mixture model of NT distributions. The measured free beta-hCG and PAPP-A were converted into a multiple of the median (MoM) for gestational age, adjusted for maternal weight, ethnicity, smoking status, method of conception and parity, and a likelihood ratio was subsequently calculated. The likelihood ratios for NT and for the biochemical markers were multiplied by the a-priori risk to derive the patient-specific risk. Detection rates and false-positive rates were calculated by taking the proportions with risks above a given risk threshold after adjustment for maternal age according to the distribution of pregnancies in England and Wales in 2000-2002. These standardized rates were compared with detection and false-positive rates estimated using Monte Carlo methods to sample from the modeled Gaussian distributions.

RESULTS: The performance of screening based on the model was in good agreement with that observed in our population. In a strategy for first-trimester combined screening where the blood test and scan are carried out in the same visit it was estimated that, for false-positive rates of 3% and 5%, the detection rates were 92% and 94%, respectively, at 11 weeks, 85% and 90% at 12 weeks, and 79% and 83% at 13 weeks. In an alternative strategy, with the blood taken at 10 weeks and the measurement of NT performed at 12 weeks, the estimated detection rates were 94% and 96% for false-positive rates of 3% and 5%, respectively.

CONCLUSIONS: The aim of the first-trimester scan is not just to screen for trisomy 21 but also to diagnose an increasing number of fetal malformations. In this respect the ability to visualize fetal anatomy is better at 12-13 weeks than at 11 weeks. Consequently, the ideal gestation for combined testing in the same visit would be 12 weeks. An alternative strategy, with the blood taken at 10 weeks and the measurement of NT performed at 12 weeks, is associated with higher detection rates of trisomy 21. However, the cost of two-stage screening would be higher and, in addition, the potential advantage in terms of detection rate may be eroded by the likely increased non-compliance with the additional step.