First-Trimester Biochemical Markers of Aneuploidy and the Prediction of Small-for-Gestational Age Fetuses

Abstract

Measurement in the first trimester of blood levels of the placentally derived biochemical markers pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG), together with ultrasound measurement of nuchal translucency thickness, are increasingly being used as part of screening programs for trisomy 21 and other aneuploidies. Preliminary studies have suggested that reduced levels of PAPP-A and free β-hCG could be useful for identifying pregnancies that result in small-for-gestational age (SGA) infants and other adverse outcomes. This study evaluated the ability of measurement of free β-hCG and PAPP-A levels to predict SGA in a cohort of 49,801 British women prospectively screened in the first trimester. Between 1998 and 2003, singleton pregnant women presenting for maternity care at United Kingdom hospitals were screened for trisomy 21 by combined measurement of maternal serum free β-hCG and PAPP-A and nuchal translucency thickness scans at 11 + 0 to 13 + 6 weeks of gestation. All study participants had complete outcome data and normal fetal karyotypes. The free β-hCG and PAPP-A measurements were expressed as multiples of the expected normal median (MOM) for a pregnancy of the same gestational age. The control group consisted of 46,262 pregnancies resulting in live births at full term; the study group included 3539 pregnancies resulting in live births of SGA infants, divided into 3 subgroups based on birth weight below the 10th, fifth, and third centiles for gestational age. The association between these 2 biochemical markers and the frequency of SGA were investigated by comparing the relative incidence of each marker at a number of MoM cutoffs and various birth weight centile cutoffs. The median PAPP-A level was significantly lower in the SGA group than in the normal group for all 3 categories of SGA (P < 0.001). When the PAPP-A level was 0.415 MoM, which corresponded to the fifth percentile in the normal group, the odds ratios for SGA below the 10th, fifth, and third percentiles were 2.70, 3.21, and 3.66, respectively, and the respective detection rates for SGA were 12.0%, 14.0%, and 16.0%. Significant differences in free β-hCG MoM between the SGA group and the normal group were not found (P = ns). The investigators believe that these findings together with earlier studies provide sufficient evidence to use low levels of maternal serum PAPP-A to help in identifying the pregnancies at increased risk for delivery of an SGA infant.