Screening for trisomy at 11–13 weeks' gestation: use of pregnancy‐associated plasma protein‐A, placental growth factor or both
Authors: Mazer Zumaeta A. , Wright A. , Syngelaki A. , Maritsa V. A. , Bardani E. , Nicolaides K. H. 
Published: July 2020

Objective

Serum pregnancy‐associated plasma protein‐A (PAPP‐A) and placental growth factor (PlGF) at 11–13 weeks' gestation are reduced in pregnancies with fetal trisomy and in those that subsequently develop pre‐eclampsia (PE). In screening for trisomy, the established biochemical marker is PAPP‐A, whereas in screening for PE, the preferred marker is PlGF. The objective of this study was to examine the impact of replacing PAPP‐A by PlGF in first‐trimester screening for trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency thickness (NT) and free β‐human chorionic gonadotropin (β‐hCG).

Methods

This was a prospective screening study in singleton pregnancies for trisomies 21, 18 and 13 by a combination of maternal age, fetal NT and serum PAPP‐A and free β‐hCG at 11–13 weeks' gestation in which we also measured PlGF. Multiples of the median (MoM) values were calculated for PAPP‐A, free β‐hCG and PlGF. The dataset was split randomly into training and test datasets of roughly equal size, and the parameters for PlGF obtained from the training dataset were used in risk calculation for the test dataset. Standardized detection rates were computed by obtaining the likelihood ratios for biochemistry and fetal NT for trisomy‐21, ‐18 and ‐13 pregnancies in the sample and then applying these to each year of maternal age from 12 to 50 to estimate the age‐specific detection rates. These were then weighted according to the maternal age distributions of trisomy‐21, ‐18 and ‐13 pregnancies in England and Wales in 2018. Similarly, standardized false‐positive rates (FPR) were computed by obtaining the likelihood ratios for biochemistry and NT, as appropriate, in normal pregnancies in the sample and then applying these to each year of maternal age from 12 to 50 to estimate the age‐specific FPRs. A modeling approach was used to assess the performance of screening according to gestational age at biochemical testing.

Results

The study population of 71 266 pregnancies included 70 858 (99.4%) with normal fetal karyotype or birth of a phenotypically normal neonate and 263 with trisomy 21, 109 with trisomy 18 and 36 with trisomy 13. There are five main findings of this study. First, the performance of screening for trisomy by the first‐trimester combined test or the combined test in which PAPP‐A is replaced by PlGF is substantially better at 11 than at 13 weeks' gestation; for example, the detection rates of trisomy 21 by the combined test were 94%, 90% and 84%, at 5% FPR, when testing was carried out at 11, 12 and 13 weeks, respectively, and the corresponding values in screening by a test in which PAPP‐A is replaced by PlGF were 90%, 87% and 86%, respectively. Second, in trisomy‐21 pregnancies, the deviation of median PAPP‐A MoM from normal decreases with increasing gestational age, whereas the deviation in PlGF does not change with gestational age. Third, the performance of screening for trisomy 21 during the 11th and 12th gestational weeks is superior if screening includes PAPP‐A rather than PlGF, whereas during the 13th week the performance is slightly higher with the use of PlGF rather than PAPP‐A. Fourth, in our population with mean gestational age at testing of 12.7 weeks, screening by maternal age, fetal NT, serum free β‐hCG and serum PAPP‐A predicted 88%, 96% and 97% of cases of fetal trisomies 21, 18 and 13, respectively, at a FPR of 5%; the respective values in screening by a test in which PAPP‐A is replaced by PlGF were 85%, 96% and 96%. Fifth, addition of serum PlGF does not improve the prediction of trisomy provided by maternal age, fetal NT and serum free β‐hCG and PAPP‐A.

Conclusion

In first‐trimester screening for trisomy, the preferred biochemical marker is PAPP‐A rather than PlGF, especially when biochemical testing is carried out during the 11th week of gestation or earlier. However, if PlGF was to be used rather than PAPP‐A, the same detection rate can be achieved but at a higher FPR. This may be an acceptable compromise to minimize cost and achieve effective screening for both trisomy and PE. © 2020 International Society of Ultrasound in Obstetrics and Gynecology