Modified multiple marker aneuploidy screening as a primary screening test for preeclampsia

Abstract

Background Abnormal levels of maternal biochemical markers used in multiple marker aneuploidy screening have been associated with adverse pregnancy outcomes. This study aims to assess if a combination of maternal characteristics and biochemical markers in the first and second trimesters can be used to screen for preeclampsia (PE). The secondary aim was to assess this combination in identifying pregnancies at risk for gestational hypertension and preterm birth. Methods This case-control study used information on maternal characteristics and residual blood samples from pregnant women who have undergone multiple marker aneuploidy screening. The median multiple of the median (MoM) of first and second trimester biochemical markers in cases (women with PE, gestational hypertension and preterm birth) and controls were compared. Biochemical markers included pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF), human chorionic gonadotropin (hCG), alpha feto-protein (AFP), unconjugated estriol (uE3) and Inhibin A. Logistic regression analysis was used to estimate screening performance using different marker combinations. Screening performance was defined as detection rate (DR) and false positive rate (FPR). Preterm and early-onset preeclampsia PE were defined as women with PE who delivered at < 37 and < 34 weeks of gestation, respectively. Results There were 147 pregnancies with PE (81 term, 49 preterm and 17 early-onset), 295 with gestational hypertension, and 166 preterm birth. Compared to controls, PE cases had significantly lower median MoM of PAPP-A (0.77 vs 1.10, p < 0.0001), PlGF (0.76 vs 1.01, p < 0.0001) and free-β hCG (0.81 vs. 0.98, p < 0.001) in the first trimester along with PAPP-A (0.82 vs 0.99, p < 0.01) and PlGF (0.75 vs 1.02, p < 0.0001) in the second trimester. The lowest first trimester PAPP-A, PlGF and free β-hCG were seen in those with preterm and early-onset PE. At a 20% FPR, 67% of preterm and 76% of early-onset PE cases can be predicted using a combination of maternal characteristics with PAPP-A and PlGF in the first trimester. The corresponding DR was 58% for gestational hypertension and 36% for preterm birth cases. Conclusions Maternal characteristics with first trimester PAPP-A and PlGF measured for aneuploidy screening provided reasonable accuracy in identifying women at risk of developing early onset PE, allowing triage of high-risk women for further investigation and risk-reducing therapy. This combination was less accurate in predicting women who have gestational hypertension or preterm birth.

Clinical validation of novel second-trimester preterm preeclampsia risk predictors combining clinical variables and serum protein biomarkers

“…46 However, Inhibin A on its own or in combination with other serum biomarkers developed for aneuploidy and fetal anomaly screening demonstrates insufficient predictive performance to be clinically useful. 47,48 INHBC is a less well-characterized member of the inhibin family. After the work reported here was performed, INHBC was reported to act through the activin receptor-like kinase 7 (ALK7).…”

“…49 However, Inhibin A, alone or in combination with other aneuploidy and fetal anomaly biomarkers, demonstrates insufficient predictive performance for clinical use. 50,51 INHBC, a less well-characterized inhibin family member comprised of activin C homodimers, was recently reported to function through activin receptor-like kinase 7 (ALK7), which participates in angiogenesis, cytokine activity, hormone signaling, and embryonic development. 52 Expressed in villous and extravillous trophoblasts, ALK7 is dysregulated in placentas from individuals with PE 53 and is a mediator of hypoxia-induced impairment trophoblast invasion.…”

Pravastatin in preeclampsia: A meta-analysis and systematic review

“…Another important field of preeclampsia screening is based on laboratory biochemical markers. These mentioned biochemical markers are the following: pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF), alpha feto-protein (AFP), human chorionic gonadotropin (hCG), unconjugated estriol (uE3), Inhibin A, soluble-endoglinin (sEng), and soluble Flt-1 (sFlt-1) (65,67).…”

Prenatal screening for preeclampsia: the roles of placental growth factor and pregnancy–associated plasma protein A in the first trimester and placental growth factor and soluble fms-like tyrosine kinase 1–placental growth factor ratio in the early second trimester

“…This study was based on the same study population as our previously published study; however, unique to this study is the focus on PAPP-A and PlGF in the first trimester and the addition of sFlt-1 and the sFlt-1–PlGF ratio in the early second trimester. 9 The markers were also measured using a different assay platform in each study. Although the most optimal screening protocol for PE in the first trimester uses a combination of maternal characteristics, MAP, maternal serum PlGF and PAPP-A, and UTPI, it may not be feasible to implement this comprehensive protocol in a routine screening population because of limitations in resources and access to UTPI measurement.…”

“…Given that PlGF and PAPP-A are already used in enhanced first-trimester screening (eFTS) for aneuploidy, PE screening may be introduced before UTPI is widely available or as a 2-stage test with maternal characteristics and biochemical markers as the primary test, reserving MAP and UTPI as secondary tests for pregnancies determined to be at increased risk. 9 , 10 In this study, we will evaluate the performance of PE screening using maternal characteristics and PlGF and PAPP-A only to assess if they can be used to identify women who should proceed with MAP and UTPI for a more accurate PE risk assessment.…”