Evaluation of a Maternal Plasma RNA Panel Predicting Spontaneous Preterm Birth and Its Expansion to the Prediction of Preeclampsia

Abstract

Preterm birth is the principal contributor to neonatal death and morbidity worldwide. We previously described a plasma cell-free RNA panel that between 16 and 20 weeks of pregnancy had potential to predict spontaneous preterm birth (sPTB) ≤ 32 weeks caused by preterm labor (PTL) or preterm premature rupture of membranes (PPROM). The present study had three objectives: (1) estimate the RNA panel prognostic accuracy for PTL/PPROM ≤ 32 weeks in a larger series; (2) improve accuracy by adding clinical characteristics to the predictive model; and (3) examine the association of the RNA panel with preeclampsia. We studied 289 women from Memphis TN prospectively sampled 16.0–20.7 weeks and found: (1) PSME2 and Hsa-Let 7g were differentially expressed in cases of PTL/PPROM ≤ 32 weeks and together provided fair predictive accuracy with AUC of 0.76; (2) combining the two RNAs with clinical characteristics improved good predictive accuracy for PTL/PPROM ≤ 32 weeks (AUC 0.83); (3) NAMPT and APOA1 were differentially expressed in women with ‘early-onset preeclampsia’ (EOP) and together provided good predictive accuracy with AUC of 0.89; and (4) combining the two RNAs with clinical characteristics provided excellent predictive accuracy (AUC 0.96). Our findings suggest an underlying common pathophysiological relationship between PTL/PPROM ≤ 32 weeks and EOP and open inroads for the prognostication of high-risk pregnancies.

Maternal Plasma RNA in First Trimester Nullipara for the Prediction of Spontaneous Preterm Birth ≤ 32 Weeks: Validation Study

“…The RNA-only AUC for APOA1 = 0.73 (95% CI 0.60–0.87) provided a DR = 75%. This DR is similar to the RNA-only AUC = 0.76 (95% CI 0.65–0.87) achieved in a prospective cohort study at 16–20 weeks [ 10 ], suggesting the overall accuracy of the RNA panel for sPTB ≤ 32 weeks is unaffected by parity and may be useful in the first trimester. Combining APOA1 with CRL, MW, MA, race, and tobacco use achieved an AUC = 0.79 (95% CI 0.66–0.91) for sPTB ≤ 32 weeks with a DR = 79%.…”

“…Combining APOA1 with CRL, MW, MA, race, and tobacco use achieved an AUC = 0.79 (95% CI 0.66–0.91) for sPTB ≤ 32 weeks with a DR = 79%. This is similar to the AUC = 0.83 (95% CI 0.74–0.92) achieved in the 16–20-week samples with a DR = 77% when race and a history of prior PTB were combined [ 10 ]. The fact that the majority of women destined for sPTB ≤ 32 weeks can be identified by 12–14 weeks suggests that their risk is already ‘set’ in the absence of therapeutic intervention.…”

“…The five RNAs comprising the current panel were previously shown to have low expression in controls but overexpressed in cases [ 9 , 10 ], and in the current study, there were subjects in whom one or more of the RNA levels fell below assay detection, and more often than was seen in the 16–20 weeks study [ 10 ]. PSME2 was undetectable in 5% (1/20) of controls and 10% (4/40) of cases ( Figure 1 ), NAMPT was undetectable in 60% (12/20) of controls and 52.5% (21/40) of cases, APOA1 was undetectable in 50% (10/20) of controls and 17.5% (7/40) of cases, APOA4 was undetectable in 65% (13/20) of controls and 32.5% (13/40) of cases, and, lastly, Hsa-LET-7g was undetectable in 10% (2/20) of controls and 5% (2/40) of cases.…”

“…The current study is the third validation study of this five RNA panel specifically selected based on their relationship to a unique set of myometrial RNAs overexpressed in women delivering <32 weeks [ 9 ]. Like the prospective cohort validation study performed at 16–20 weeks [ 10 ], only two of the five panel RNAs were predictive, PSME2 and APOA1 at 12–14 weeks, and APOA1 was the best performer. The RNA-only AUC for APOA1 = 0.73 (95% CI 0.60–0.87) provided a DR = 75%.…”

“…Prior reports demonstrate a maternal blood test consisting of five plasma cell-free (PCF) RNAs ( PSME2 , NAMPT , APOA1 , APOA4 , and Hsa-Let-7g ) measured at 16–20 weeks may be a good predictor of sPTB ≤ 32 weeks [ 9 , 10 ]. A prospective cohort validation study revealed specific panel markers had good to excellent predictive accuracy for PTB ≤ 32 weeks, whether due to spontaneous labor (± preterm premature rupture of membranes (PPROM)) or early-onset preeclampsia (EOP) < 34 weeks independent of parity [ 10 ]. While the predictive accuracy for sPTB ≤ 32 weeks was encouraging (AUC = 0.83), antenatal screening has moved progressively to the first trimester for EOP and potentially sPTB ≤ 32 weeks.…”