Plasma RNA-Based Dual Screening for Early/Extreme Spontaneous Preterm Birth and Early Onset Preeclampsia to Enable Prevention

<b>Background/Objectives</b>: Preterm birth (PTB) at <33 wks' gestation annually accounts for more than 60,000 births in the United States and 2 million births worldwide. Of these, spontaneous PTB (sPTB) at <33 wks' gestation complicates about 1.8% of US births, while early onset preeclampsia (EOP), necessitating delivery at ≤33 wks' gestation, complicates an additional 0.8% of US births. Current screening is based on medical and pregnancy history and biophysical variables with the goal of sensitizing patients and caregivers to early symptom identification. There is no individual patient risk prediction for sPTB at ≤33 wks' gestation. We now have preventative therapies for women at high risk for EOP with delivery at <33 wks' gestation (aspirin) and sPTB at ≤33 wks' gestation (+/- preterm premature rupture of membranes (PPROMs)) (docosahexaenoic acid (DHA). Both require initiation of therapy by ~16 wks' gestation for optimal effect, a requirement that current screening options cannot satisfy except for the FMF Combined Test for EOP. Neither do we have either an effective first-trimester screen for sPTB nor a dual screen for both of these major obstetric disorders. <b>FutureBIRTH</b>^® is a maternal five-plasma RNA panel supported by multiple external validation studies to provide effective dual screening for sPTB at <33 wks' gestation and EOP with delivery at ≤33 wks' gestation. Herein, we present the second external validation study for EOP with delivery at ≤33 wks with maternal sampling 12-13 wks 6 d combined with a review of the potential clinical impact of <b>FutureBIRTH</b>^® on the prevention of sPTB and EOP. <b>Methods</b>: Two NIH cohorts totaling 494 women were sampled from 12 to 20 wks. <b>FutureBIRTH</b>^® marker expression was quantified by polymerase chain reaction (PCR) as in the four preceding external validation studies. <b>Results</b>: After appropriate exclusions, there were nine cases (2.4%) of EOP with delivery at ≤33 wks gestation and 370 controls. Of this cohort, 79 (21%) were sampled at <14 wks' gestation. Two of the nine cases were sampled at <14 wks' gestation. NAMPT expression at 12-20 wks' gestation was significantly increased in women destined for EOP with delivery at ≤33 wks' gestation. Only the addition of diastolic blood pressure improved the predictive accuracy of NAMPT, yielding an AUC of 0.89 with a DR of 89% (8/9). Two cases sampled at <14 wks' gestation who developed EOP with delivery at ≤33 wks' gestation were screen positive, and two subjects placed on aspirin before 14 wks' gestation were screen false positives. <b>Conclusions</b>: <b>FutureBIRTH</b>^® offers dual screening for EOP and sPTB with a sampling window extending down to 12 wks' gestation, thus enabling the widespread use of preventative therapy.