Serum Assessment of Preterm Birth Outcomes Compared to Historical Controls: AVERT PRETERM TRIAL

Background: Preterm birth (PTB) remains the leading cause of neonatal mortality and long term disability throughout the world. Recently treatments early in pregnancy such as progesterone, cervical support and maternal support have been demonstrated to delay delivery amongst at risk women. Nonetheless, the majority of women who are at risk are not identified using current screening modalities. Hypothesis: A cohort of pregnancies who are screened using the PreTRM® test around 20 weeks gestation in which a bundle of interventions is given for elevated PreTRM® risk will show either decreased neonatal morbidity/and mortality (measured as a composite score, "NMI"), or decreased length of neonatal stay in the hospital (NNOLOS). Secondarily, they will show an increase in gestational age at birth (GAB) and a reduction in length of neonatal NICU stay (NICULOS), compared to an unscreened historical control group. Study Design Type: Prospective cohort study of screened women compared to a historical control of 10000 women.

Population: Women who are 18 years or older, with a singleton pregnancy between 195/7 weeks and 206/7 weeks gestational age (GA) confirmed by ultrasound prior to enrollment, and no history of prior preterm birth (delivery between 160/7 weeks and 366/7 weeks) will be invited to participate. A comparable population will be identified using a historical control group in a contemporaneously maintained database. Intervention: Qualifying women will be screened using the PreTRM® test (Sera Prognostics, Inc.) at a large tertiary care center. Predicated upon the degree of risk, women will be treated according to a prespecified algorithm. The outcomes of these women will be compared to a historical control group at the same tertiary care center. Outcomes: Primary outcome: Co-Primary outcomes: To determine whether a cohort of women who are screened with the PreTRM® test and then managed according to a prespecified protocol will have statistically significant reductions in either (a) composite neonatal morbidity and mortality (NMI score), or (b) length of neonatal hospital stay (NNOLOS), compared to a historical control group. The NMI is defined below DEFINITIONS OF COMPOSITE PERINATAL MORTALITY/NEONATAL MORBIDITY OUTCOME SCORES: 1) 0 to 4 scale without NICU: This score was derived as an ordinal scale based upon severity. The score was defined by the following: 0 = no events; = one event for (RDS, BPD, grade III or IV IVH, PVL, proven sepsis, or NEC) and no perinatal mortality, = two events and no perinatal mortality; = three or more events and no perinatal mortality; 4=perinatal mortality. 2) 0 to 4 scale with NICU: This score was defined as the following: 0 = no events, = one event for (RDS, BPD, grade III or IV IVH, PVL, proven sepsis, or NEC) or <5 days in the NICU, and no perinatal mortality; = two events or between 5 and 20 days in the NICU, and no perinatal mortality; = three or more events or >20 days in the NICU, and no perinatal mortality; = perinatal mortality. 3) 0 to 6 scale without NICU: This score was defined as the following: 0 = no events; = one event for (RDS, BPD, grade III or IV IVH, proven sepsis, or NEC) and no perinatal mortality, = two events and no perinatal mortality; = three events and no perinatal mortality; = four events and no perinatal mortality; = five events and no perinatal mortality; = perinatal mortality. 4) Any morbidity or mortality event: (yes/no) Adapted from Hassan SS, et al. Ultrasound Obstet Gynecol 2011; 38:18-31 Supplementary Information Secondary outcomes: To determine whether women who are screened with the PreTRM® test and then managed according to a pre-specified treatment algorithm will have a statistically significant reduction in proportion of any type of preterm births (spontaneous and indicated), the total length of hospital stay for spontaneous preterm births, and total length of hospital stay for any preterm birth. Observations: Neonatal death and stillbirth Birth weight and number of subjects with birth weight <1500g and <2500g Total number of days spent in the NICU and nursery Composite neonatal morbidity score and components Whether or not received surfactant Occurrence of pneumonia Number of days of mechanical ventilation Number of subjects with 5 minute Apgar < 7 Occurrence of asphyxia Number of preterm deliveries at <37, <35 and <32 weeks Occurrence of preeclampsia Proportion of primiparous women experiencing preterm birth and spontaneous preterm birth NICU days for spontaneous preterm birth in primiparous women in prospective treatment arm are significantly less than NICU days in primiparous women in the control group of sPTB Correlation of blood levels of 17-OHPC and other progestin levels to outcomes and observations General Outcomes: Total cost of hospital care for both the mother and fetus beginning at initiation of care through primary delivery and 28 days of life.

Women who are found to have an elevated risk of preterm birth will receive counseling regarding potential interventions and compared to historical controls

This will be an arm of women who are prospectively screened and receive a risk score for preterm birth. They will be recommended treatment strategies and their outcomes compared to an historical control.

Woman who are identified as high risk will be advised of potential interventions which will include support through care link(nurse education), cervical surveillance, consider vaginal progesterone, low dose aspirin if not already taking.

Outcomes: Co primary outcomes will consist of the Neonatal Morbidity Index as defined by Hassan and Neonatal NICU length of stay

Inclusion Criteria: Women 18 years of age or older Singleton intrauterine pregnancy No medical contraindications to continuing pregnancy Subject has no signs and/or symptoms of preterm labor and has intact membranes Planned delivery at Christiana Care Health System, English speaking as consents from other languages will not be provided. Exclusion Criteria: Women who have taken or plan to take progesterone beyond 14weeks gestation prior to study enrollment Previous history of sPTB less than37 weeks gestation or PPROM less than34 weeks gestation Multiple gestations-including a pregnancy that is now a single fetus due to a reduction procedure, vanishing twin, etc Known fetal genetic anomalies that are incompatible with life. Examples would include trisomy 13 and trisomy 18. Others would be left to the discretion of the site investigators Any other medical conditions that may be considered a contraindication per the judgment of the site investigator The subject has a planned cesarean section or induction of labor prior to 370/7 weeks of gestation The subject has a planned cerclage placement for the current pregnancy Major structural anomalies that may shorten pregnancy- examples would include anencephaly, holoprosencephaly, schizencephaly, gastroschisis, omphalocele, congenital diaphragmatic hernia, pyloric stenosis, etc. Minor anomalies such as polydactyly, unilateral hydronephrosis are not viewed as exclusions. Others would be left to the discretion of the site investigators History of cervical conization The subject has a uterine anomaly, History of classical cesarean section in a previous pregnancy The subject has had a blood transfusion during the current pregnancy The subject has known elevated bilirubin levels (hyperbilirubinemia) Previously identified short cervix (< 2.5 cm by TVUS) The subject has taken or plans to take any of the following medications after the first day of the last menstrual period: Enoxaparin, heparin, heparin sodium, low molecular weight heparin or the subject has a history of allergic reaction to aspirin or progesterone.

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