Clinical trial NCT03151330: Serum Assessment of Preterm Birth Outcomes Compared to Historical Controls: AVERT PRETERM TRIAL
Official title: Serum Assessment of Preterm Birth: Outcomes Compared to Historical Controls
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Preterm Birth
Lead sponsor: Christiana Care Health Services
Sponsor class: OTHER
First posted: 2017-05-12
Enrollment: 1873
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Women who are found to have an elevated risk of preterm birth will receive counseling regarding potential interventions and compared to historical controls
Primary purpose: DIAGNOSTIC

Brief summary: 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.

Detailed description: 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;

1. = one event for (RDS, BPD, grade III or IV IVH, PVL, proven sepsis, or NEC) and no perinatal mortality,
2. = two events and no perinatal mortality;
3. = 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,

1. = 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;
2. = two events or between 5 and 20 days in the NICU, and no perinatal mortality;
3. = three or more events or \>20 days in the NICU, and no perinatal mortality;
4. = perinatal mortality.

3) 0 to 6 scale without NICU: This score was defined as the following: 0 = no events;

1. = one event for (RDS, BPD, grade III or IV IVH, proven sepsis, or NEC) and no perinatal mortality,
2. = two events and no perinatal mortality;
3. = three events and no perinatal mortality;
4. = four events and no perinatal mortality;
5. = five events and no perinatal mortality;
6. = 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Neonatal Mortality Index
timeFrame: Birth through 6 months
measure: Neonatal NICU length of stay
timeFrame: Birth to 6 months
Secondary outcomes:
measure: Preterm birth
timeFrame: Through pregnancy completion, typically 42 weeks
measure: Total length of hospital stay for any preterm birth
timeFrame: From birth to 60 days post delivery
Other outcomes:
measure: Neonatal death and stillbirth
timeFrame: Through 42 days post delivery
measure: Birthweight and if birthweight was <1500g
timeFrame: At time of delivery
measure: Birthweight and if birthweight was <2500gm
timeFrame: At time of delivery
measure: Whether or not received surfactant and amount of surfactant
timeFrame: Through hospitalization or 60 days post delivery
measure: Occurrence of pneumonia
timeFrame: Through hospitalization or 60 days post delivery
measure: Number of days of mechanical ventilation
timeFrame: Through hospitalization or 60 days post delivery
measure: Occurrence of 5 minute Apgar<7
timeFrame: At time of birth
measure: Occurrence of asphyxia, diagnosed either via intrapartum cord gas or via clinical findings
timeFrame: At tiem of birth
measure: Occurrence of preterm delivery at <37, <35 and <32 weeks
timeFrame: At time of birth
measure: Occurrence of preeclampsia
timeFrame: Through 60 days post delivery
measure: Progesterone levels determined by LC-MS
timeFrame: at 32 weeks
Locations:
city: Newark
country: United States
facility: Christiana Hospital
state: Delaware
Study officials:
affiliation: ChristianaCare
name: Matthew K Hoffman, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Berghella V, Rafael TJ, Szychowski JM, Rust OA, Owen J. Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis. Obstet Gynecol. 2011 Mar;117(3):663-671. doi: 10.1097/AOG.0b013e31820ca847.
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citation: Esplin MS, Elovitz MA, Iams JD, Parker CB, Wapner RJ, Grobman WA, Simhan HN, Wing DA, Haas DM, Silver RM, Hoffman MK, Peaceman AM, Caritis SN, Parry S, Wadhwa P, Foroud T, Mercer BM, Hunter SM, Saade GR, Reddy UM; nuMoM2b Network. Predictive Accuracy of Serial Transvaginal Cervical Lengths and Quantitative Vaginal Fetal Fibronectin Levels for Spontaneous Preterm Birth Among Nulliparous Women. JAMA. 2017 Mar 14;317(10):1047-1056. doi: 10.1001/jama.2017.1373.
citation: Rittenberg C, Newman RB, Istwan NB, Rhea DJ, Stanziano GJ. Preterm birth prevention by 17 alpha-hydroxyprogesterone caproate vs. daily nursing surveillance. J Reprod Med. 2009 Feb;54(2):47-52.
citation: Saade GR, Boggess KA, Sullivan SA, Markenson GR, Iams JD, Coonrod DV, Pereira LM, Esplin MS, Cousins LM, Lam GK, Hoffman MK, Severinsen RD, Pugmire T, Flick JS, Fox AC, Lueth AJ, Rust SR, Mazzola E, Hsu C, Dufford MT, Bradford CL, Ichetovkin IE, Fleischer TC, Polpitiya AD, Critchfield GC, Kearney PE, Boniface JJ, Hickok DE. Development and validation of a spontaneous preterm delivery predictor in asymptomatic women. Am J Obstet Gynecol. 2016 May;214(5):633.e1-633.e24. doi: 10.1016/j.ajog.2016.02.001. Epub 2016 Feb 11.
citation: Romero R, Conde-Agudelo A, El-Refaie W, Rode L, Brizot ML, Cetingoz E, Serra V, Da Fonseca E, Abdelhafez MS, Tabor A, Perales A, Hassan SS, Nicolaides KH. Vaginal progesterone decreases preterm birth and neonatal morbidity and mortality in women with a twin gestation and a short cervix: an updated meta-analysis of individual patient data. Ultrasound Obstet Gynecol. 2017 Mar;49(3):303-314. doi: 10.1002/uog.17397.