Personalized Care for Prenatal Stress Reduction & Prevention of Preterm Birth (PTB) Disparities

Personalized Toolkit Building a Comprehensive Approach to Resource Optimization and Empowerment in Pregnancy & Beyond (PTBCARE+) A Randomized Controlled Trial (RCT) of Personalized Care for Prenatal Stress Reduction and Preterm Birth Disparities Prevention

The goal of this clinical trial is to learn if a personalized prenatal support program [(Personalized Toolkit Building a Comprehensive Approach to Resource optimization and Empowerment in Pregnancy & Beyond, (PTBCARE+)] works to lower stress and lower the risk of early delivery in pregnant individuals at high-risk for delivering preterm. The main question[s] it aims to answer are:

• Does the PTBCARE+ patient support program lower patient-reported stress levels during pregnancy?
• Does the PTBCARE+ patient support program improve biologic measures of stress during pregnancy?
• Does the PTBCARE+ patient support program result in a higher chance of delivering a healthy baby at or close to full term?

Researchers will compare people who participate in the PTBCARE+ patient support program to those receive usual care to see if the PTBCARE+ patient support program lowers patient-reported stress, improves biologic measures of stress, and increases the chance of delivering a healthy baby at or close to full term.

Participants will be randomly assigned to receive the PTBCARE+ patient support program or usual prenatal care.

All participants will be asked to:

• complete 2 study visits during pregnancy - including completing electronic surveys, providing a blood and urine sample, measuring the heart rate variability by a clip or the ear or finger, and body composition evaluation using a simple scale-like device.
• complete one study visit postpartum that includes completing electronic surveys, and measuring heart rate variability. Blood and urine sample collection and body composition evaluation via InBody scale are optional at the postpartum visit.

People who are randomly assigned to receive the PTBCARE+ support program will receive several resources to help them during pregnancy. These things include items such as:

• a stress reduction toolkit;
• access to an online website that can also be downloaded as a smart phone app;
• the option to receive an electronic massage while in clinic, and more.
• additional support gifts provided at routine clinical appointments

People who are randomly assigned to receive usual prenatal care will not receive any additional support resources from the study during pregnancy.

This project addresses the major public health problem of preterm birth (PTB), delivery <37 weeks, by deploying a novel, personalized, comprehensive 3-tier PTB prevention program [University of North Carolina (UNC) PTBCARE+]. PTB affects 1 in 10 infants born in the United States (US) and is the leading cause of neonatal morbidity and mortality; survivors are at high risk for lifelong adverse health sequelae. Stress is an established risk factor for both spontaneous PTB (sPTB) and medically indicated PTB miPTB). Of significant public health concern, Black patients have 49% higher rates of PTB, are more likely to have early PTB, and increased perceived stress in pregnancy compared to patients of other races. Stress may alter biology, including stress-related gene expression in maternal blood and allostatic load index. Evidence from other fields of medicine supports incorporation of both stress reduction programs and 'patient navigators' as effective approaches to improve health outcomes, and data in obstetrics supports improved outcomes with PTB specialty clinics. However, such programs are not routinely employed in obstetrics. The effect of a specialty prenatal care program targeting stress reduction as a strategy to reduce PTB and PTB disparities remains unknown, representing a critical knowledge gap.

The central hypothesis of this project is that enrollment in a personalized, comprehensive PTB support program (UNC PTBCARE+) is associated with reduced perceived stress, stress-related gene expression, allostatic load, and lower rates of PTB <35 weeks. This hypothesis is supported by published and preliminary data as follows: First, UNC pregnant patients at high risk for PTB have high rates of stress and life stressors (e.g., financial insecurity, racism). Second, biologic stress markers including gene transcript levels differ by PTB status in mid-pregnancy blood. Third, specialty PTB care reduces stress in a NC cohort. Building upon prior work and that of others, this exciting proposal evaluates the efficacy of the novel UNC PTBCARE+ program.

The investigation focus on PTB <35 weeks due to its relative frequency, higher association with neonatal morbidity and mortality as compared to later PTB, to include PTB in the 34th week of gestation (because the delivery gestational age considered 'standard of care' for delivery among individuals with stable but severe preeclampsia and preterm membrane rupture), and to align with multiple other published PTB RCTs. This study will recruit 1,350 pregnant patients between 8+0 and 19+6 weeks gestation with an elevated a priori risk of either medically-indicated preterm birth or spontaneous preterm birth. Subjects will be randomized 2:1 to receive UNC PTBCARE+ vs. usual care. Randomization will be stratified based on maternal race and ethnicity (individuals who identify only as White and non-Hispanic vs. individuals who identify as belonging to one or more other races and/or Hispanic ethnicity and (b) perceived stress scores (those with perceived stress scores ≥20 vs. those with lower perceived stress scores scores).

All participants, regardless of randomization assignment, will have 2 study visits during pregnancy.

• Visit 1 (V1) will occur at randomization, 8+0 - 19+6 weeks gestation.
• Visit 2 (V2) will occur in mid pregnancy, between 22+0 and 29+6 weeks gestation.

At both visits, patients will complete validated surveys evaluating a broad spectrum of stressors, discrimination, adverse childhood experiences, perceived social support, resiliency, medication barriers and adherence, care access and satisfaction,, intervention fidelity and sustainability, use of stress relief modalities, and have blood collected to measure biologic stress markers.

The UNC PTBCARE+ program is personalized. All patients randomized to UNC PTBCARE+ receive a stress reduction toolkit and will work with a PTB Care Coordinator who will provide support, facilitate clinician-prescribed medical care, and serve as a patient-provider liaison. Additional benefits / support items and support elements are provided to some participants on an "as needed" basis, per study protocol, and are not included in the initial registration to preserve scientific integrity and protect the rights of research participants. This study registration will be updated with complete intervention details after the study is fully enrolled and all participants have delivered.

Psychosocial and financial stressor screening results from V1 will determine UNC PTBCARE+ tier assignment. Thus, participants are randomized only after Visit 1 surveys are completed.

This solutions-oriented RCT of UNC PTBCARE+ vs. usual care provides an ideal forum to test the primary hypothesis and study stress-related PTB pathophysiology through the following Aims:

• Aim 1. Evaluate the effects of the UNC PTBCARE+ program on perceived stress and resilience in pregnant patients at high risk for PTB. Hypothesis: Patients randomized to UNC PTBCARE+ will have lower levels of perceived stress and higher levels of resilience at V2 vs. V1; those randomized to usual care will have no change.
• Aim 2. Quantify the extent to which the UNC PTBCARE+ program is associated with improved biologic stress measures during pregnancy. Hypothesis: Patients randomized to UNC PTBCARE+ will have reduced stress-related gene expression and allostatic load scores in maternal blood at V2 vs. V1 compared to those randomized to usual care who will have no change, increasing insight into PTB pathophysiology.
• Aim 3. Determine the effects of the UNC PTBCARE+ program on PTB <35 weeks. Hypothesis: Patients randomized to UNC PTBCARE+ will have lower rates of early PTB compared to those randomized to usual care.

This study provides tangible, personalized solutions to the major public health problem of PTB and carries enormous potential to provide generalizable, low-risk strategies to reduce PTB and related disparities.

Inclusion Criteria:

1. Viable, singleton pregnancy, 8+0 to 19+6 weeks, dated by last menstrual period ± ultrasound using standard obstetric criteria per American College of Obstetricians and Gynecologists.

   Gestational age at first ultrasound by last menstrual period (LMP) / Ultrasound method / Measurement agreement with LMP required • Up to 8 weeks 6 days / crown rump length / ± 5 days

   • 9 weeks 0 days to 13 weeks 6 days / crown rump length / ± 7 days
   • 14 weeks 0 days to 15 weeks 6 days / standard fetal biometry / ± 7 days
   • 16 weeks 0 days to 19 weeks 6 days / standard fetal biometry / ± 10 days
   • Gestational dating / fetal viability must be confirmed by ultrasound prior to enrollment / randomization.
   • Ultrasound report must include documentation of normal fetal heart rate of ≥ 120 beats per minute, or subsequent medical record documentation of auscultation of fetal heart rate ≥ 120 beats per minute.
   • Viability must be confirmed / re-confirmed within 7 days of randomization.

   If initial consent occurs early in pregnancy and V1/randomization occur later, viability must be reconfirmed to ensure ongoing eligibility prior to initiating V1 activities (including surveys) and proceeding with randomization.

2. No signs or symptoms of, or clinical diagnosis of, evolving miscarriage, active preterm labor, preterm prelabor rupture of membranes at the time of enrollment.

   • Cervical dilation at the time of enrollment is an exclusion criterion. However, cervical evaluation and digital cervical exam is not required prior to enrollment.

     (3a) High a priori risk for medically indicated preterm birth - must meet at least one of the following 3 criteria (maternal medical history, prior pregnancy history, or moderate risk factor history)

   • miPTB criteria #1: Maternal Medical History - any one of the following:

     o Known chronic hypertension requiring medications in the 3 months prior to conception or prior to 22 weeks gestation.

     o At least 2 blood pressure readings 6 hours apart, <20 weeks gestation, with systolic ≥ 130 mmHg or diastolic ≥ 80 mmHg *regardless of need for medication or formal diagnosis of hypertension in chart*

     o Pre-gestational diabetes mellitus.

     • Diabetes diagnosed <20 weeks gestation.

     • Maternal chronic or sub-acute renal disease, including chronic kidney failure, chronic renal insufficiency, glomerulonephritis, lupus nephritis, defined as any:

       *biopsy proven chronic renal disease history; and/or

       *serum creatinine ≥ 1.1 mg/dL at any time during pregnancy prior to enrollment, in the absence of other identifiable transient factors per clinician's assessment (e.g., extreme dehydration, cystitis, pyelonephritis); and/or

       *chronic proteinuria, defined as baseline urine protein:creatinine ratio ≥ 0.30 mg/dL or 24 hour total urine protein ≥ 300 mg in the absence of other identifiable transient factors per clinician's assessment (e.g., extreme dehydration, cystitis, pyelonephritis)

       *Systemic Lupus Erythematosus

       • Antiphospholipid Antibody Syndrome

   • miPTB criteria #2: Prior pregnancy history - any ONE of the following: o Previous pregnancy complicated by preeclampsia or hypertensive disorders of pregnancy at any gestational age, in a singleton gestation; the fetus must not have had major structural anomalies or aneuploidy.

     o Previous history of stillbirth ≥ 16+0 weeks in a singleton gestation; the fetus must not have had major structural anomalies or aneuploidy. The stillbirth etiology must not have been attributed to physical trauma (e.g., domestic violence, motor vehicle accident) or illicit drug use (e.g., cocaine use leading to abruption and stillbirth).

   • miPTB criteria #3: Any two or more of the following moderate risk factors: o Nulliparity, defined as no prior pregnancy to reach at least 20 weeks gestation note that this is the traditional / classic definition of 'nulliparous' and that there is overlap between nulliparity as defined this way and 'preterm birth' due to cervical insufficiency, which allows for deliveries in the 16-19 week gestational age range to be considered as 'preterm births'

     o Obesity: current or pre-pregnancy body mass index ≥30 kg/m^2

     o Family history: first degree relative with a history of preeclampsia

     o Advanced maternal age: maternal age ≥ 35 years at estimated date of confinement

     o Prior adverse obstetric history - one or more of the following:

     - history of low birth weight or small for gestational age baby in a singleton gestation, defined as weight <10% for gestational age and fetal sex; the fetus must not have had major structural anomalies or aneuploidy.

     - history of adverse pregnancy outcome in a singleton gestation; the fetus must not have had major structural anomalies or aneuploidy.

     o Long interpregnancy interval: ≥ 10 year (3650 day) pregnancy interval, defined as the time (in days) between the date of delivery of the last pregnancy to reach ≥ 20 weeks gestation and the first day of the last menstrual period for the current pregnancy.

     o Black or African-American race (as a proxy for underlying racism) - self-reported. Participants who self-identify as being of more than one racial group will be considered to be of Black race for the purposes of this criterion if one of the racial groups is Black or African-American.

     • Low socioeconomic status, defined as one or more of the following: housing or food insecurity noted in chart within the last year, self-pay or Medicaid insurance, less than high school education

and/or

(3b) High a priori risk for spontaneous preterm birth - must meet at least one of the following 2 criteria (prior pregnancy history or current pregnancy course)

• sPTB criteria #1: Prior pregnancy history

  • EITHER a history of a delivery of a singleton, non-anomalous baby between 16+0 and 34+6 weeks gestation or delivery of a twin, non-anomalous pregnancy between 160 /7and 276 /7 weeks gestation due to spontaneous preterm labor, preterm premature rupture of membranes, cervical insufficiency, or placental abruption - Chart documentation of prior preterm birth, the gestational age of the prior preterm birth (referred to as the 'qualifying delivery') should be determined. If the gestational age at delivery is obtained directly from the medical record and more than one gestational age appears, the greater of the two will be used assuming that neither is the 'source document' (i.e. an ultrasound report with a due date, a c-section report, a delivery note, etc).

Use the following table as a validation of the previous delivery. For example, if the infant was male and weighed more than 2763 grams (6 pounds, 1.5 ounces) then the patient would be ineligible based on history of a preterm birth criteria. This table should only be used to determine whether the qualifying delivery is most likely to be preterm less than 35 weeks gestation when the gestational age CANNOT be verified/calculated by review of the medical records or is not available in the medical records.

Gestational age 90th percentile - boys 90th percentile - girls 33 weeks > 2488g 5 lbs 7.8 oz > 2116g 4 lbs 10.6 oz 34 weeks > 2763g 6 lbs 1.5 oz > 2379g 5 lbs 3.9 oz 35 weeks > 3084g 6 lbs 12.8 oz > 2661g 5 lbs 13.9 oz

• Documented history of a prior pregnancy complicated by asymptomatic cervical shortening <25mm between 16+0 and 23+6 weeks gestation or cervical dilation ≥ 0.5cm requiring cervical cerclage placement prior to 24+0 weeks gestation, even if delivery ultimately occurred ≥ 35 weeks gestation or at term.

  • sPTB criteria #2: Current pregnancy course

• Asymptomatic cervical shortening <25mm in the current pregnancy, diagnosed by transvaginal ultrasound that is performed ≥14+0 weeks gestation, per Registered Diagnostic Medical Sonographer(RDMS) certified Sonographer or physician with transvaginal ultrasound training program (or similar) qualifications

• Cervical cerclage in situ in the current pregnancy due to concern for risk of preterm birth, at the discretion of the primary obstetric provider

  (4) Ability to provide written, informed consent in English or Spanish

  (5) Planned prenatal care at the University of North Carolina at Chapel Hill obstetrics clinics and planned delivery at the University of North Carolina Women's Hospital (Chapel Hill, NC).

Exclusion Criteria:

1. Participation in another intervention based clinical trial during pregnancy that is deemed, at the discretion of the investigative team for the current study or the other concurrent study, to conflict with this research and/or confound the study results.

   o There are some concurrent studies, even those designed to test an intervention, which may be compatible with the current study; this will be reviewed by the investigative leadership team on a case-by-case basis.

2. Previous participation in the PTBCARE+ program in another pregnancy, with randomization to the PTBCARE+ (active intervention) group.

3. Current, ongoing, illicit drug use ≥ 12 weeks gestation.

   • Use of tobacco and/or marijuana products is not an exclusion.
   • Receiving treatment for opioid use disorder with methadone, suboxone, or similar in an approved treatment program is not an exclusion.

4. History of radical trachelectomy

5. Planned voluntary termination of pregnancy.

6. Heavy vaginal bleeding or large subchorionic hemorrhage - defined as:

   • Bleeding as primary reason for unplanned clinic evaluation or emergency room visit within 14 days of potential enrollment
   • Subjective bleeding accompanied by ≥ 4 point drop in the hematocrit within 14 days of potential enrollment
   • Subchorionic hemorrhage or abruption on formal ultrasound with a volume ≥ 64 cubic cm (4cm x 4cm x 4cm) within 14 days of potential enrollment

7. Major congenital anomaly such as major structural deficit of the heart, lungs, brain, or other major organ system

   1. Mild renal abnormalities, clubfoot, isolated cleft lip/palate, etc. in the fetus are not a reason for exclusion.
   2. Isolated 'soft markers' for aneuploidy (such as choroid plexus cysts, echogenic bowel, etc.) are not a reason for exclusion.
   3. If a major congenital anomaly is diagnosed *after* enrollment, the patient will continue to participate in the study, however, the investigators will plan to analyze the study results with and without these individuals included.

8. Positive aneuploidy screening test (traditional biochemical assay, e.g., quad screen - risk of aneuploidy of 1:25 or higher or cell free deoxynucleic acid (DNA) test result that is screen positive for trisomy 13, trisomy 18, trisomy 21, or sex chromosome abnormality) in the absence of definitive fetal karyotype evaluation.

   • Definitive fetal karyotype evaluation can only be obtained through direct testing of the tissue from the conceptus - by chorionic villus sampling or amniocentesis during pregnancy.
   • The term "suspected aneuploidy" is commonly used in the medical record but this is not a diagnosis and by itself is not informative and not an exclusion criteria.

9. Cystic hygroma or abnormally thickened nuchal translucency ≥ 3 mm at any time in the current gestation, regardless of subsequent diagnostic testing results.

   • Note that a cystic hygroma remains an exclusion criterion regardless of subsequent diagnostic testing results because fetuses with this history carry an elevated risk of major congenital heart disease.
   • Fetal echocardiogram is most accurately performed at 22-24 weeks gestation, which is later than the enrollment gestational age window.

10. Polyhydramnios at or prior to enrollment.

    o Polyhydramnios is defined as a maximum vertical pocket ≥ 8.0 cm, given that polyhydramnios <22 weeks has a high likelihood of being associated with congenital anomalies/aneuploidy and/or preterm birth due to preterm prelabor rupture of membranes.

11. For potential participants who meet eligibility criteria ONLY due to prior spontaneous or medically indicated preterm birth: if the prior preterm birth was in a pregnancy complicated by twins, confirmed fetal aneuploidy, or major congenital fetal anomalies in the absence of another pregnancy meeting inclusion criteria they are not eligible.

12. Known HIV positive with viral load greater than 1,000 copies/mL or cluster of differentiation 4 (CD4) count less than 350/mm^3

13. Unwillingness to undergo randomization.