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The Center for Women’s Health Research provides support for Research Grants and Clinical Trials. The following studies are currently underway

Active Research Grants

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Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Principal Investigator: Kate Menard, MD, MPH – Obstetrics and Gynecology

Project Period: 4/1/23 – 3/1/28

The United States (US) is the only developed nation with rising rates of maternal morbidity and mortality (3M). These unacceptably high rates of 3M in the US are also wrought with racial and ethnic disparities. From 2014-2017 Non-Hispanic Black (NHB) women delivering in the US had a 3.1-fold increased risk of death compared to their Non-Hispanic White (NHW) counterparts. Additionally, the risk of severe maternal morbidity (SMM) among NHB women was 2.1 times higher than NHW women. Both the overall rates of 3M and the racial and ethnic disparities in 3M have become a critical public health focus for the US. It is not entirely understood why US 3M rates are rising nor why the stark racial and ethnic disparities exist, but it is likely that increasing rates of comorbidities such as hypertension, diabetes and obesity, as well as structural barriers to care and systemic racism, are major contributors. A Center for Disease Control and Prevention (CDC) report described that the pregnancy-related mortality (PMR) ratio is higher in rural counties and it increases with increasing rurality. Within each urban-rural category, PMRs were higher among NHB women compared to NHW women. The authors suggested that “geographic location might reflect the intersection of historical structural disadvantage, chronic health conditions, and access to care, including risk appropriate care.” There are evidence-based prevention interventions that can improve outcomes, but many have not been implemented at scale.

Hypertensive disorders of pregnancy, a major contributor to 3M, affect 2-8% of pregnancies globally, with 16% of maternal deaths attributable to hypertensive disorders. In the US, the rate of preeclampsia increased by 25% in the last three decades and severe preeclampsia increased 6.7-fold. Hypertensive disorders of pregnancy are also related to heart failure and other cardiovascular and cerebrovascular contributors to 3M. Unfortunately, NHB women are more likely to have pre-existing chronic hypertension and to be diagnosed with a hypertensive disorder of pregnancy. There are also notable racial differences in onset, presentation, and short- versus long-term complications of hypertensive disorders of pregnancy. NHB women diagnosed with hypertensive disorders of pregnancy have an increased risk of intrauterine fetal demise, stroke, pulmonary edema, heart failure and renal failure relative to NHW women, often necessitating iatrogenic preterm delivery. Compared to NHW women, NHB women are also at a higher risk of in-hospital mortality related to hypertension.

Focus on treatment of severe pregnancy-related hypertension was selected by the Alliance for Innovation on Maternal Safety (AIM) for development and implementation of a safety bundle because it is recognized as a leading cause of preventable morbidity and mortality. According to the Institute of Healthcare Improvement, patient safety bundles are “a structured way of improving the processes of care and patient outcomes: a small, straightforward set of evidence-based practices…that, when performed collectively and reliably, have been proven to improve patient outcomes”. The Severe Hypertension During Pregnancy and Postpartum Safety Bundle (the HTN bundle) intends to improve life-saving care for pregnant women with chronic hypertension, pregnancy-related hypertension and preeclampsia or eclampsia. The bundle has largely been implemented in inpatient settings, but barriers and opportunities for implementation in an outpatient, community setting are unknown.

North Carolina (NC) is an ideal setting to study implementation strategies to improve treatment of severe pregnancy-related hypertension with specific attention to health disparities. According to the US Census, NC’s population is 63% White, 21% Black or African American, 10% Hispanic or Latino. The 2018 PRAMS survey of women who had given birth in NC found that approximately 14% had experienced high blood pressure during their pregnancy. A study of 56,000 NC births had similar findings; 13% of women experienced hypertension while pregnant. Preeclampsia was the most common disorder among these women and was associated with premature delivery. A 2017-2018 review of SMM in NC found that non-transfusion related SMM occurred in 68.6 women per 10,000 delivery hospitalizations with a significant racial disparity (rate in NHB women 99.1 per 10,000, NHW women 56.0 per 10,000). Additionally, 37% of NC births are to women living in rural counties, where the rate of SMM exceeds that of urban counties. The NC maternal mortality review committee has recognized hypertension as a major contributor to preventable deaths and recommended identification and treatment of severe preeclampsia as a priority for provider education in NC.

Our well-established academic/community partnership is ideally positioned for this work. The NC Department of Public Health and The University of North Carolina’s (UNC) Center for Maternal and Infant Health are already collaborating in NC’s Maternal Health Innovation Program. The program provides a region-based infrastructure to build coalitions to address disparities in maternal health and improve outcomes, inclusive of preventing 3M. The state has six perinatal regions and UNC is situated in Region IV. In a gap analysis carried out by Region IV’s Provider Support Network, our community partner, Piedmont Health Services (PHS), noted the need for the HTN bundle in their federally qualified health center (FQHC) settings. While paths for treatment of hypertensive emergency are being addressed in the inpatient settings in Region IV, adaptation and adoption are needed for effective care in the outpatient, community-based context.

PHS is a non-profit, community-governed organization created in 1970 to broadly address barriers to health care access for low-income and other medically vulnerable populations across a multi-county region. PHS operates ten FQHCs located in Alamance, Caswell, Chatham, and Orange counties, serving more than 48,000 individuals of all ages annually with full-scope family medical and dental care, integrated behavioral health care, comprehensive pharmacy, and nutrition counseling. Additional care support services include care management, interpretation, eligibility assistance and outreach. In 2020, PHS served a population comprised of 45% Hispanic/Latino (of any race), 25% White/Caucasian, 21% Black/African American, 4% unreported, 3% Asian, and 2% more than one race. The population was 52% uninsured, 23% Medicaid, 17% privately insured, and 8% Medicare. Nearly all who applied for sliding fee care had documented household incomes below 200% of the federal poverty level, and 38% preferred care in a language other than English. Hypertension control is one of four quality measures of focus for PHS in 2021, so this project is well-timed for the agency. This project also aligns well with a national focus on hypertension control in community health centers.

Researchers from UNC will convene a regional coalition to carry out Community Implementation of the Severe Hypertension During Pregnancy and Postpartum Safety Bundle, or outpatient bundle (the O-HTN bundle). This community-based coalition includes UNC, PHS, and the community coalition Equity for Moms and Babies Realized Across Chatham (EMBRACe), with representation from key state/regional program efforts on an Advisory Group. The coalition will carry out Phase I of this project to identify adaptations needed to the bundle in PHS clinic settings. Importantly, given the need to address social determinants of health, this project will incorporate elements from the Reduction of Peripartum Racial and Ethnic Disparities complementary bundle into the O-HTN bundle as the 5th “R” – Respectful Care.

Learn more about this study: Maternal Health Community Implementation Project, Press Release

Sponsor: Gilead Research Sciences

Principal Investigator: Chemtai Mungo, MD, MPH – Obstetrics and Gynecology

Project Period: 2/15/23 – 2/14/25

Cervical cancer incidence and mortality trends represent a dire global health inequity, and women living with HIV in low- and middle-income countries (LMICs) bear the greatest burden. LMIC’s accounted for 85% of the estimated 570,000 incident cervical cancer cases and 90% of deaths in 2020. Cervical cancer is an AIDS-defining malignancy. Women with HIV-infection have increased incidence and persistence of human papillomavirus (HPV) the causative agent, and a six- to eight-fold increased risk of developing invasive cervical cancer compared with HIV-negative women. As a result, cervical cancer is the leading cause of cancer death among women with HIV in LMICs, which accounts for 71% of the global burden of HIV infection, despite being home to only 12% of the global population. The World Health Organization (WHO) recommends excisional or ablative treatment for precancerous cervical lesions in a ‘screen-and-treat’ strategy adopted by many LMICs, where a positive screening test is coupled with same-day ablative treatment to reduce loss-to-follow-up. However, women with HIV are more likely to have large lesions not amenable to ablation and need excisional (surgical) therapy which requires referral to tertiary centers with specialized equipment and technical expertise not routinely available in primary care facilities. Due to limited access to specialists, these referrals often result in significant treatment delays, increasing the risk of disease progression where curative options are limited. In a study from a referral hospital in Kenya, the median time from an abnormal screening result to excisional treatment was 167 days. Additionally, excisional treatment is associated with increased obstetrical risks, including preterm birth, which is particularly significant for women with HIV who develop precancer at a younger age and may need multiple excisional procedures to cure cervical precancer. These challenges highlight a need for innovative yet readily accessible strategies, including medical therapies, to help mitigate barriers to excisional treatment for cervical precancer in LMICs, particularly among women with HIV.

The objective of this proposal is to build on evidence from US-based studies and perform a Phase I trial in a LMIC to evaluate the safety, tolerability, and clinical response to self-administered intravaginal Artesunate among both HIV-positive and HIV-negative women with CIN2/3 awaiting excisional therapy. My decade-plus collaboration with Ministry of Health-affiliated clinics in Kenya providing HIV care16–22 combined with the existing robust research infrastructure at the Kenya Medical Research Institute (see letter of collaboration) will enable me to successfully carry out the proposed study. The central hypothesis is that self-administered intravaginal Artesunate will be safe, tolerable, and result in a clinically significant response among both HIV-positive and HIV-negative women in LMICs, paving the way for larger efficacy studies. This proposal is in line with Gilead’s HIV program’s emphasis on supporting innovative clinical research from emerging investigators incorporating new perspectives to advance scientific knowledge in areas of unmet medical need in HIV globally, especially related to management of HIV-related comorbidities or co-infections. Results from this study will inform an NIH R01 proposal for a Phase II randomized efficacy to support my transition to research independence.

Sponsor: The Colombo Plan

Principal Investigator: Hendrée Jones, PhD – Obstetrics and Gynecology

Project Period: 12/1/22 – 5/31/24

Development and training of a strength-based course to help providers improve parenting practices of parents or caregivers of children with substance use disorders.

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Principal Investigator: Michelle Meyer, PhD, MPH – Emergency Medicine

Project Period: 12/1/22 – 7/31/25

In the United States, cardiovascular disease (CVD) is the leading cause of mortality in women, and the prevalence of cardiometabolic risk factors and cardiometabolic-related pregnancy complications are greater in Black and underrepresented women than White women. Race is a social construct and not biological, thus ethnicity/race alone cannot explain the disparities in cardiometabolic complications in pregnancy. These inequalities in cardiometabolic diseases during pregnancy may be explained in part by structural racism, which includes neighborhood environment and residential segregation. Yet, studies on structural racism and CVD risk are limited, particularly in pregnancy and the postpartum period. Therefore, the objective of this proposal is to understand whether structural racism is associated with CVD risk during pregnancy and postpartum among women and infants. This proposal supplements the Mother and Infant Determinants of vascular Aging Study (MIDAS; R01HL157075). The MIDAS study will enroll 840 racially/ethnically diverse healthy and medically complicated mother/infant dyads between 34-40 weeks’ gestation. At 34-40 weeks’ gestation, within 48 hours of delivery, and at 6 and 12 months postpartum, the MIDAS study will assess CVD risk by measuring pulse wave velocity (PWV), and examine relationships among biologic, personal, social, and ecological disease risk factors with PWV. Although neighborhood was a proposed CVD risk factor in the parent grant, this proposal will complement the existing MIDAS study by adding structural racism data and in-depth analysis of these data and CVD risk among women and infants. The study specific aims are to: 1) examine the association between structural racism and maternal arterial stiffness at the 3rd trimester in pregnancy and the trajectory to 1 year postpartum, and 2) determine the association between structural racism and infant arterial stiffness at 6 months and its change to 12 months. This time sensitive supplement leverages access to a large, diverse cohort of pregnant and postpartum women and their infants, and a multi-disciplinary team of mentors with expertise in CVD risk, maternal health, and racial health disparities. As a result, we are well positioned to complete the proposed aims. Additionally, this supplement will enable an early career investigator to: 1) gain experience conducting a well-defined research project evaluating CVD risk in pregnant women and their infants, 2) develop her knowledge on pregnancy-related cardiometabolic biomarkers and macro level risk factors (neighborhood and community-level), 3) further skills in statistical analysis and grantsmanship, and 4) expand her research network and learn from a successful mentorship team. This supplement will be an integral component to the MIDAS study by focusing on structural racism-related risk to maternal and infant cardiovascular health and it will provide an early career investigator with support to advance her career trajectory and establish an independent, fundable research line.

Learn more about this study: NIH RePORT

Sponsor: Doris Duke Charitable Foundation

Principal Investigator: Andrea Knittel, MD, PhD, FACOG – Obstetrics and Gynecology

Project Period: 7/1/22 – 6/30/25

Perinatal incarceration is a critical issue that impacts the health and well-being of an increasing number of pregnant parents and infants affected by substance use disorders (SUD) each year. Pregnancy and the postpartum period present important opportunities for SUD intervention, but incarceration falls short of addressing the needs of this population. This project will define the scope of perinatal incarceration across North Carolina (NC) using a mixed methods assessment of NC jails to determine the prevalence of perinatal incarceration, estimate the magnitude of SUD in this population, and describe jail policies and resources related to perinatal SUD. We will then develop, disseminate, and evaluate the feasibility of a statewide UNC Horizons Justice Core hotline for NC jails to build capacity for SUD referral to case management and treatment instead of incarceration. Outcomes will include 1) a county-level map of perinatal incarceration and local perinatal SUD resources across NC with integrated rich qualitative data to identify areas for intervention and jail and county systems strengths to draw upon for evidence-based treatment of SUD; 2) an assessment of Justice Core feasibility as measured by the number and geographic distribution of contacts/referrals, satisfaction of jail/county staff, and qualitative interviews with jail staff and Justice Core clients. This work will directly impact society by taking important steps to minimize the harms of perinatal incarceration in NC and will set the stage to definitively evaluate the effectiveness of innovative interventions to break generational cycles of incarceration, trauma, and substance use for families affected by SUD.

Learn more about this study: Doris Duke Charitable Foundation, Press Release

Sponsor: National Cancer Foundation

Principal Investigator: Victoria Bae-Jump, MD, PhD – Gynecologic Oncology

Project Period: 12/1/21 – 11/30/23

Obesity is associated with increased risk of developing and succumbing to endometrial cancer (EC), with ~60% of EC patients being obese. Since programmed death protein-1 (PD-1) and its ligand, programmed death-ligand 1 (PD-L1), are highly expressed in ECs, immuno-oncologic inhibitors for these two targets hold great promise for the treatment of obesity-driven EC, especially as ~25% of ECs have microsatellite instability, a known biomarker for PD-1/PD-L1 inhibitor response. Atezolizumab is one such anti-PD-L1 monoclonal antibody (mAb). Our studies suggest the obesity-triggered pro-inflammatory uterine tumor milieu increases PD-L1/2, culminating in enhanced susceptibility to atezolizumab. The efficacy of atezolizumab in EC may be enhanced via ONC201, a small molecular selective dopamine receptor 2 antagonist that upregulates Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand and activates T and natural killer (NK) cells. Thus, ONC201 is a logical therapeutic partner for atezolizumab. However, the use of atezolizumab + ONC201 in EC is complicated by obesity. Compared to small molecule drugs, mAbs are cleared via cells of the mononuclear phagocyte system (MPS; monocytes) which is part of the innate immune system. MPS cells serve as a natural mechanism of uptake and clearance for mAbs via their Fc- gamma-receptors (FcɣRs). Our studies show MPS mediators, number of FcɣRs and function in blood are highly variable and associated with the high and clinically relevant variability in the pharmacokinetics/pharmacodynamics (PK/PD) of mAbs. Obese patients have higher and more variable MPS mediators, FcɣRs and function, resulting in lower exposures of mAbs. Thus, evaluating effects of obesity on the PK/PD of atezolizumab and ONC201 in EC patients is clinically relevant and critically important. Our hypothesis is that atezolizumab + ONC201 will be safe in EC; however, despite obese EC patients having higher expression of PD-L1 and a pro-inflammatory tumor milieu, they will have lower atezolizumab plasma levels, than the non- obese at the same dose due to increased phagocytic clearance, necessitating higher dosing in the obese to achieve serum levels comparable to those of the non-obese patients. We propose a phase 1 clinical trial of the novel combination of atezolizumab + ONC201 using an innovative design of parallel cohorts of obese and non-obese patients with metastatic and recurrent EC. Our primary objective is to evaluate the safety and tolerability of the dual regimen of atezolizumab and ONC201 in obese and non-obese EC patients to find the maximal tolerable dose combination to then advance for both cohorts in a future phase 2 study. In order to comprehensively delineate the impact of obesity on the combination of atezolizumab + ONC201, we will compare between the obese and non-obese EC groups the PK/PD of both agents, biomarkers reflective of the immune-oncology and of the MPS clearance of both agents, and their inflammatory metabolic signatures.

Learn more about this study: NIH RePORT

Sponsor: The National Institute for Occupational Safety and Health (NIOSH)

Principal Investigator: Eric Ryan, PhD – Exercise and Sport Science

Project Period: 9/30/21 – 9/29/23

The fire service has one of the highest rates of occupational injuries incurring a large economic burden. Sudden cardiac death, and strains and sprains from slips, trips and falls and overexertion are frequently cited as the most common fatal and non-fatal injuries. Recent research has demonstrated that high-intensity interval training (HIIT) and multi-factorial neuromuscular training programs that include dynamic stretching, core stability, balance, and medicine ball exercises can specifically target the primary risk factors of these injuries, while improving firefighter performance. However, 75% of firefighters fail to achieve minimum physical activity recommendations, with those exercising on-duty experiencing surprisingly high rates of exercise-related injuries. In addition, with only 27% of fire departments implementing fitness programs, novel strategies are needed to improve implementation efforts of safe and evidence-based exercise that address key barriers to worksite exercise adherence. Preliminary work from our team has demonstrated that a ‘train-the-trainer’ (TRAINER) model, including professional supervision, can reduce the risk of injury in similar populations (i.e. military cadets). The objective of the current proposal is to determine the feasibility and obtain preliminary data on the initial changes and intervention fidelity to a TRAINER delivered integrated exercise routine (including a neuromuscular warm-up and HIIT) at fire stations. The main hypotheses are that firefighters will adhere to the TRAINER delivered integrated exercise program as intended and will exhibit clinically important improvements in primary risk factors for cardiovascular disease (CVD) and strain and sprain injuries. A two- arm cluster randomized feasibility and proof-of-concept study of a 6-week TRAINER intervention will be conducted with 40 career firefighters clustered by fire station. This study is innovative because 1) it includes an exercise strategy that facilitates on-duty exercise adherence and targets the primary fatal and non-fatal injuries in the fire service, and 2) explores a novel use of the TRAINER model to improve the implementation efforts of exercise programs at fire stations. In Aim 1, our multidisciplinary team will examine the feasibility of the TRAINER delivered integrated exercise program in firefighters. We will determine recruitment and retention rates, the willingness to be randomized, and the adherence to and acceptability of the 6-week intervention. In Aim 2, we will determine intervention fidelity and short-term changes in risk factors for CVD and strain and sprain injuries. The expected outputs and outcomes of this innovative project are critical to further Research to Practice (r2p) efforts in the fire service. Furthermore, a unique strength of this R03 includes the strong support from a leading tactical fitness organization with a national network of certified fitness professionals to enhance the dissemination of this project nationwide in a future large-scale trial. This proposal directly addresses 3 primary strategic goals (# 1,3, and 6) outlined in the Public Safety sector and cross-sector agenda items that include the reduction of CVD, musculoskeletal injuries, and fall-related injuries.

Learn more about this study: NIH RePORT

Sponsor: Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)

Principal Investigator: Stephen Young, MD, PhD – Obstetrics and Gynecology

Project Period: 9/1/21 – 7/31/26

The overarching goal of this Center is to develop advanced tools and insights for improved understanding of the pathophysiology of endometriosis, a disease in which endometrial tissue grows outside the uterus and can cause severe dysmenorrhea, pain, infertility and other sequelae. We pursue this goal to enhance the diagnosis, assessment, and treatment of women suffering from this common and devastating disease. A clear pathophysiologic understanding of endometriosis has been difficult to achieve due, in part, to the reliance on surgery for diagnosis and lesion assessment. Reliance on surgery delays diagnosis and prevents frequent or repeated evaluation. In recent years, however, collaborations between scientists in our team have advanced a unifying pathophysiological principle–that of progesterone resistance. Most other pathophysiological features of endometriosis, including persistent epithelial estrogen receptor action, persistent estrogen receptor and progesterone receptor expression, cellular proliferation, inflammation, pain, and infertility, can be ascribed to progesterone resistance. Recently, important findings by this consortium show that Sirtuin 1 (SIRT1), an epigenetic modulator, can cause progesterone resistance, resulting in exacerbation of downstream effects. SIRT1 is a histone deacetylase that also directly regulates the function of proteins directing inflammatory and metabolic signaling. We find consistent overexpression of endometrial SIRT1 across all species that we have tested, including humans, non-human primates, and mice, highlighting a likely central role for SIRT1 in endometriosis pathophysiology. Furthermore, preliminary studies indicate that SIRT1 overexpression plays a direct role in lesion survival as well as infertility and has a potential role as a therapeutic target. We present three key projects based on our burgeoning pathophysiological data to deepen our knowledge, catalyze the development of novel, non-invasive diagnostic and assessment methods and promote non-hormonal therapeutic options for affected women. The impact of these three projects on women will be enhanced by patient and provider educational initiatives from the Endometriosis Outreach and Education (EOE) Core and deep integration of synergistic data from human, non-human primate, mouse, and in vitro systems, enhanced by the Comparative Genomics and Bioinformatics (CGB) Core. Collectively, the projects and cores contribute to three synergistic aims: 1) Enhance early diagnosis and assessment of endometriosis lesions by developing non-invasive imaging techniques and promoting public awareness; 2) Determine inflammatory and metabolic changes that underlie the disease process; and 3) Develop new molecular targets for non-hormonal, non-surgical treatments for endometriosis; The successful completion of these aims will lead to a long-lasting improvement in the lives of women suffering from endometriosis.

Learn more about this study: NIH RePORT

Sponsor: Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)

Principal Investigator: Neeta Vora, MD – Obstetrics and Gynecology

Project Period: 8/12/21 – 6/30/26

Fetal brain abnormalities (FBA) are one of the most common prenatal sonographic abnormality detected and account for ~20% of birth defects posing a substantial burden on the health care system. FBA can be isolated or syndromic and have vast phenotypic heterogeneity. The paired approach of prenatal diagnosis using ultrasound to characterize aberrant phenotypes with genetic analysis to determine causal lesions has improved the ability to accurately counsel families about diagnosis, prognosis, and recurrence risk. Recently, prenatal exome sequencing (ES) has been applied in cases of lethal or multiple fetal abnormalities to determine a molecular diagnosis that otherwise could not be identified with traditional testing. Our group and others using ES have shown a diagnostic rate of 23.6% in cases of multiple fetal abnormalities, but only 2.6% in isolated FBA abnormalities, indicating a need to improve diagnostic capabilities for FBA. We posit that the overabundance of unresolved fetal cases is due to a gap in our understanding of the repertoire of genotypes underlying prenatal FBA and limitations of population genetics to establish causality of rare variants in novel candidate genes. Our team who is at the forefront of prenatal genetic diagnostics and in vivo zebrafish modeling of human disease will overcome the current challenges of diagnosing prenatal FBA. We will intersect exome- and genome-wide variation with a relevant model system (zebrafish). We hypothesize that we will 1) generate initial discoveries directly relevant to human brain development by modeling novel candidate FBA genes in zebrafish; and 2) improve prenatal diagnosis for FBA using whole genome sequencing (WGS) and deep phenotyping. We will: 1. Perform bioinformatic analysis of 200+ clinically ascertained fetuses with FBA and their parents using a tiered filtering strategy on already available parent-fetus trio exome data 2. Perform WGS on 114 prospectively enrolled fetuses and their parents paired with comprehensive prenatal and postnatal phenotypic data to further characterize genotype/phenotype of FBA; 3. Establish relevance of candidate genes to FBA development and determine variant pathogenicity using genome-editing and phenotyping tools in zebrafish. Our work will expand the understanding of molecular processes governing human brain development, establish a clinical-research hybrid platform readily applicable to FBA and other anatomical defects detectable by fetal imaging, build an animal model of aberrant FBA development with potential for future use in therapeutic target identification. Our immediate results will improve counseling/management of prenatally diagnosed FBA and lead to future work to develop novel therapeutic and preventative strategies for FBA.

Learn more about this study: NIH RePORT

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Principal Investigator: Michelle Meyer, PhD, MPH – Emergency Medicine

Project Period: 8/1/21 – 7/31/25

Cardiovascular disease (CVD) is the leading cause of death for U.S women, annually killing >400,000 women. Compared to whites, non-Hispanic Black and Latina women are at higher CVD risk. Despite the burden of CVD in women, risk factors specific to women are understudied and thus not considered in current CVD risk prediction or prevention strategies. Early detection of subclinical disease is key to CVD risk stratification and prevention. Since prenatal and postpartum care is the sole health care access point for most U.S. women, pregnancy represents a critical opportunity to measure CVD risk and implement innovative strategies to address this critical gap in women’s health care. Furthermore, CVD risk factor trajectories begin in utero and in early life, so pregnancy is also an opportunity to identify CVD risk in children. Our long-range goal is to identify and disseminate obstetric care practices that mitigate CVD risk for women and their children. The objective of this prospective, multicenter study is to estimate CVD risk in healthy and medically complicated pregnant women and their infants. We will also examine the relationships among personal, social, and ecological factors and CVD risk for 3 years postpartum. Our primary outcomes are maternal and infant central pulse wave velocity (PWV), a validated measure of arterial stiffness (vascular aging) that predicts CVD, independent of other established CVD risk factors. We will enroll a cohort 840 pregnant women of diverse race/ethnicity and socioeconomic status: 420 healthy and 420 women with preeclampsia, gestational diabetes, and/or suspected fetal growth restriction. We will measure maternal and infant PWV, cardio-metabolic (e.g., blood pressure, lipids, adiposity, HbA1c) and inflammatory (e.g., hs-CRP, IL-6, adiponectin) markers of CVD risk, and assess personal, social, and ecological factors at 34-40 weeks’ gestation, delivery, 6 months, 18 months, and 3 years. The study aims are the following: 1) Measure arterial stiffness by PWV during and after pregnancy; 2) Measure infant/child PWV following healthy and complicated pregnancies; and 3) Identify maternal and infant modifiable risk factors associated with CVD risk measured by PWV. To date, no studies have longitudinally measured CVD risk in pregnant women and their infants, nor ascertained the effect of biologic, personal, social, and/or ecological factors on CVD risk. Using a noninvasive measure of arterial stiffness, we propose to determine CVD risk in a cohort of mother-infant dyads. Our interdisciplinary study team of experts in CVD, high-risk pregnancy, exercise and sports physiology, CVD epidemiology, public health, and cardiology are well poised to complete the proposed aims by using a synthesis of expertise to achieve our common, shared goal of mitigate CVD risk for women and their children. We are proposing an innovative paradigm shift in the goals of prenatal care to use pregnancy as a time in a woman’s life, particularly if she is at high risk for CVD, to identify and mitigate early markers of CVD for herself and her offspring.

Learn more about this study: NIH RePORT, Press Release

Sponsor: Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)

Principal Investigator: Genevieve Neal-Perry, MD, PhD – Obstetrics and Gynecology

Project Period: 7/23/20 – 6/30/25

Obstetrician-gynecologists have an integral role to play in women’s reproductive health research. However, Ob- Gyn investigators have historically been underrepresented in the field, leading to critical missed opportunities to generate clinically-relevant research questions and to translate new findings into clinical practice. To address this important gap, we propose to re-establish the Women’s Reproductive Health Research Career Development Program at the University of North Carolina at Chapel Hill. Our aims are to catalyze early career development of promising Ob-Gyn clinician investigators and to support collaborative, cutting edge research that advances the field of women’s reproductive health. This program provides mentorship, structured career development activities, and at least 75% protected research time for two Ob-Gyn scholars annually. Building upon prior WRHR success (2005-2010), we have designed a program that addresses the needs of early career Ob-Gyn researchers. First, our scholars are embedded in a vibrant research environment within our Department of Ob- Gyn, which is supported by $14 million in annual research funding from NIH, other federal agencies, and foundations. Our scholars will conduct mentored research within emphasis areas designated in the application, at their intersection with women’s reproductive health. These include established research domains led by program faculty and supported by multiple NIH awards (complications of pregnancy, mood disorders and substance use, obesity and cardiometabolic disease, sexual and reproductive health). Opportunities to work in emerging areas with individual, funded investigators will also be offered. Second, our scholars will be mentored by experienced faculty. Mentorship committees are led by NIH-funded Ob-Gyn investigators and supported by collaborating faculty from the UNC Schools of Medicine, Public Health, Pharmacy, Nursing, and Social Work. Third, we have developed a robust career development curriculum that leverages existing K12/KL2 resources at UNC, while remaining distinct in its goals and purpose. This broader community of early career, research- oriented faculty provides opportunities for networking, shared learning, and peer-to-peer mentorship, and minimizes the risk of academic isolation. Fourth, our program has exceptional institutional support from the UNC School of Medicine. This includes a commitment of significant cost-sharing to ensure competitive junior faculty salaries, commensurate with specialty and subspecialty faculty in the department. Scholars will also have access to additional institutional resources through university-wide centers and institutes. The overarching goal of the UNC WRHR Program is to support promising early career Ob-Gyns during the often tenuous transition to research independence. Through access to an unparalleled group of experienced faculty mentors and the strength of its career development curriculum, our program will develop the next generation of independent NIH investigators in women’s reproductive health.

Learn more about this study: NIH RePORT, UNC WRHR Website

Sponsor: National Institutes of Health (NIH)

Principal Investigator: Kavita Arora, MD – Obstetrics and Gynecology

Project Period: 5/5/20 – 1/31/24

Female sterilization, the second most commonly used contraceptive method in the United States, is commonly performed during the postpartum period. However, women with Medicaid insurance are half as likely to obtain a desired postpartum sterilization as those with private insurance. Compounding this disparity, women of color with Medicaid insurance are less likely to achieve sterilization fulfillment compared to white women with Medicaid insurance. Sterilization non-fulfillment puts women at high risk of subsequent unintended pregnancy with a short interpregnancy interval and the associated risks to maternal and infant health. There are significant policy barriers to equitable postpartum sterilization that impact those with Medicaid but not private insurance. However, the federal Medicaid policy (including specific consent form and subsequent thirty- day waiting period) was established in 1976 due to coerced sterilizations on women of color and low socioeconomic status. Therefore, sensitive consideration of the complex social and cultural backdrop is required to balance protection of a vulnerable population with the unintended consequence of disparities in sterilization fulfillment. Furthermore, barriers at the patient, provider, and hospital level have also been noted, though it is unclear the extent to which these barriers interact. Advocating for the complete removal of the Medicaid sterilization process, then, ignores both the complex history as well as the additional, non-policy barriers to equitable postpartum sterilization. The overall objective for this proposal is to determine the discrete barriers at various levels of analysis (patient, provider, hospital, and policy). The central hypothesis is that the layering of barriers individually and collectively contributes to disparities in postpartum sterilization fulfillment for the Medicaid population. The rationale for the project is that identifying and understanding potential barriers is the critical next step to eradicating the disparities surrounding postpartum sterilization. Guided by strong preliminary data, this hypothesis will be tested through an explanatory sequential mixed methods design by pursuing three specific aims: 1) Model the association between Medicaid insurance and sterilization fulfillment after adjusting for clinical and demographic differences in a pooled multi-institution sample (patient- and policy- level barriers aim); 2) Identify the attitudes, beliefs, and practices of postpartum women and their obstetricians regarding postpartum sterilization (patient-, provider-, hospital-, and policy-level barriers aim); 3) Assess the impact of hospital and state policy barriers on postpartum sterilization (hospital- and policy-level barriers aim). The approach is innovative because it departs from the status quo by shifting focus away from studying barriers individually and toward the identification and assessment of various layers of barriers. This contribution will be significant because it is expected to inform an evidence-based and patient-centered health policy to eradicate health disparities and improve clinical outcomes due to sterilization non-fulfillment and resultant unintended pregnancies.

Learn more about this study: NIH RePORT, Dr. Arora’s Research Website

Sponsor: National Institute of Environmental Health Sciences

Principal Investigator: Tracy Manuck, MD, MS – Obstetrics and Gynecology

Project Period: 1/15/20 – 12/31/24

This K24 proposal builds on over a decade of clinical and translational research – which the candidate – Dr. Tracy Manuck, MD, MSc, has focused on spontaneous preterm birth (SPTB). In this application, Dr. Manuck has recruited a team of multidisciplinary faculty experts to collaborate and support her in this endeavor, one that reflects the breadth and depth of UNC’s resources in environmental research. This work will greatly augment her current portfolio in patient-oriented research, allowing her to expand her current work and incorporate environmental contaminants into her current R01 funded study (R01-MD011609), creating a rich, multi- dimensional dataset. Candidate: Dr. Manuck is a recognized thought leader in the pharmacogenomics of SPTB. She has won numerous national accolades and has led high-impact clinical prematurity studies; here, she seeks to complement these skills by incorporating toxicogenomics into her research. Mentoring Plan/Environment: Dr. Manuck has an established track record in research training, including serving as Maternal Fetal Medicine (MFM) fellowship research director and a small group instructor for 2 graduate-level grant writing courses for fellows and junior faculty. However, competing administrative and clinical responsibilities limit her available time for mentorship. K24 award support will enable a more comprehensive mentoring portfolio within prematurity, and help to develop the critical mass of researchers investigating reproductive health effects of environmental contaminant exposure that is urgently needed in this field. With K24 support, she will have the appropriate time and resources to mentor advanced trainees (e.g., postdoctoral fellows, junior faculty) in their pursuit of independent funding. Dr. Manuck will leverage UNC’s extensive resources to accomplish this goal, including NIH-funded centers and training programs, networks and collaborations, and global health institutes. Career Goals and Objectives: Dr. Manuck will accomplish the following career development aims, including: Career Aim 1 – Expand knowledge of environmental health; Career Aim 2 – Improve mentorship skills; Career Aim 3 – Strengthen the ability to disseminate scientific results. Research Plan: Dr. Manuck will leverage her R01 study (currently recruiting) to evaluate the effects of exposure to pro-inflammatory environmental contaminants as an additional key driver of SPTB. She will integrate mentorship across the research aims: Aim 1 – Quantify exposure to environmental contaminants during pregnancy through self-report and biomonitoring of maternal urine, serum, and placentas; Aim 2 – Determine which contaminant or combination of contaminants is most strongly associated with SPTB; and Aim 3 – Test the effects of gene x environment interactions on recurrent SPTB risk. This plan offers a framework for Dr. Manuck’s training in the incorporation of environmental contaminants into prematurity studies, with potential for lifelong impact on the >450,000 babies delivered too soon in the US each year, while simultaneously providing a platform for mentoring future investigators committed to patient-oriented research.

Learn more about this study: NIH RePORT

Sponsor: Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)

Principal Investigator: Steven Young, MD, PhD – Obstetrics and Gynecology

Project Period: 9/26/19 – 8/31/24

Infertility is a common complication of endometriosis; while IVF successfully treats endometriosis- associated infertility, pregnancy rates are diminished compared to other etiologies of infertility. Our long- term objectives are to better identify and treat endometriosis related infertility. Our central hypothesis is that in infertile woman with endometriosis undergoing in vitro fertilization- embryo transfer (IVF-ET), live birth rates will improve in those pretreated with GnRH antagonist compared to placebo. The use of gonadotropin releasing hormone (GnRH) agonist prior to IVF has been suggested to improve success, however studies have been small and rarely reported live birth rates. Further, use of this approach is limited by the long treatment time required. Recent approval of an oral GnRH antagonist for endometriosis provides a novel option for women with endometriosis who are undergoing IVF. This agent avoids parenteral administration and the prolonged delay in initiation of action as was seen with GnRH agonists. There have been no studies on the efficacy of GnRH antagonists for the treatment of endometriosis-related infertility. We propose a randomized clinical trial of oral GnRH antagonist pre-treatment for women with endometriosis who are undergoing IVF, with a primary outcome of live birth rate. We have also recently demonstrated aberrant microRNAs in the circulation of women with endometriosis, a panel of which we have subsequently validated as a biomarker with high sensitivity and specificity for the detection of active disease. We secondarily propose that disease biomarkers will identify women who will benefit from GnRH antagonist pre-treatment, allowing a precision medicine approach to endometriosis-related infertility. The proposed study is significant due to the common occurrence of both infertility and endometriosis as well as the lack of precision in both diagnosis and therapy. We use an innovative approach to identify endometriosis as well as a novel intervention designed to improve the prognosis of women with endometriosis undergoing IVF.

Learn more about this study: NIH RePORT

Sponsor: National Institute of Child Health and Human Development (NICHD)

Principal Investigator: John Thorp, MD – Obstetrics and Gynecology

Project Period: 4/18/01 – 9/25/27

Over the past nine years as a member of the MFMU network, the UNC MFMU site has completed six randomized clinical trials and has one observational study and two network trials ongoing. We are number four in recruiting among the 14 sites, and are ranked number three in adherence and quality overall. UNC excels at Hispanic recruitment; overall 31% of our participants are Hispanic. This track record as a strong site, coupled with our tradition of excellence in clinical trials research and perinatal epidemiology makes us ideally suited to continue as a highly productive member of the Network. We have assembled a talented and committed team of physicians, fellows, graduate students, research nurses, clinical research assistants, laboratory staff, and other investigators in our Perinatal Research Core, an alliance of investigators dedicated to understanding and improving pregnancy outcomes through state-of-the-art research. The Core is supported by a well-established infrastructure consisting of clinical tracking systems, data management resources, an NIH Clinical Nutrition Research Center, and one of the top General Clinical Research Centers in the nation. UNC serves as the lead organization with two other UNC Healthcare locations (Wake AhecA/WakeMed and Rex Hospital) serving as recruitment sites. With the addition of a third recruitment site, MAHEC/Mission Hospital in this application, we have more than 19,000 births each year across sites, 33% of which are high-risk by virtue of maternal co-morbidities, including substance abuse, fetal anomalies, pregnancy complications, or preterm birth risk profile, including multiple gestations. UNC and WakeMed provide virtually all of the high-risk prenatal clinic and hospital-based care for this region, and MAHEC/Mission Hospital provides the same for 17 counties in the western part of the state. Overall, the majority of prenatal patients at WakeMed and UNC are indigent; the Rex patient population is predominately lower risk patients and the majority has some form of private coverage; MAHEC/Mission Hospital patients are roughly half and half. Racial and ethnic diversity in our recruitment has been strong with 64% white participants and 27% African Americans; additionally 31% are Hispanic. UNC, Wake AHEC/WakeMed, and MAHEC/Mission have state of the art Level III neonatal intensive care units, and Rex has a Level II nursery. Together, these four components of the UNC Healthcare System bring more than twenty years of productive multi-site research, experienced investigators, state-of-the-art care facilities, a stable population, ongoing enhancements of computerized perinatal databases, and commitment to excellence in collaborative research as part of the MFMU.

Learn more about this study: NIH RePORT, National MFMU website, UNC MFMU Website

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