In the U.S., one in eight births is preterm (<37 weeks gestation). Black women are 1.5 and 2 times more likely to deliver at <37 and <35 weeks than White, respectively, representing a significant racial health disparity. Increasingly shortened gestation results in rising neonatal risk, with preterm birth (PTB)-related costs exceeding $26.2 billion annually. Biological predictors of impending early birth are lacking. Tertiary treatments predominate and are non-efficacious. Methods to prolong pregnancy are sorely needed and require an understanding of early birth not yet achieved.
We aim to address these deficits by evaluating a potential pathway leading to shortened gestation among Black women. Labor is driven by an inflammatory cascade. Elevated interleukin (IL)-1? is capable of propagating this cascade and promoting labor-associated mediator production and processes. IL-1? elevations have been noted in the periphery and amniotic fluid of Black women with PTB compared to Black term controls. These findings do not extend to White populations. Impaired regulation of IL-1?, then, may play an important role in shortened gestation specifically among Black women. Prior to notable IL-1? elevations, impaired ability to regulate IL-1? may be appreciated by measuring production of IL-1? upon immune challenge, responsiveness to the anti-inflammatory actions of cortisol, and ability to inhibit IL-1? activity through production of its competitive inhibitor, IL-1 receptor antagonist(Ra). Psychosocial stress, experienced disproportionately by U.S. Black women, is associated with greater IL-1? production, lower cortisol responsiveness, and shorter gestation. Three genetic variants more commonly possessed by Blacks than Whites are linked to lower peripheral IL-1Ra and genetics play a role in PTB. Using a prospective cohort design, we will evaluate if: 1) psychosocial stress (dose/type) and genetic variation predict length of gestation, 2) psychosocial stress (dose/type) predicts IL-1? production and cortisol responsiveness, 3) genetic variation predicts IL-1Ra production, and 4) this bio-panel of IL-1? regulation predicts length of gestation and mediates Aim 1 relationships. The dose of three types of stress will be assessed using the prenatal life events, revised prenatal distress, and experiences of discrimination scales and whole blood collected at 28-32 weeks gestation. Genetic variation at three chromosomal positions will be determined by allelic discrimination. IL-1? and IL-1Ra production will be determined using whole blood ex vivo stimulation methods. Cortisol responsiveness will be determined by the plasma cortisol to neutrophil:lymphocyte ratio correlation. Length of gestation will be determined by chart review. Study results will advance mechanistic understanding. Further, a bio-panel prospectively predicting length of gestation would allow for delivery of available preventive therapies to those at risk. A bio-panel identifying the pathway by which shortened gestation will ensue could reveal targets for novel preventive therapies. Completion of the study and training plan will superbly prepare the applicant for a career in transdisciplinary research aimed at preventing PTB.
One in six births to U.S. Black women is preterm, resulting in heightened risk for newborn death and illness and representing a significant racial health disparity. Mechanisms driving early labor and birth are unknown but may be related to a combination of stress- and genetically-induced impairments in regulation of the pro- inflammatory cytokine interkeukin-1?. Hypotheses related to this proposed pathway will be tested in order to better understand mechanisms leading to early birth, develop screening tools to predict who is at risk for early birth, and identify targets for new treatments to prevent early birth and improve maternal and newborn health.
