Antenatal corticosteroid (ANCS) treatment is recommended for all pregnant women expected to deliver between 24 and 34 weeks gestation, and over 100,000 fetuses are exposed to ANCS in the United States each year. ANCS significantly decreases neonatal mortality and morbidity, but has been associated with elevated blood pressure, insulin resistance, and reduced renal funcfion in adolescents and young adults. Our data indicate that 14 year olds who were born with very low birth weight (<1500g) and were exposed to ANCS show physiological differences that might predispose them to elevated blood pressure later in life. Specifically, the ANCS-exposed adolescents had lower levels of urinary Angiotensin Converting Enzyme 2, higher rafios of urinary Angiotensin II (Ang 11) to Angiotensin (1-7), lower urinary sodium levels, and higher urinary albumin levels. Thesefindingsin humans correspond to our colleagues'findingsthat ANCS-exposed sheep have reduced nephron number and sodium excretion, alterations in the renin-angiotensin system (RAS) favoring increased Ang 11 tone, increased blood pressure, insulin resistance, and increased leptin. ANCS-exposed sheep also have alterations in the central RAS that were associated with decreased heart rate variability and baroreflex sensitivity, and these alterations preceded the blood pressure elevation. In addifion, the effects of ANCS in sheep are exacerbated by obesity, which has important implications for our cohort in which >34% are ovenweight. In the current application, we propose to study our human cohort at age 19 years, to assess the relationship of ANCS exposure to the following: 1) autonomic balance as reflected in heart rate variability and baroreflex sensitivity, 2) renal sodium handling, as indicated by stress-induced pressure natriuresis, 3) insulin sensitivity as assessed by oral glucose tolerance testing, 4) levels of circulating adipokines (leptin, adiponecfin, and resistin), and 5) blood pressure. We hypothesize that young adults who had very low birth weight and were exposed to ANCS will have decreased baroreflex sensitivity, decreased ability to excrete sodium, decreased insulin sensitivity, increased leptin levels, and increased blood pressure, and that these findings will be associated with alterations in the RAS that promote increased Ang II tone. We will collect data on known modifiable correlates, such as physical activity, adiposity, and diet. Our studies may identify a population at increased risk for cardiometabolic disease and inform approaches for monitoring and eariy intervention that will improve health outcomes of ANCS-exposed individuals as they mature.

Public Health Relevance

Corticosteroids are commonly given to pregnant women with threatened preterm delivery to improve the survival of the infant. Exposure to antenatal steroids may have adverse long-term consequences. These studies will investigate the long-term effects of antenatal steroid exposure on cardiovascular and metabolic risk factors with a goal of prevenfing and treafing hypertension and metabolic disease in individuals born with very low birth weight and exposed prenatally to steroids.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Wake Forest University Health Sciences
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Washburn, Lisa K; Brosnihan, K Bridget; Chappell, Mark C et al. (2015) The renin-angiotensin-aldosterone system in adolescent offspring born prematurely to mothers with preeclampsia. J Renin Angiotensin Aldosterone Syst 16:529-38
Marshall, Allyson C; Shaltout, Hossam A; Pirro, Nancy T et al. (2014) Enhanced activity of an angiotensin-(1-7) neuropeptidase in glucocorticoid-induced fetal programming. Peptides 52:74-81
Wilson, Bryan A; Marshall, Allyson C; Alzayadneh, Ebaa M et al. (2014) The ins and outs of angiotensin processing within the kidney. Am J Physiol Regul Integr Comp Physiol 307:R487-9
Chappell, Mark C; Marshall, Allyson C; Alzayadneh, Ebaa M et al. (2014) Update on the Angiotensin converting enzyme 2-Angiotensin (1-7)-MAS receptor axis: fetal programing, sex differences, and intracellular pathways. Front Endocrinol (Lausanne) 4:201
Lee, J-H; Zhang, J; Massmann, G A et al. (2014) Antenatal betamethasone increases vascular reactivity to endothelin-1 by upregulation of CD38/cADPR signaling. J Dev Orig Health Dis 5:56-62
Marshall, Allyson C; Pirro, Nancy T; Rose, James C et al. (2014) Evidence for an angiotensin-(1-7) neuropeptidase expressed in the brain medulla and CSF of sheep. J Neurochem 130:313-23
Bi, Jianli; Contag, Stephen A; Chen, Kai et al. (2014) Sex-specific effect of antenatal betamethasone exposure on renal oxidative stress induced by angiotensins in adult sheep. Am J Physiol Renal Physiol 307:F1013-22
Nixon, P A; Washburn, L K; O'Shea, T M (2013) Antenatal steroid exposure and pulmonary outcomes in adolescents born with very low birth weight. J Perinatol 33:806-10
Washburn, Lisa; Nixon, Patricia; Russell, Gregory et al. (2013) Adiposity in adolescent offspring born prematurely to mothers with preeclampsia. J Pediatr 162:912-7.e1
Marshall, Allyson C; Shaltout, Hossam A; Pirro, Nancy T et al. (2013) Antenatal betamethasone exposure is associated with lower ANG-(1-7) and increased ACE in the CSF of adult sheep. Am J Physiol Regul Integr Comp Physiol 305:R679-88

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