Although hypertensive disorders affect 5-10 percent of all pregnancies and lead to significant maternal and neonatal morbidity and mortality, the causes are unclear and preventive and therapeutic strategies have largely been unsuccessful. Recent studies indicate hypertensive disorders of pregnancy are characterized by endothelial cell dysfunction, altered endothelium-dependent relaxation, and atherosclerotic-like lesion. In the non-pregnant state, alterations in serum androgens, lipids, and insulin have been associated with endothelial cell dysfunction, vasoconstriction, andatherosclerosis. Recent work from our group and others suggests that alterations in androgens, lipids, and insulin may also be associated with increased risk hypertensive disorders during pregnancy. Prospective data are sparse, however, and the lack of substantial prospective studies may have hampered development of effective therapies. Therefore, the primary objective of this proposal is to examine prospectively the association between levels of testosterone, specific lipid fractions, and markers on insulin resistance at three time points (at 10 and 28 weeks of gestation and at delivery) and the risk of gestational hypertension and preeclampsia. We will test our hypotheses in an open cohort of women who receive prenatal care at the Massachusetts General Hospital and three affiliated neighborhood health centers. Over the next 5 years, we expect to enroll approximately 9000 women, with 470 cases of gestational hypertension and 405 cases of preeclampsia. Our pilot data on 2289 women show that loss to follow-up and missing data are minimal, women who enroll in the study have similar characteristics to those who do not enroll, and Hispanic and African-American women comprise approximately 19 percent of all enrolled women. Other advantages of this study include: pilot data demonstrates successful enrollment of approximately 150 women every month; prospective design with supportive preliminary work in a large clinical population; and, dedicated team of investigators with expertise in complementary areas. We believe this proposal has the potential to advance our understanding of the pathogenic mechanisms of hypertensive disorders of pregnancy, improve identification and monitoring of women at highest risk, and uncover potential therapies to reduce the widespread impact of these disorders.
| Faupel-Badger, Jessica M; Staff, Anne Cathrine; Thadhani, Ravi et al. (2011) Maternal angiogenic profile in pregnancies that remain normotensive. Eur J Obstet Gynecol Reprod Biol 158:189-93 |
| Troisi, R; Hoover, R N; Thadhani, R et al. (2008) Maternal, prenatal and perinatal characteristics and first trimester maternal serum hormone concentrations. Br J Cancer 99:1161-4 |
| Rana, Sarosh; Karumanchi, S Ananth; Levine, Richard J et al. (2007) Sequential changes in antiangiogenic factors in early pregnancy and risk of developing preeclampsia. Hypertension 50:137-42 |
| Hubel, Carl A; Wallukat, Gerd; Wolf, Myles et al. (2007) Agonistic angiotensin II type 1 receptor autoantibodies in postpartum women with a history of preeclampsia. Hypertension 49:612-7 |
| Levine, Richard J; Lam, Chun; Qian, Cong et al. (2006) Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 355:992-1005 |
| Thadhani, Ravi; Tonelli, Marcello (2006) Cohort studies: marching forward. Clin J Am Soc Nephrol 1:1117-23 |
| Levine, Richard J; Thadhani, Ravi; Qian, Cong et al. (2005) Urinary placental growth factor and risk of preeclampsia. JAMA 293:77-85 |
| Smirnakis, Karen V; Chasan-Taber, Lisa; Wolf, Myles et al. (2005) Postpartum diabetes screening in women with a history of gestational diabetes. Obstet Gynecol 106:1297-303 |
| Smirnakis, Karen V; Martinez, Abelardo; Blatman, Karen Hsu et al. (2005) Early pregnancy insulin resistance and subsequent gestational diabetes mellitus. Diabetes Care 28:1207-8 |
| Maynard, Sharon E; Venkatesha, Shivalingappa; Thadhani, Ravi et al. (2005) Soluble Fms-like tyrosine kinase 1 and endothelial dysfunction in the pathogenesis of preeclampsia. Pediatr Res 57:1R-7R |
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