VASCULAR REMODELING ASSOCIATED WITH PREGNANCY by Nancy Anderson Niemczyk B.A in Religion, Swarthmore College, 1988 B.S.N., University of Pennsylvania School of Nursing, 1992 M.S.N. in Midwifery, University of Pennsylvania School of Nursing, 1994 Submitted to the Graduate Faculty of Graduate School of Public Health in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2014 UNIVERSITY OF PITTSBURGH Graduate School of Public Health This dissertation was presented by Nancy Anderson Niemczyk It was defended on December 2, 2014 and approved by Janet Catov, PhD, Assistant Professor, Departments of Epidemiology, Obstetrics and Gynecology and Clinical and Translational Research, Graduate School of Public Health and School of Medicine, University of Pittsburgh James Roberts, MD, Professor, Departments of Epidemiology, Obstetrics and Gynecology and Clinical and Translational Research, Graduate School of Public Health, University of Pittsburgh, and Magee Women’s Research Institute Akira Sekikawa, MD, PhD, Associate Professor, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh Ping Tepper, PhD, Assistant Professor, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh Dissertation Advisor: Emma Barinas-Mitchell, PhD, Assistant Professor, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh ii Copyright © by Nancy A. Niemczyk 2014 iii Emma Barinas-Mitchell, PhD VASCULAR REMODELING ASSOCIATED WITH PREGNANCY Nancy A. Niemczyk, PhD University of Pittsburgh, 2014 ABSTRACT Objectives: Research indicates a relationship between pregnancy and cardiovascular disease, but the cause of this relationship is unknown. One possible explanation is that there is a relationship between pregnancy and vascular change. The objective of this dissertation is to illuminate this relationship by exploring 1) the association between parity and structure of the carotid arteries in a population of overweight or obese women of reproductive age and 2) the normal course of common carotid artery (CCA) remodeling and changes in stiffness of the brachial artery throughout a healthy first pregnancy and postpartum. Methods: The first paper provides a cross-sectional analysis of the relationship between reproductive factors and structural measures of the carotid artery in overweight and obese young women participating in the Slow Adverse Vascular Effect of Obesity (SAVE) clinical trial. The subsequent 2 papers provide results of the Maternal Vascular Adaptation to Healthy Pregnancy (MVP) study, in which 43 healthy young women were assessed prospectively throughout their first pregnancies with ultrasounds of their carotid arteries, a measure of brachial artery distensibility, and physical and metabolic measures. Results: In the SAVE study, nulliparous women had greater common carotid inter-adventitial diameter (IAD) and mean CCA intima media thickness (IMT) compared with parous women iv after adjustment for age, race, and CVD risk factors. In the MVP study, after adjustment for age and pre-pregnancy BMI, mean IAD increased each trimester and returned to baseline postpartum. Mean CCA IMT was increased postpartum compared to 1st and 2nd trimester values. Mean brachial artery distensibility decreased from 1st trimester to 3rd trimester and then remained unchanged postpartum. Conclusions: Among overweight and obese young women, nulliparity was associated with less healthy carotid arteries. During the course of healthy first pregnancy, some negative vascular changes (greater CCA IMT and stiffer brachial arteries) occurred that persisted into the postpartum period. Public Health Significance: Cardiovascular disease is the leading cause of death in women. Early identification of women at high risk (nulliparous) offers early opportunity for risk reduction. Understanding normal vascular changes of pregnancy may help explain the pathophysiology of preeclampsia, the cause of 50,000 maternal deaths per year. v TABLE OF CONTENTS PREFACE ................................................................................................................................. XIII 1.0 INTRODUCTION................................................................................................................... 1 1.1. VASCULAR REMODELING AND VASCULAR STIFFNESS .............................. 1 1.1.1 Definitions ............................................................................................................ 1 1.1.2 Assessment of Vascular Remodeling ................................................................. 2 1.1.3 Assessment of Arterial Stiffness ......................................................................... 3 1.1.4 Significance of Intima Media Thickness and Adventitial Diameter ............... 4 1.1.5 Significance of Arterial Stiffness........................................................................ 6 1.2 IMPORTANCE OF UNDERSTANDING VASCULAR CHANGES OF PREGNANCY ....................................................................................................................... 7 1.2.1 Pregnancy Complications with Vascular Components ................................... 7 1.2.2 Pregnancy’s Association with Changes in CVD Risk Factors ........................ 9 1.2.3 Pregnancy as a CVD Risk Factor .................................................................... 10 1.3 STIMULI FOR VASCULAR REMODELING AND THE EFFECTS OF PREGNANCY ..................................................................................................................... 12 1.3.1 Hemodynamic Changes .................................................................................... 12 1.3.3 Metabolic Changes ............................................................................................ 15 1.4 UTERO-PLACENTAL VASCULAR REMODELING IN PREGNANCY ........... 17 1.4.1 Uterine Artery Remodeling .............................................................................. 17 1.4.2 Spiral Artery Remodeling ................................................................................ 18 1.5 STUDIES OF SYSTEMIC VASCULAR REMODELING ASSOCIATED vi WITH PREGNANCY ........................................................................................................ 20 1.5.1 Anatomic Data ................................................................................................... 20 1.5.2 Cross-Sectional Studies of IMT in Healthy vs. Complicated Pregnancies .. 20 1.5.3 Prospective Studies of IMT in Pregnancy ....................................................... 22 1.5.4 Intima vs. Media ................................................................................................ 22 1.5.5 Cross-Sectional Studies of Parity and IMT in Midlife and Older Women .. 23 1.5.6 Studies of Arterial Stiffness in Healthy versus Complicated Pregnancies... 24 1.5.7 Prospective Studies of Arterial Stiffness in Healthy Pregnancy ................... 25 1.6 GAPS IN KNOWLEDGE AND GOALS OF DISSERTATION ............................. 26 1.7 SPECIFIC AIMS .......................................................................................................... 29 2.0 NULLIPARITY IS ASSOCIATED WITH LESS HEALTHY MARKERS OF SUBCLINICAL CARDIOVASCULAR DISEASE IN OVERWEIGHT AND OBESE YOUNG WOMEN ...................................................................................................................... 32 2.1 ABSTRACT .................................................................................................................. 33 2.2 INTRODUCTION ........................................................................................................ 34 2.3 METHODS .................................................................................................................... 35 2.3.1 SAVE Study Design and Population ............................................................... 35 2.3.2 Carotid Artery Measures ................................................................................. 36 2.3.3 Reproductive Histories ..................................................................................... 37 2.3.4 Demographic, Physical, and Laboratory Measures ....................................... 38 2.3.5 Statistical Analysis ............................................................................................ 38 2.4 RESULTS ...................................................................................................................... 40 2.5 DISCUSSION ................................................................................................................ 42 vii 2.6 TABLES AND FIGURES ............................................................................................ 47 3.0 COMMON CAROTID ARTERY INTIMA-MEDIA THICKNESS INCREASES OVER PREGNANCY CYCLE .............................................................................................................. 52 3.1. ABSTRACT ................................................................................................................. 53 3.2 INTRODUCTION ........................................................................................................ 54 3.3 METHODS .................................................................................................................... 56 3.3.1 MVP Study Design and Population ................................................................. 56 3.3.2 Carotid Artery Measures ................................................................................. 57 3.3.3 Demographic, Pregnancy History, Physical and Laboratory Measures ...... 58 3.3.4 Statistical Analysis ............................................................................................ 59 3.4 RESULTS ...................................................................................................................... 60 3.5 DISCUSSION ................................................................................................................ 62 3.6 TABLES AND FIGURES ............................................................................................ 67 4.0 BRACHIAL ARTERY STIFFENS DURING THE PREGNANCY CYCLE IN HEALTHY PRIMIGRAVIDAS ................................................................................................ 78 4.1 ABSTRACT .................................................................................................................. 79 4.2 INTRODUCTION ........................................................................................................ 80 4.3 METHODS .................................................................................................................... 81 4.3.1 MVP Study Design and Population ................................................................. 81 4.3.2 Brachial Artery Distensibility and Cardiac Output ...................................... 82 4.3.3 Demographic, Physical and Laboratory Measures ........................................ 83 4.3.4 Statistical Analysis ............................................................................................ 85 4.4 RESULTS ...................................................................................................................... 86 viii 4.5 DISCUSSION ................................................................................................................ 87 4.6 TABLES AND FIGURES ............................................................................................ 92 5.0 CONCLUSIONS AND PUBLIC HEALTH SIGNFICANCE .......................................... 98 5.1 CONCLUSION ............................................................................................................. 98 5.2 PUBLIC HEALTH SIGNIFICANCE ...................................................................... 101 APPENDIX: REVIEW OF LITERATURE .......................................................................... 103 BIBLIOGRAPHY ..................................................................................................................... 111 ix LIST OF TABLES Table 1.1 Hemodynamic and Metabolic Changes of Healthy Pregnancy .................................... 30 Table 2.1 Baseline characteristics of participants in SAVE reproductive substudy by parity .... 47 Table 2.2 Age and race-adjusted mean carotid measures by parity in women without infertility history. .......................................................................................................................................... 48 Table 2.3 Carotid measures for parous vs. nulliparous women. Regression coefficients represent change from a baseline parity of 0. ............................................................................................... 48 Table 2.4 Comparison of participants and non-participants in reproductive study .................... 49 Table 2.5 Effect of infertility on common carotid artery measures ............................................. 49 Table 3.1 Unadjusted values for outcomes and key time-varying covariates by trimester ......... 67 Table 3.2 Association between covariates and inter-adventitial diameter ................................... 68 Table 3.3 Association between covariates and common carotid artery intima-media thickness . 69 Table 3.4 Adventitial diameter models adjusted for age and pre-pregnancy BMI with individual physical predictors ........................................................................................................................ 70 Table 3.5 Common carotid artery intima-media thickness models adjusted for age and pre- pregnancy BMI with individual physical predictors………………………………….………….71 Table 3.6 Adventitial diameter models adjusted for age, pre-pregnancy BMI, weight and individual biomarkers ................................................................................................................... 72 Table 3.7 Common carotid artery intima media thickness models adjusted for age, pre-pregnancy BMI, systolic blood pressure, weight change and individual biomarkers.................................... 73 Table 3.8 Number of weeks postpartum as a continuous predictor.............................................. 75 x