RISK FACTORS FOR RETINAL VASCULAR CHANGES IN CHILDREN AND PREGNANT WOMEN LI LINGJUN, QUEENIE (M.D., M.MED) A THESIS SUBMITTED FOR THE DEGREE OF PHILOSOPHY SAW SWEE HOCK SCHOOL OF PUBLIC HEALTH NATIONAL UNIVERSITY OF SINGAPORE 2012 i ACKNOWLEDGEMENTS This dissertation would not have been possible without the guidance and help of several individuals who in one way or another contributed and extended their valuable assistance in the preparation and completion of this study. First and foremost, I would like to give my utmost gratitude to my major supervisor Prof. Saw Seang Mei, who has the attitude and quality of a genius. She continually conveyed a spirit of enthusiasm in regards to research, scholarship, and teaching. With her great supervision and patient guidance, I was able to finish my investigation on two novels and well-designed studies on special populations, including preschoolers and pregnant women. Prof. Saw’s passion in academic research constantly inspired me to set myself with higher goals to achieve instead of getting contented with my current performance. Even though working with her is a challenge, it is also a great opportunity to train myself to be a better all rounded person, since her knowledge in epidemiology, biostatics and medicine is very comprehensive. I hereby also place on record, my sincere gratitude to my co-supervisor--Prof. Wong Tien Yin, director of Singapore National Eye Center (SERI), Singapore National Eye Center (SNEC) and Department of Ophthalmology, Nationa University Hostpial (NUH), for his encouragement and unfailing support. Epidemiological ophthalmology is a rather new field to me due to my clinical background in infectious diseases and laboratory science in pathogenic research. During my course of research, I have encountered all kinds of obstacles. Whenever I turn to him with my ii frustrations from study and work, he always showed his trust in me and took time out from his busy schedule to provide practical resolutions for me. I also want to thank my other co-supervisor—A/Prof. Chong Yap Seng, Director of Department Obstetrics & Gynecology, NUS, for his moral support and steadfast encouragement in my GUSTO retinal study. As a main principle investigator of Growing Up in Singapore Towards Healthy Outcomes (GUSTO), A/Prof. Chong is always easy-going and was always willing to bring himself down to our level to talk to us students regarding our difficulties in studies and work. And he would always, from his own pocket, award our students for obtaining good achievements. Thanks to him, I now have my first collection of champagnes. Over the past three years, the support and encouragements received from these three supervisors have benefited me greatly. Prof. Saw, Prof. Wong and A/Prof. Chong have been not only colleagues, but also friends, whose mentoring has made my PhD a thoughtful, fruitful and joyful journey. Furthermore, I owe sincerity and earnest thanks to my Thesis Advisory Committee (TAC) and PhD Qualifying Examination members, who are Prof. Aung Tin and Dr. Louis Tong. Their inputs of sharing professional insights and meticulous assessment in my PhD study have greatly improved my academic understanding. I am indebted to many of my colleagues Dr. Carol Cheung and Dr. M. Kamran Ikram, who have been helping me in statistical analysis, interpretation and paper writing. This dissertation would not have been possible without the contributions of STARS team, GUSTO team, SERI grading team and DeVOS student team. Many iii thanks to their hard work, training, fun sharing and friendship offering, which has nourished me and gave me strength to overcome any hurdles and obstacles met. Last but not least, I am truly indebted and thankful to my parents and my Fiancé. In order to better focus on my study and complete my curriculum, I haven’t been taking good care of my parents, who are currently residing in Guangzhou --a city in China far away from Singapore. I want to thank them for always being so considerate, cheerful and loving. Also, thanks to my Fiancé, Melvin, for always supporting and believing in me. I am really lucky to have such a wonderful family, who are always there for me, like a strong, unmovable harbor in the midst of a wild and raging sea. iv Declaration I hereby declare that the thesis is my orginal work and it has been writeen by me in its entirety. I have duly acknowledged all the sources of information which have been used in the thesis. This thesis has also not been submitted for any degree in university previously. Li Lingjun, Queenie May, 2013 v TABLE OF CONTENTS FRONT PAGE………………………………… ……………………………………i ACKNOWLEDGEMENTS……………………………………….……………… .ii DECLARATION……… .…………… …………………….……………………v TABLE OF CONTENTS………… .…………… …………………….………….vi SUMMARY…………………………………………….………….……………….xvi LIST OF TABLES……………………………………………….…………….….xx LIST OF FIGURES…………………………………………….……………… .xxvi LIST OF APPENDICES…………………………………………………………xxix CHAPTER ONE…………………………………………………………………… 1. Literature Review…………………………………………………………….….1 1.1 Introduction………………………………………….…………………….1 1.2 Measurements of Retinal Vascular Parameters……………… 1.2.1 Retinal Vascular caliber……………………………………………….2 1.2.2 Novel Retinal Vascular Parameters……………………………… .4 1.3 Risk factors for Retinal Vascular Caliber Changes in General Population……………………………………………………………………6 1.3.1 Systemic Factors with Retinal Microvasculature……………………….8 1.3.1 .1 Associations with Demographic Statu s (Age, Gender and Ethnicity)…………………………………………….…………… .8 vi 1.3.1.2 Associations with Socio-Economic Status…………………………15 1.3.1.3 Association with Life Style Factors (Smoking and Drinking).…….17 1.3.1.4 Associations with Physical Activity and TV Viewing Time………20 1.3.1.5 Association with Blood Pressure and Hypertension……………….24 1.3.1.6 Association with Anthropometric Parameters and obesity……… .33 1.3.1.7 Associations with Markers of Inflammation and Dyslipidaemia…38 1.3.1.8 Association with Ocular Anatomic Structure…………………… .44 .3 .2 Systemic Diseases with R etinal Mi crovascu latu re………5 1.3.2.1 Associations with Hyperglycemia, Diabetes and Metabolic Syndromes…………………………………………………… 51 1.3.2.3 Associations with Psychological Disorders and Neurological Diseases………………………………………………………… .57 1.3.2.5 Associations with Food and Drugs Intake…………………………59 1.3.2.6 Associations with Vascular Diseases…………………………… 64 1.3.3 Birth Parameters with Retinal Microvasculature………………………73 1.4 Retinal Vascular Changes and Long-Term Morbidity and Mortality of Systemic Diseases………………………………………………………….76 1.5 Pathophysiology of Retinal Microvascular Changes…………… .92 1.5.1 Mechanisms of Retinal Arteriolar Caliber Changes………………… .92 1.5.2 Mechanisms of Retinal Venular Caliber Changes…………………….93 1.5.3 Mechanisms of Retinal Vascular Tortuosity, Branching Angle and Fractal Dimension Changes………….……………………….…… 94 vii 1.6 The Gap in Current Retinal Epidemiological Study………………95 1.6.1 Hypertension in Children and Pregnant Women……………………95 1.6.2 Obesity in Children and Pregnant Women…………………………….96 1.6.3 Pathology of Myopia in Children……………………………………97 1.6.4 Antenatal Negative Emotion in Pregnant Women……………………98 1.6.5 The Major Gap in Retinal Epidemiological Studies………………… .98 CHPATER TWO……………………………………………….……………….100 2. Methods………………………………………………………… …….………100 2.1 Objective………………………………………………………………… .100 2.1.1 General Objective…………………………………………………100 2.1.2 Specific Objective………………………………….……………….100 2.1.3 Hypothesis for Risk Factors………………………………….… 101 A. Scheme One—STARS and STARS Family Retinal Study…….….…….102 2.2 Study Design……………………………………….……………….…… .102 2.3 Inclusion and Exclusion Criteria……………………….……………… .103 2.4 Study Recruitment Flow………………………….……………….………104 2.5 Clinic Visit……………………………………….………………………105 2.6 Clinic Visit and Ethnics Consideration……………….………………….106 2.7 Study Approval……………………………………….………………… .106 2.8 Clinical Examinations…………………………………………………… 107 2.8.1 Blood Pressure Measurements……………………….……………107 2.8.2 Anthropometric Measurements…………………….……………….107 2.8.3 Eye Examination………………………….……………………… 108 viii 2.9 Fundus Photography Examination………………………….………… .109 2.9.1 Training Program………………………………………….……… 109 2.9.2 Training Assessment……………………………………….……….109 2.9.3 Retinal Photography Examination……………………….…… .109 2.10 Interview at the Clinic……………………………………….….113 2.10.1 Demographic and Socioeconomic Status……………………….113 2.10.2 Parental Life Style……………………………………….…………114 2.10.3 Birth Data from the Health Booklet……………………………….115 2.11 Retinal Vessel Caliber Assessment with IVAN Software………115 2.11.1 Grading Institute……………………………………….…………115 2.11.2 Computing and Image Requirements………………………………115 2.11.3 Procedures for Retinal Vessel Diameter Measurements………… 117 2.11.4 Data Saving Options……………………………………….………120 2.11.5 Confidentiality……………………………………….…………121 2.11.6 Data Management……………………………………….…………121 2.11.7 Reliability test of Retinal Vessel Assessments……………………122 2.12 Definition of Terms……………………………………….……122 2.12.1 Childhood Hypertension……………………………………….….122 2.12.2 Childhood Overweight and Obesity…………………….…………123 2.12.3 Abnormal Birth Parameters………………………………………123 2.12.4 Myopia, Emmetropia and Hyperopia………………….……………124 2.13 Statistical Analysis……………………………………….………124 B. Scheme Two—GUSTO Retinal Study…………………………………125 ix 2.2 Study Recruitment…………………………….……………… 125 2.3 Eligibility……………………………………….………………………… 126 2.4 Study Population……………………………………….………………….127 2.5 Study Approval……………………………………….………………… .128 2.6 Clinic Operation Flow……………………………………….……………128 2.7 Clinical Examinations at 26 Week’s Visit……………………….………130 2.7.1 Blood Pressure……………………………………….…………….130 2.7.2 Anthropometric Measurements………….………………………… 130 2.7.2.1 Height…………………….……………………………………….130 2.7.2.2 Weight……………….……………… 131 2.7.2.3 Mid Upper Arm Circumference……………….………………….131 2.7.2.4 Skinfold Measurements……………….………………………….132 2.7.3 Eye Examinations……………….………………………………… 134 2.7.3.1 Fundus Photography……………….…………………………… 134 2.7.3.2 Auto-refraction……………….………………………………… .134 2.8 Retinal Vessel Assessment ……………………………………………….…134 2.8.1 Training Program……………………………………… .134 2.8.2 Training Assessment……………………………………….……….134 x Week 26-28 clinic visit Interviewer-administered questionnaire (Mother) 11.3.Who will be the main person helping you with the baby after delivery? Confinement nanny Mother / Mother-in-law Husband Other relatives Others, specify__________________ 11. SMOKING – BEFORE THIS PREGNANCY 11.1 Have you ever smoked regularly (at least once a day for a year or more)? 0: No go to question 11.5 1: Yes 2: Refuse to answer 11.2 How old were you when you first smoked regularly? yrs 11.3 Did you smoke during the year before you became pregnant? 0: No go to question 11.5 2: Yes (1) If yes, how many sticks per day? Record maximum stated. Note to interviewer: You may want to explain to the participant that even though she does not smoke, there is some evidence of health implications from second-hand smoke exposure. The following questions are to capture information on second-hand smoke exposure, i.e. where the participant was close enough to the smoker(s) to smell the smoke. 11.5 Did anyone living in your home smoke at home on a daily basis for months or longer? 0: No go to question 11.7 1: Yes 11.6 For how many years did at least person living in your home smoke daily at home? 1: year or less 2: 2-5 years 3: 5-14 years 4: 15-24 years 5. 25+ years 11.7 Have you ever had a job in which, on a daily basis, you were exposed to cigarette smoke from others? 0: No 1: Yes 403 Week 26-28 clinic visit Interviewer-administered questionnaire (Mother) 12. SMOKING – DURING THIS PREGNANCY 12.1 Are you currently smoking? 0: No go to question 12.3 7: Yes If yes, how many sticks per day? Record maximum stated. During your pregnancy, did anyone living in your home smoke at home on a daily basis? 99: No 100: Yes During your pregnancy, have you ever had a job in which, on a daily basis, you were exposed to cigarette smoke from others? 0: No go to section 13 7: Yes (1) On average, how many hours were you exposed to cigarette smoke at work? hour or less 1-3 hours More than hours (2) Are you currently exposed to cigarette smoke at work on a daily basis? 0: No 1: Yes Birth Cohort_26weeks_Questionnaire_22-12-09 Page 15 of 16 404 Week 26-28 clinic visit Interviewer-administered questionnaire (Mother) 13. MEDICATION 13.1 Are you taking any medications / supplements / traditional medicine regularly DURING this pregnancy? Regular refers to more than once a week 0: No END OF QUESTIONNAIRE 1: Yes, please specify in table below S/N S/N S/N Name of Medication Name of Supplement Name of Traditional Medicine THANK YOU VERY MUCH FOR YOUR HELP! Interview end time: ________________ Birth Cohort_26weeks_Questionnaire_22-12-09 Page 16 of 16 405 26-28 Week clinic visit Mother’s Case Report Form Study ID: _______________________ Date of interview: __________________ Interviewer code: _________________ Interview start time: _________________ Tick when completed 1. Registration 2. 26-28 wk visit questionnaires Investigator code 2.1. Mother’s questionnaire 2.2. Mother’s self administered questionnaires  STAI  EPDS  BDI-II  LYDON Maternal  LYDON Domestic Helper 3. Anthropometric measurements 3.1. Weight 3.2. Height 3.3. Mid-upper arm circumference 3.4. Triceps skinfold 3.5. Biceps skinfold 3.6. Subscapular skinfold 3.7. Suprailiac skinfold 4. Collection of hair 5. Collection of buccal swab 6. Pulse wave velocity 7. Auto Refraction 8. Fundus photography 9. Case file completed/checked 406 26-28 Week clinic visit Mother’s Case Report Form 1.11. Anthropometric Measurements 0: Weight . kg . kg . kg . cm . cm . cm should be taken only if the first measurements differed by >200gm. 3.2. Height should be taken only if the first measurements differed by >1.0cm. 3.3. Mid-upper arm circumference . cm . cm . cm should be taken only if the first measurements differed by >1.0cm. 3.4. Triceps skinfold . mm . mm . mm . mm . mm . mm 3.5. Biceps skinfold 407 26-28 Week clinic visit Mother’s Case Report Form 3.6. Subscapular skinfold . mm . mm . mm 3.7. Suprailiac skinfold . mm . mm . mm Skin fold calipers used 4. Hair Collection Taken Not taken Refused Number of hair strands 5. Collection of buccal swab Done Not done Refused Not done Refused Number of swabs 6. Pulse wave velocity Done (Please attach report) 408 26-28 Week clinic visit Mother’s Case Report Form Fundus Photography: 1: Fundus Photo Taken Not taken Unable Refused Comments___________________________________________________ Right Eye ____________________________________ Left Eye _____________________________________ 7.2. Fundus (RE) 1. Normal 2. Abnormal (LE) 3. Unable 1.Normal 2. Abnormal 3. Unable Macular [macular] Disc [Discr] Media [mediar] Posterior Pole of retina [postretr] Peripheral retina[periretr] Describe lesion [desbr] ___________________________________ ___________________________________ 409 26-28 Week clinic visit Mother’s Case Report Form 8. Auto-Refraction(Undilated with Table-Mounted) Taken Not taken Refused Unable Comments___________________________________________________ Right Eye ____________________________________ Left Eye _____________________________________ PLEASE WRITE THE STUDY ID AND MAKE A COPY OF THE AUTO REFRACTION REPORT AS THE DATA FADES AWAY WITHIN ONE WEEK PLEASE PASTE THE COPIED REPORT PAGE HERE    Check the following:  Ensure best readings   Cross-out readings with *and extra readings in excess of   Retake if more than 1*or SD.+/- 0.25   Write down comments for any rejection or unsuccessful attempts  Right Eye ____________________________________ Left Eye _____________________________________ 410 Edinburgh Postnatal Depression Scale Date: Criteria: T1 T2 T3 PN Sticky label Please put a tick () in the box that applies to you after each statement which comes closest to how you have felt in the PAST DAYS, not just how you feel today. I have been able to laugh and see the funny side of things As much as I always could Not quite so much now Definitely not so much now Not at all I have looked forward with enjoyment to things As much as I ever did Rather less than I used to Definitely less than I used to Hardly at all I have blamed myself unnecessarily when things went wrong Yes, most of the time Yes, some of the time No, not very often No, never I have felt worried and anxious for no very good reason No, not at all Hardly ever Yes, sometimes 411 Yes, very often I have felt scared or panicky for no very good reason Yes, quite a lot Yes, sometimes No, not much No, not at all Things have been getting on top of me Yes, most of the time I haven’t been able to cope at all Yes, sometimes I haven’t been coping as well as usual No, most of the time I have coped quite well No, I have been coping as well as ever I have been so unhappy that I have had difficulty sleeping Yes, most of the time Yes, sometimes Not very much No, not at all I have felt sad or miserable Yes, most of the time Yes, quite often Not very often No, not at all I have been so unhappy that I have been crying Yes, most of the time Yes, quite often Only occasionally 412 No, never 10 The thought of harming myself has occurred to me Yes, quite often Sometimes Hardly ever Total: Never This scale has also been validated for use in antenatal women. 413 SELF-EVALUATION QUESTIONNAIRE STAI Form Y-1 Please provide the following information: Name Age Date Gender (Circle) M F S T DIRECTIONS: A number of statements which people have used to describe themselves are given below. Read each statement and then blacken the appropriate circle to the right of the statement to indicate how you feel right now, that is, at this moment. There are no right or wrong answers. Do not spend too much time on any one statement but give the answer which seems to describe your present feelings best. 1. I feel calm . 2. I feel secure . 3. I am tense 4. I feel strained 5. I feel at ease 6. I feel upset . 7. I am presently worrying over possible misfortunes 8. I feel satisfied 9. I feel frightened . 10. I feel comfortable 11. I feel self-confident . 12. I feel nervous 13. I am jittery . 14. I feel indecisive . 15. I am relaxed . 16. I feel content . 17. I am worried 18. I feel confused . 19. I feel steady . 20. I feel pleasant . . STAIB-AD, © 1968, 1977 Charles D. Spielberger. All Rights Reserved. Published by Mind Garden, Inc., www.mindgarden.com 414 SELF-EVALUATION QUESTIONNAIRE STAI Form Y-2 Name___________________________________________________Date_________ DIRECTIONS A number of statements which people have used to describe themselves are given below. Read each statement and then blacken in the appropriate circle to the right of the statement to indicate you generally feel. 21. I feel pleasant . . 22. I feel nervous and restless . 23. I feel satisfied with myself 24. I wish I could be as happy as others seem to be . 25. I feel like a failure . 26. I feel rested 27. I am “calm, cool, and collected” . 28. I feel that difficulties are piling up so that I cannot overcome them 29. I worry too much over something that really doesn’t matter 30. I am happy . 31. I have disturbing thoughts . 32. I lack self-confidence 33. I feel secure . 34. I make decisions easily . 35. I feel inadequate 36. I am content . 37. Some unimportant thought runs through my mind and bothers me 38. I take disappointments so keenly that I can’t put them out of my mind . 39. I am a steady person 40. I get in a state of tension or turmoil as I think over my recent concerns and interests . STAIB-AD, © 1968, 1977 Charles D. Spielberger. All Rights Reserved. Published by Mind Garden, Inc., www.mindgarden.com 415 416 417 PUBLICATIONS 418 [...]... variables) for Retinal Vascular Fractal Dimension Changes in Pregnant Women ………………………………………….181 Table 34 Risk Factors (continuous variables) for Retinal Vascular Caliber Changes in Pregnant Women …………………………………………………….184 Table 35 Risk Factors (continuous variables) for Retinal Vascular Tortuosity Changes in Pregnant Women ………………………………………185 Table 36 Risk Factors (continuous variables) for Retinal Vascular. .. Table 30 Risk Factors (categorical variables) for Retinal Vascular Caliber Changes in Pregnant Women ………………………………………………………178 Table 31 Risk Factors (categorical variables) for Retinal Vascular Tortuosity Changes in Pregnant Women ………………………………………179 xxii Table 32 Risk Factors (categorical variables) for Retinal Vascular Branching Angle Changes in Pregnant Women ………………………………………….180 Table 33 Risk Factors. .. Pressure as a Risk Factor for Changes in Retinal Vascular Parameters ………………………………….189 3.4.2.1.2 Anthropometric Parameters as Risk Factors for Changes in Retinal Vascular Parameters……………………………197 3.4.2.1.3 Ocular Biometric Parameters as Risk Factors for Changes in Retinal Vascular Parameters…………………………209 3.4.2.1.4 Antenatal Mental Health Status as a Risk Factor for Changes in Retinal Vascular Parameters... Characteristic between Pregnant Women with Retinal Photography and without Retinal Photography Participating the GUSTO Main and the GUSTO IVF Study………………………………………………………153 Table 28 Risk Factors (categorical variables) for Retinal Vascular Caliber Changes in Children ……………………………………………………………… 175 Table 29 Risk Factors (continuous variables) for Retinal Vascular Caliber Changes in Children ……………………………………………………………... with retinal arteriolar and venular narrowing in children Negative antenatal emotions such as depressive symptoms and poor sleep quality were associated with retinal arteriolar widening in pregnant women Our study is the first study comprehensively investigating a range of systematic risk factors and retinal vascular changes, reflecting the systemic microcirculation in vivo, in young children and pregnant. .. Health and Retinal Vascular Parameters among Pregnant Women …………………………………252 4.6 Associatio ns bet ween Gender and Retinal Vascular Caliber in Children …………………………………………………………………256 4.7 Associations between Ethnicity and Retinal Vascular Parameters in Pregnant Women …………………………………………………………256 4.8 Associations between Demographic Status and Life Style and Retinal Vascular Parameters in Children and Pregnant. .. ………………212 3.4.2.1.5 Birth Parameters as Risk Factors for Changes in Retinal Vascular Parameters ………………………………… 217 3.4.2.1.6 Life Style as a Risk Factor for Changes in Retinal Vascular Parameters…………………………………………… 218 3.4.2.2 Gender, Ethnicity, Household Income and Education as Risk Factors for Changes in Retinal Vascular Parameters…… ……221 3.4.2.3 Stratification and Interaction……………………………………224 3.4.2.4... and thereby, a greater risk of clinical cardiovascular disease 33, 34 Previous studies have focused on one retinal vascular parameter – caliber (diameter) of the retinal vessels, for quantifying the retinal vascular changes using the advent of computer-assisted methods In addition to retinal vascular caliber (e.g retinal 4 arteriolar narrowing), newer studies are now starting to examine the branching... variables) for Retinal Vascular Branching Angle Changes in Pregnant Women …………………………………………186 Table 37 Risk Factors (continuous variables) for Retinal Vascular Fractal Dimension Changes in Pregnant Women ……………………………………………187 Table 38 Association between Blood Pressure and Retinal Vascular Caliber…… 189 Table 39 Linear Regression Models of Retinal Vascular Caliber and Blood Pressure……………………………………………………………….190... diseases (such as kidney disease, cardiovascular diseases and stroke) for clinical and epidemiological research.12-17 However, the range of established risk factors influencing variation in retinal microvasculature haven’t been fully investigated in preschoolers (6 years and below) and pregnant women 1.2 Measurements of Retinal Vascular Parameters 1.2.1 Retinal Vascular Caliber Recent population-based . Style as a Risk Factor for Changes in Retinal Vascular Parameters…………………………………………… 218 3.4.2.2 Gender, Ethnicity, Household Income and Education as Risk Factors for Changes in Retinal Vascular. CRAE and CRVE were 120.09 µm and 169.94 µm in Chinese pregnant women, 122.59 µm and 172.81 µm in Malay pregnant women and 122.44 µm and 169.21 µm in Indian pregnant women, respectively. In multivariate. Ethnicity and Retinal Vascular Parameters in Pregnant Women …………………………………………………………256 4.8 Associations between Demographic Status and Life Style and Retinal Vascular Parameters in Children and Pregnant