COLLEGE OF BASIC AND APPLIED SCIENCES SCHOOL OF BIOLOGICAL SCIENCES PREDICTORS OF POTENTIALLY HIGH RISK FOR PREECLAMPSIA AMONG PREGNANT WOMEN ATTENDING ANTENATAL CLINICS AT SELECTED HOSPITALS IN ACCRA BY HECKEL AMOABENG ABBAN (10599793) THIS THESIS IS SUBMITTED TO THE UNIVERSITY OF GHANA, LEGON IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE AWARD OF DOCTOR OF PHILOSOPHY (PHD) IN NUTRITION DEGREE DEPARTMENT OF NUTRITION AND FOOD SCIENCE JULY, 2021 University of Ghana http://ugspace.ug.edu.gh i DECLARATION University of Ghana http://ugspace.ug.edu.gh ii ABSTRACT Introduction: Preeclampsia/Toxemia (PE) is a genuine hypertension condition related with maternal and infant ill health and death during pregnancy. Preeclamptics as well as their babies/children develop health conditions including cardiovascular disease as well as growth conditions well along in life. In Ghana, prevalence of PE has been known to be as low as 2.5% in Ghana Police hospital and as high as 48.8% in Komfo Anokye Teaching Hospital. Most of the studies carried out on PE has been case control and hence do not have enough data on the possible exposures at the early stages of pregnancy which may have led to the developing of PE. Also only a few studies has been carried out on the predictors associated with preeclampsia. Objective: This current prospective cohort study sought to determine the factors at the various stages of pregnancy; ≤ 20 weeks gestation through 28 – 32 weeks and during 6 weeks postpartum which may predispose the pregnant women to a potentially high risk for PE. Methodology: This was prospective cohort study involving 403 pregnant women who were recruited at ≤ 20 weeks gestation. Nonetheless, 21 participants dropped out between weeks 28 and 32, and 24 participants also dropped out at 6 weeks postpartum leaving 358 participants in the study. The study took place at the Ghana Police Hospital, Cantonment, and the University of Ghana Hospital, Legon, both in Accra. The entire study lasted for 21 months (May, 2018 – Feb.2020). Structured questionnaires that had been pre-tested were used to obtain information on the participants' backgrounds, lifestyle practices, gynecological factors, dietary factors, stress status, BMI, biochemical data (haemoglobin, proteinuria), clinical data (blood pressure), family history of chronic conditions, morbidities among other factors. The criteria used for potentially high risk for preeclampsia was having at least a systolic University of Ghana http://ugspace.ug.edu.gh iii blood pressure of ≥130 mmHg or diastolic blood pressure of ≥80 mmHg or oedema or proteiunuria. Background categorical variables were computed as frequencies and percentages, whereas continuous variables were enumerated as median (interquartile range; Q1, Q3) or means ± SD, as appropriate. The predictors of possibly high risk for PE were investigated using binary logistic regression and finally path analysis was run to determine the path way through which the predictors operate. Results: The age on average of expectant mothers is 31 ± 5 years, a greater number 194 (48%) of expectant mothers had attained tertiary education, median gestational age at first time ante natal booking was 14 (12, 17) weeks, Akan ethnicity was dominating 166 (41.0%) and 347 (86.0%) of the women were married. Prevalence of serum vitamin D and calcium deficiencies were 48.3% and 53.2% respectively with 34.0% being at a potentially high risk for PE. Predictors of potentially high risk for PE were the following; estimated pre – pregnancy body mass index (≥ 30 kg/m2) AOR = 3.6 (95% CI = 1.01 – 11.750) p value 0.040 and estimated pre- pregnancy weight (> 71 kg) AOR = 3.4 (95% CI = 1.250 - 12.703) p 0.019. From path analysis, path relationship for anthropometric indices (estimated pre – pregnancy BMI and estimated pre- pregnancy weight) and potentially high risk for preeclampsia shows a favorable and significant direct association (β = 0.519; t-value = 8.545; p-value = 0.001). Conclusion: Predictors of potentially high risk for PE among the participants were estimated pre-pregnancy BMI and estimated pre-pregnancy weight (weight measured at the first antenatal clinic). In contrast to findings of most studies, serum vitamin D and calcium deficiencies had no association with PE. University of Ghana http://ugspace.ug.edu.gh iv DEDICATION I dedicate this work to my entire family who believed in me and supported me to undertake this academic pursuit. University of Ghana http://ugspace.ug.edu.gh v ACKNOWLEDGEMENT I am indebted to the Almighty God for bringing me this far in life and in the pursuit of this academic goal. Prof. Matilda Steiner-Asiedu, my main supervisor, deserves my sincerest gratitude for intellectual, social, and spiritual support, as well as for being a mother to me. Without the close supervision of my three co-supervisors, Dr. Seth Adu – Afarwuah, Dr. Frederick Vuvor, and Dr. Timothy Senunyeme, this work would not have been completed. May God generously bless you all for your patience and advice as you worked on this thesis. Am also grateful to the Administration of Ghana Police Hospital and University of Ghana Hospital for the permission granted me to undertake sample collection at their facility. My special gratitude to ACP Dr. Samuel Otu – Nyarko and DSP Edem Wornenor of Ghana Police Hospital for the assistance given me; your warm reception and timely advice will forever remain with me. God bless you. To all friends and field assistants, may the good Lord bless you. My genuine appreciation additionally goes to my dearest spouse, Eddie Abban, for his shrewd advice, backing, and support all through this time of study, also my folks, Mr. and Mrs. Dokyi Amoabeng, who intensely appealed to God for me and upheld me to complete this course. University of Ghana http://ugspace.ug.edu.gh vi TABLE OF CONTENTS DECLARATION ........................................................................................................... i ABSTRACT .................................................................................................................. ii DEDICATION ............................................................................................................. iv ACKNOWLEDGEMENT .............................................................................................v TABLE OF CONTENTS ............................................................................................. vi LIST OF TABLES ....................................................................................................... ix LIST OF FIGURES .......................................................................................................x LIST OF ABBREVIATIONS ...................................................................................... xi CHAPTER ONE ............................................................................................................1 1.0 INTRODUCTION ...................................................................................................1 1.1 Background Information ..........................................................................................1 1.2 Research Problem ....................................................................................................6 1.3 Research Questions ..................................................................................................8 1.4 Objectives ................................................................................................................8 CHAPTER TWO ...........................................................................................................9 2.0 LITERATURE REVIEW ........................................................................................9 2.1 Hypertensive Disorders in Pregnancy (HDP) ..........................................................9 2.1.1 Chronic Hypertension in Pregnancy ...................................................................10 2.1.2 Gestational Hypertension (GH) ..........................................................................10 2.1.3 Preeclampsia: Forms and Prevalence..................................................................11 2.1.3.1 Pathogenesis and Pathophysiology of Preeclampsia .......................................12 2.1.3.2 Risk Factors of Preeclampsia ...........................................................................21 2.2 Oedema in Pregnancy ..........................................................................................56 2.3 Other Previous Works Carried Out in Ghana ........................................................57 CHAPTER THREE .....................................................................................................60 3.0 METHODOLOGY ................................................................................................60 3.1 Research Design and Setting .................................................................................60 3.2 Subject Recruitment and Selection ........................................................................61 3.3 Sample Size Determination....................................................................................62 University of Ghana http://ugspace.ug.edu.gh vii 3.4 Data Collection ......................................................................................................65 3.4.1 Interviews ............................................................................................................65 3.4.2 Anthropometric Data ..........................................................................................66 3.4.3 Biochemical Data ................................................................................................66 3.4.4 Clinical Data .......................................................................................................68 3.5 Quality Assurance ..................................................................................................68 3.6 Data Capture and Statistical Analysis ....................................................................68 3.7 Ethical Consideration .............................................................................................79 CHAPTER FOUR ........................................................................................................81 4.0 RESULTS ..............................................................................................................81 4.1 Preamble ................................................................................................................81 4.2 Socio-demographic Characteristics .......................................................................81 4.3 Dietary Characteristics of Pregnant Women at Baseline and Midline ..................83 4.4 Body Mass Index and Blood Pressure measurements of the Pregnant Women ....85 4.5 Lifestyle Characteristics of Pregnant Women .......................................................87 4.6 Gynaecological Factors of Pregnant Women ........................................................88 4.7 Maternal Other Health Condition and Family Medical History at Baseline and Midline .........................................................................................................................89 4.8 Biochemical Measurements of Pregnant Women at Baseline, Midline and Endline ......................................................................................................................................90 4.9 Correlation between Independent Binary Variables and Dependent Variable ......92 4.10 Predictors of Potentially High Risk for Preeclampsia .........................................94 4.11 Path Analysis of Factors Influencing Potentially High Risk for PE ....................95 CHAPTER FIVE .......................................................................................................105 5.0 DISCUSSIONS ....................................................................................................105 5.1.1 Lifestyle Characteristics of Pregnant Women ..................................................106 5.1.2 Body Mass Index and Blood Pressure Levels of the Pregnant Women ...........107 5.1.3 Biomakers Profiles of the Pregnant Women .....................................................109 5.2 Summary of the Main Findings ...........................................................................113 5.3 Prevalence of Potentially High Risk for Preeclampsia (PE) ................................113 5.4 Predictors of Potentially high Risk for Preeclampsia ..........................................119 5.5 Pathway of Predictors of Potentially High Risk for PE .......................................120 5.6 Strengths and Weaknesses ...................................................................................120 University of Ghana http://ugspace.ug.edu.gh viii CHAPTER SIX ..........................................................................................................122 6.0 CONCLUSIONS AND RECOMMENDATIONS ..............................................122 6.1 Conclusions ..........................................................................................................122 6.2 Recommendation .................................................................................................122 6.2.1 Recommendations for Future studies................................................................122 6.2.2 Recommendations for Policy Makers ...............................................................123 REFERENCES ..........................................................................................................124 APPENDICES ...........................................................................................................153 University of Ghana http://ugspace.ug.edu.gh ix LIST OF TABLES Table 3.1 Independent Binary Variables, Definitions and Rationale .......................... 70 Table 4.1 Socio-demographic Characteristics of Pregnant Women at Baseline ......... 82 Table 4.1 Socio-demographic Characteristics of Pregnant Women at Baseline continued ..................................................................................................... 83 Table 4.2 Dietary Characteristics of Pregnant Women at Baseline and Midline ........ 85 Table 4.3 Body Mass Index and Blood Pressure Measurement of the Pregnant Women at Baseline, Midline and Endline ................................................................ 86 Table 4.4 Lifestyle Characteristics at Baseline and Midline ....................................... 87 Table 4.5 Gynecological Factors of the Pregnant Women .......................................... 88 Table 4.6 Maternal Other Health Condition and Family Medical History at Baseline and Midline .................................................................................................. 89 Table 4.6 Maternal Other Health Condition and Family Medical History at Baseline and Midline continued ................................................................................. 90 Table 4.7 Biochemical Measurement of Pregnant Women ......................................... 91 Table 4.8 Correlation between Independent Variables and Dependent Variable (Potentially High Risk for PE) .................................................................... 92 Table 4.8 Correlation between Independent Variables and Dependent Variable (Potentially High Risk for PE) continued .................................................... 93 Table 4.9 Logistic Regression to show Factors Associated with Potentially High Risk for Preeclampsia .......................................................................................... 94 Table 4.10 Initial Confirmatory Factor Analysis (CFA) Results of Initial Measurement Model .................................................................................... 96 Table 4.11 Final CFA Results of Measurement Model ............................................... 99 Table 4.12 Pearson Correlation Matrix ...................................................................... 101 Table 4.13 Structural Model Assessment .................................................................. 102 University of Ghana http://ugspace.ug.edu.gh x LIST OF FIGURES Figure 1.1: The Two Stage Pathophysiological Process Underlying PE ....................... 5 Figure 3.1 A Flow Chart of Loss to Follow up ............................................................ 64 Figure 3.2: Proposed Conceptual Model of Potentially High Risk for PE .................. 78 Figure 4.1 Percentages of Food items Consumed in a Week at Baseline and Midline 84 Figure 4.2: Post-Study Framework ............................................................................ 104 University of Ghana http://ugspace.ug.edu.gh xi LIST OF ABBREVIATIONS anti-AT1-AA Anti- angiotensin II type 1 receptor autoantibody AT1 Angiotensin II type 1 AT1-AA Angiotensin II receptor 1 Autoantibodies CBS Cystathionine β-synthase CHP Chronic Hypertension in Pregnancy CO Carbon Monoxide COPP Cobalt Protoporphyrin CSE or Cth Cystathionine-γ-lyase DIC - Disseminated Intravascular Coagulation ET-1 Endothelin-1 ET-1163 Endothelin – 1163 G. S.S. Ghana Statistical Service G.H.S. Ghana Health Service GSH-Px Glutathione Peroxidase H2S Hydrogen Sulphide HDP Hypertensive Disoders in Pregnancy HELLP Hemolysis, Elevated Liver Enzymes and Low Platelets HIF Hypoxia-inducible factors HLA-C Human Leukocyte Antigen-C Hmox1 or HO-1 Haem oxygenase 1 HO Heme oxygenase IL-10 Interleukin -10 KATH Komfo Anokye Teaching Hospital KBTH Korle Bu Teaching Hospital KIR Killer cell Ig-like Receptors MBRN Medical Birth Registry of Norway MDC NSW Midwives Data Collection MHCs self-Major Histocompatibility Complexes University of Ghana http://ugspace.ug.edu.gh xii NSW New South Wales PE Preeclampsia PIGF placental growth factor PIH pregnancy-induced hypertension RAAS Renin–angiotensin–aldosterone system ROS Reactive Oxygen Species sFlt 1 soluble fms-like tyrosinekinase SLE systemic lupus erythematosus SOD Superoxide dismutase TAS Total Antioxidant Status Th 2 T helper type 2 phenotype uNK uterine Natural Killer VEGF Vascular Endothelial Growth Factor WHO World Health Organization University of Ghana http://ugspace.ug.edu.gh 1 CHAPTER ONE 1.0 INTRODUCTION 1.1 Background Information Preeclampsia (PE) is a pregnancy–induced hypertensive disorder characterised by blood pressure of more than 140/90 mmHg, significant proteinuria with or without oedema or signs of damage of an essential organ such as the kidney (Lorquet et al., 2010; Mayo Foundation for Medical Education and Research, 1998 - 2017; Rudra et al., 2011). Mostly, the symptoms of the condition become evident after gestational age of 20 weeks among women who used to have regular blood pressure readings (Abalos et al., 2013; James et al., 2010; Jeyabalan, 2013). Hypertensive pregnancy has been recognised as a complication of pregnancy for ages but its aetiology remains unclear to date. There are two stages to the pathophysiologic processes that underpin this illness; reduced placental perfusion, presumably related to aberrant placenta placement with decreased invasion of the trophoblast and deficient modification of the spiral arteries of the uterus was the initial phase whilst the final phase is linked to maternal disease symptoms, with inflammatory, metabolic, and thrombotic responses convergent to alter vascular function, potentially leading to multi-organ damage (Roberts and Gammill, 2005; Steegers et al., 2010). Also Tomimatsu and colleagues decribed this two-stage process with the claim that “ predisposing immunological, genetic and preexisting maternal risk factors may affect abnormal cytotrophoblast invasion of spiral arteries (abnormal placentation) (first stage) and the second stage involving a reduction of the uteroplacental perfusion which induces placental release of antiangiogenic factors (soluble fms-like University of Ghana http://ugspace.ug.edu.gh 2 tyrosinekinase 1 (sFlt 1) into the maternal circulation, which antagonizes proangioangenic factors leading to endothelial dysfunction. Preexisting maternal health conditions such as chronic hypertension, systemic lupus erythematosus (SLE) and obesity also contribute to endothelial dysfunction” (Tomimatsu et al., 2019) (Fig 1.1). Hippocrates (O'Dowd and Philipp, 1994) recorded the frequency of seizures in expectant mothers as right on time as the fourth century B.C., subsequently the term eclampsia, which is gotten from the Greek word eclampsia, which in a real sense signifies "streak forward," inferring an unexpected turn of events. Toxemia was consequently authored after it was found that hypertension and albuminuria flagged the improvement of seizures in these expectant mothers. The term pregnancy-actuated hypertension (PIH) is most generally utilized at present, since not all preeclamptics go along these lines foster eclampsia (Lewis and Chamberlain, 1990). Research has shown that 10 million women develop PE worldwide yearly, of which 76,000 die as a result of it and other hypertensive related disorders, with 500,000 babies dying in a year (Kuklina et al., 2009). Preeclampsia is found in 1.8 % to 16.7 % of pregnant women in underdeveloped nations (Ige and Osungbade, 2011). In 2007, the WHO estimated that 10 – 25% maternal deaths were caused by PE (WHO, 2007). Furthermore, a study by (Nour, 2008) indicated that PE alone has nearly 12% of direct influence on maternal death. PE is estimated to affect 3.4 % of the American populace (Ananth et al., 2013). University of Ghana http://ugspace.ug.edu.gh 3 In comparison to their counterparts in the developed world, women in poor countries are seven times more likely to suffer preeclampsia (WHO, 2007). Preeclampsia has been known to be the number one cause of maternal deaths in Latin America (Preeclampsia Foundation, 2010) with a prevalence of 8.9% recorded in Brazil in a descriptive and retrospective analysis of data acquired from medical histories of pregnant women who were with and without preeclampsia admitted at the Guilherme Álvaro Reference Hospital Santos/SP – Brazil (Bergamo et al., 2015). In Asia, a research on singleton births in Australia, showed the prevalence of PE was 3.3 %, according to data taken from the New South Wales (NSW) Department of Health that collects mother and newborn data for all births weighing more than 400 grams or occurring after 20 weeks of pregnancy, accounting for more than one-third of all births in Australia) (Thornton et al., 2013), 12% among non pre-gestational diabetic patients and 18.2 % among pre-gestational diabetic patients in Bangladesh in a cross- sectional research in which participants were sourced from selected hospitals in Dhaka city (Jahan et al., 2015) and 4.7% was found in a review of medical files of 7013 singleton women who were pregnant and gave birth in the hospital between 2008 and 2009 in Bangkok, Thailand (Pitakkarnku et al., 2011). In Ghana, prevalence of PE has been found to be 7.0% in a longitudinal study involving 11784 nulliparous pregnant women at the Out Patient Department who were followed up from 14 – 16 gestational weeks till delivery at the Korle Bu Teaching hospital (Obed and Aniteye, 2006), 6.6% in a retrospective observational hospital-based study among referral and Out Patient Department pregnant women in Komfo Anokye Teaching hospital (Owiredu et al., 2010), 2.5% in an unmatched case control study in the Police hospital among referral and Out Patient Department University of Ghana http://ugspace.ug.edu.gh 4 pregnant women who delivered at the facility (Otu-Nyarko et al., 2015), 7.9% in Korle Bu Teaching hospital (Adu-Bonsaffoh et al., 2017a) and 3 in 10 in a study with mismatched participants involving all referrals and regular ante natal clients deliveries at the Regional hospital in Accra (Aseidu et al., 2019). Though the aetiology of PE is unknown, major risk factors include history of PE (personal or family), obesity, chronic hypertension, first pregnancy, multiple pregnancies, new paternity, age, interval between pregnancies, history of certain health conditions and in vitro fertilization (Mayo Foundation for Medical Education and Research, 1998 – 2017). Turpin et al. (2008) found preeclamptics to have a higher prevalence for obesity, hypertension and high fasting blood glucose. Reports from (Wei et al., 2013; Zhao et al., 2017) studies specified that maternal 25- hydroxyvitamin D insufficiency between 23 and 28 weeks of pregnancy is linked to an elevated tendency for severe PE development. Shand et al. 2010 also discovered 25 hydroxyvitamin D deficiency to be frequent among preeclamptics. In America, total dietary fibre consumption was linked to lower pregnancy-related dyslipidaemia, a culprit for PE (Qiu et al., 2008). Pre-pregnancy maternal BMI (≥ 25 kgm-2) a known modifiable risk factor for PE, has been recognized to increase one's risk for PE development by approximately three fold (Eiland et al., 2011). Low serum calcium levels as well as their dysregulation, have a role in the development of PE (Rashid et al., 2015). University of Ghana http://ugspace.ug.edu.gh 5 FIRST STAGE SECOND STAGE Figure 1.1: The Two Stage Pathophysiological Process Underlying PE Reduced placental perfusion Placental antiangiogenic proteins (sFlt) Endothelial dysfunction Systemic vascular dysfunction Immunological factors (reduced paternal antigen exposure) Preexisting risk factors (chronic hypertension SLE, obesity Genetic factors (ethnicity race, FLT1 SNPs) Increased placental mass (multifetal pregnancy, fetal hydrops) Abnormal Placentation University of Ghana http://ugspace.ug.edu.gh 6 1.2 Research Problem Preeclampsia is one of the main culprits of pregnancy-related deaths globally (Cousens et al., 2011). The major risk factors have been known to be medical, maternal, socioeconomic, parity, family history among others (Mayo Foundation, 1978 – 2017). In Ghana, medically, abnormal functioning of the endothelial contribute greatly to PE development as indicated by decreased serum vascular endothelial growth factor levels (Adu-Bonsaffoh et al., 2017b) and systolic blood pressure of 130 mmHg at initial booking has been linked with PE (Otu-Nyarko et al., 2015). Maternally, parity of one (Otu-Nyarko et al., 2015) and high percentage body fat (Yeboah et al., 2017) increase ones risk of developing PE. In addition lower levels of serum calcium and magnesium, abnormal lipid levels (Ephraim et al., 2014a), serum nitric oxide upregulation as evidenced by elevated serum nitric oxide metabolite (Adu-Bonsaffoh et al., 2015) had been reported to be associated with PE. However in the western world, total dietary fibre intake was found to be associated with reduced pregnancy-related dyslipidaemia as a cause for preeclampsia (Qiu et al., 2008) and calcium deficiency as well as their deregulation influence the onset of PE (Rashid et al., 2015), further more, WHO recommmends daily supplementation of calcium for pregnant women living in areas of low calcium intake (WHO, 2011). In Ghana, however, the few studies having been carried out indicated that even though pregnancy-related hypertensive disorders of which PE is one significant reason for maternal deaths particularly in our tertiary medical clinics; 31.7% of maternal deaths recorded in a retrospective descriptive study carried out at KorleBu Teaching hospital was attributed to pregnancy-related hypertensive disorders with eclampsia contrbuting 23.8% (Adu-Bonsaffoh et al., 2013), 3 out of 10 maternal deaths recorded University of Ghana http://ugspace.ug.edu.gh 7 were due to PE (Adu - Bonsaffoh et al., 2014), hypertensive disorders of which PE is one was found to be the second utmost culprit of mortality in a retrospective study in which 280 maternal deaths were recorded at Tamale Teaching hospital (Gumanga et al., 2011) findings from a retrospective review study in Komfo Anokye Teaching hospital by Lee et al. (2012) indicated that hypertensive disorders are the number one culprit of maternal mortality (26.4%). Nutritionally, Agyare et al. (2018) in a longitudinal study among pregnant women found initiation of iron and folic acid after completing first trimester compare with the first trimester to be significantly associated with more than three fold increase risk of developing oedema as a risk factor for PE. Darkwa et al. (2017a), in a situational control study found among expectant mothers in their first trimester an adequately low amount of sodium and potassium levels in the blood among women who foster toxemia contrast with expectant mothers with normal blood pressure. In a comparative cross sectional study among pregnant women who were > 30 weeks gestational age, an insignificant contrast in serum magnesium and overall calcium among preeclamptic and ordinary expectant mothers was found (Darkwa et al., 2017b); Ephraim et al. (2014b) found obesity to be a predictor of PE and high percentage body fat was recorded among preeclamptics compared to non preeclamptics (Yeboah et al., 2017). Most of these studies were case control and hence do not have enough data on the possible exposures at the early stages of pregnancy which may have led to the developing of PE, therefore this current study which is prospective cohort aspires to determine the factors at the very early stages of pregnancy (≤ 20 weeks gestation) and 28 – 32 weeks which may predispose the pregnant women to be at a potentially high risk for PE. The outcome of this study University of Ghana http://ugspace.ug.edu.gh 8 will add onto the knowledge already known about PE and also serve as a basis for further research into PE. 1.3 Research Questions i. What is the prevalence of potentially high risk for PE among pregnant women attending antenatal clinic at University of Ghana and the Ghana Police hospitals? ii. What are the factors associated with potentially high risk for PE among the pregnant women? iii. What are the pathways through which these factors operate? 1.4 Objectives Main Objective To identify the factors linked with potentially high risk for PE among pregnant women attending antenatal clinic at selected hospitals in Accra, and to identify the pathways through which the factors operate. Specific Objectives i. To determine the prevalence of potentially high risk for PE (presence of at least high systolic blood pressure (≥ 130 mmHg) or high diastolic blood pressure (≥ 80 mmHg) or oedema or proteinuria) among pregnant women attending antenatal clinics at University of Ghana and the Ghana Police hospitals in Accra. ii. To determine the factors associated with potentially high risk for PE among the pregnant women. iii. To identify the pathways through which these factors operate. University of Ghana http://ugspace.ug.edu.gh 9 CHAPTER TWO 2.0 LITERATURE REVIEW 2.1 Hypertensive Disorders in Pregnancy (HDP) Pregnancy induced hypertension (HDP) is defined as a systolic blood pressure (SBP) of >140 mmHg and a diastolic blood pressure (DBP) >90 mmHg, or a 30/15 mmHg increase in first or pre-pregnancy blood pressure, proteinuria, and/or edema (Lawrence and Patricia, 2008). It can occur during pregnancy, at birth, or even after delivery, with health concerns such as heart, liver, and renal disease, as well as fetal difficulties (NHBPEPWG, 2000). According to Ghulmiyyah and Sibai (2012), HDP affects 8–10% of all pregnancies globally, resulting in 14% maternal fatalities (Say et al., 2014). HDP is the leading cause of maternal deaths in Ghana's tertiary institutions, according to clinical investigations (Lee et al., 2012; Adu-Bonsaffoh et al., 2013). Adu-Bonsaffoh et al. (2017a) discovered problems in pregnant women out of 1856 who gave birth at Korle Bu Teaching Hospital (KBTH), suggesting a prevalence of 21.4 %. In an analysis involving 82 studies and 854 304 pregnant women, Noubiap et al. (2019) discovered a prevalence of 49.8% (95 percent Confidence Interval (95% CI) = 32.3 – 70.7), 14.7 % (95% CI = 11.6 – 18.2), 9.2% (95% CI = 4.2 – 16.0), 44.0% (95% CI = 36.7 – 52.0), 22.1% (95% CI = 14.8 – 30.8), 14.7% (95% CI = 8.1 – 23.2) and 2.2% (95% CI = 1.2 – 3.4) for gestational hypertension, chronic hypertension, superimposed PE, PE, severe PE, eclampsia and Haemolysis, Elevated liver enzymes, Low Platelet count (HELLP) syndrome respectively. At the continent level, Central and Western Africa had a greater prevalence, with a consistent trend of increasing University of Ghana http://ugspace.ug.edu.gh 10 HDP prevalence with increased affluence. Among the Americans, the prevalence of hypertensive disorders in pregnancy and PE was about 10% and 3%, respectively (Amro et al., 2016). 2.1.1 Chronic Hypertension in Pregnancy Chronic hypertension in pregnancy (CHP) is "hypertension that develops before pregnancy or before 20 weeks of gestation; having a systolic blood pressure of ≥140 mmHg and/or a diastolic blood pressure of ≥90 mmHg or use of antihypertensive medication before pregnancy or having high blood pressure after 12 weeks of delivery" (ACOG Committee on Practice Bulletins–Obstetrics, 2002). It's been linked to a slew of pregnancy-related issues. In a study conducted in Ghana, Dassah et al. (2019) discovered a prevalence of persistent high blood pressure in pregnancy of 5.3 % among 451 pregnant women. Furthermore, Firoza and colleagues found a prevalence of chronic hypertension to be 1.6 % (95% CI = 0.12 – 0.20) with a prevalence in middle-income and high-income countries of 0.6 % (95% CI = 0.004 – 0.009) and 1.7 % (95% CI = 0.013 – 0.022) respectively (Firoza et al., 2018). 2.1.2 Gestational Hypertension (GH) This is one of the pregnancy-induced hypertension that arises after 20 weeks with no urine protein or symptoms of renal impairment (Mayo Foundation for Medical Research, 1998–2019). In a prevalence study conducted at Komfo Anokye Teaching Hospital in Ghana, Dassah and colleagues discovered that 32.4 % of pregnant women had gestational hypertension (Dassah et al., 2019). Shen et al. (2017) discovered a 3.75% frequency of GH in 8085 pregnant women at the Ottawa Hospital and Kingston General Hospital in the United States of America. University of Ghana http://ugspace.ug.edu.gh 11 2.1.3 Preeclampsia: Forms and Prevalence Preeclampsia (PE) was previously known as Toxemia, a hypertensive disorder in pregnancy associated with blood pressure greater than 140 mmHg/90 mmHg recorded every 4–6 hours and symptoms of damage to an essential organ such as the liver or kidney (Mayo Foundation for Medical Education and Research, 1998–2019). PE can occur anytime between 48 hours and 6 weeks after delivery (Mayo Foundation for Medical Research, 1998–2020). Severe headache, impaired vision/light sensitivity/loss of vision, protein in urine and upper abdominal pain (below the right side ribs), nausea, vomiting, decreased urine output, decreased level of platelets and shortness of breath are some of the most common symptoms (Mayo Foundation for Medical Education and Research, 1998 – 2019). PE has been classified into two types: mild and severe. The mild type as having SBP ≥140 mmHg and DBP ≥90 mmHg, as well as proteinuria of 0.3g in a 24-hour period whereas the severe form is defined by SBP ≥ 160 mmHg and DBP ≥110 mmHg on two instances of not less than 6 hours interval and proteinuria of 5 g in 24 hour urine specimen or having 3+ in two urine samples obtained randomly at not less than 4 hrs interval, oliguria of 500 ml in 24 hours (Schroeder, 2002). Preeclampsia is expected to affect 4.6 % of pregnant women worldwide (95% CI = 2.7% – 8.2%) (Abalos et al., 2013). PE is prevalent in underdeveloped nations at a rate of 2 to 17 % (Lakew et al., 2013), with African women accounting for 10% of the total (Nakimuli et al., 2014). Browne et al. (2015) showed that 1.7 % of the 789 women who finished the research in Accra, Ghana had PE, based on a cohort study enrolling 1010 women who were 17 weeks pregnant. Furthermore, in a prevalence research conducted at Komfo Anokye Teaching Hospital, Dassah and colleagues discovered a prevalence of 48.8% of University of Ghana http://ugspace.ug.edu.gh 12 pregnant women with PE (Dassah et al., 2019). PE was found to be 8.8% prevalent among Nigerian women according to Musa and colleagues (Musa et al., 2018). Preeclampsia was discovered to have a 2.23 % incidence rate in Ethiopia's Dilla University Referral Hospital (Vata et al., 2015). Additionally, Belay and Wudad (2019) discovered a prevalence of PE of 12.4 % in a prevalence investigation at the Mettu Karl referral hospital in Ethiopia. PE affects one in every 25 pregnancies in the United States (ACOG, 2013; S. Preventive Serivices Task Force, 2017). 2.1.3.1 Pathogenesis and Pathophysiology of Preeclampsia Preeclampsia has been dubbed the "disease of theories" due to the numerous theories that have been linked to it. Lack of balance in the formation of new vessels, inflammation, and oxidative stress take on the role of the "accelerator," while the "braking system" includes safeguarding the functional process of haem oxygenase 1 and cystathionine-lyase. Carbon (II) oxide (CO) as well as Hydrogen sulphide (H2S) is produced by the enzymes haem oxygenase 1 and cystathionine-lyase. PE is caused by the brake system's failure to function properly. Preeclampsia is a condition that causes the accelerator and brake systems to fail. CO and H2S are therefore important to the development of PE as a result of their unrivaled potential to lower anti- angiogenic factors sFlt-1 and solubilized type I membrane glycoprotein while simultaneously promoting PlGF and endothelial NOS activity (Ahmed and Ramma, 2015). The development of PE occurs in 2 phases; abnormal placentation in the first trimester and maternal disease manifestation in the mid and later stages of pregnancy (second and third trimesters), with antiangiogenic agents being used concurrently (Redman and Sargent, 2005; Romero and Chaiworapongsa, 2013). University of Ghana http://ugspace.ug.edu.gh 13 In a healthy pregnancy, cytotrophoblasts “migrate into the maternal uterine spiral arteries to establish vascular sinuses at the fetal-maternal interface to supply nutrition for the foetus”. This leads to a greater modification of the spiral arterioles into higher flow arteries (Brosens et al., 1967; Brosens et al., 2011). Preeclamptic cytotrophoblasts are unable to transition to invasive endothelial subtype from the proliferative epithelial state, resulting in inadequate spiral artery remodeling (Zhou et al., 1997). This inadequate remodeling cause narrow maternal artery, which are prone to atherosis and therefore placenta ischaemia (Brosens and Renaer, 1972). Anomalies in the trophoblasts can also cause shallow placentation and insufficient spiral artery transformation, resulting in placental ischemia and the maternal syndrome of preeclampsia (Zhou et al., 1997). This lack of blood flow in the placenta is linked to decidual vasculopathy and is linked to a poorer clinical outcome, higher diastolic blood pressure, kidney malfunction, and neonatal death (Stevens et al., 2013). Furthermore, during the early phases of placentation, trophoblast proliferation is aided by a hypoxic (low oxygen) environment. Before invasion, the blastocyst is supported by proliferating trophoblasts, which also fix the tips of the spiral arteries within the deciduas (Burton et al., 2001). These trophoblastic-spiral artery plugs break down over time, causing an intervillous gap to be formed. The newly developed sinuses allow maternal blood to enter, increasing oxygen tension and causing oxidative stress, as well as boosting trophoblast distinction to an invasive phenotype and modify the spiral arteries (Jauniaux et al., 2000). Hypoxia-inducible factors (HIF) 1 and -2, which are indicators of cellular oxygen improvement expressed at elevated amounts in proliferative trophoblasts and placenta in PE (Rajakumar et al., 2004). HIF-1 University of Ghana http://ugspace.ug.edu.gh 14 upregulation was also detected in pregnant mice which were linked to high blood pressure and proteinuria according to Tal and colleagues (Tal et al., 2010). Oxidative Stress Imbalance between antioxidant and free radicals in cells and tissues causes a disruption in redox signaling and regulation, as well as molecular damage (Ďuraková, 2010). Oxidative stress can occur due to irregular low amount of oxygen and re- oxygenation as a result of inadequate spiral artery invasion. Molecular analysis of preeclamptic placentas reveals an imbalance of free radicals. Furthermore, there was an increase in preeclamptic ex vivo preeclamptic trophoblast, ROS-producing enzymes and activity (Many et al., 2000) and impede the Wnt/-catenin signaling pathway, which promotes trophoblast invasion (Zhuang et al., 2015). According to Huang and colleagues, the imbalance of both antioxidant and free radicals may influence the expression of antiangiogenic factors (Huang et al., 2013). Women suffering from preeclampsia have reduced placental antioxidant systems, as demonstrated by decreased appearance of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) than that of non-preeclamptics (Vaughan and Walsh, 2002), although according to Poston et al. (2006) and Roberts et al. (2010) vitamin E and C supplementation had no influence on disease severity . In a study in Sokoto, Nigeria, preeclamptics had a higher mean value of oxidative stress indicators malondialdehyde (MDA) and GSH-Px peroxidase than non- preeclamptic women (3.44 ± 1.25 and 71.53 ± 26.02) (3.024 ± 1.08 and 62.58 ± 22.45) (p < 0.001) respectively with superoxide dismutase be lower in pregnant University of Ghana http://ugspace.ug.edu.gh 15 women with preeclampsia compare with the non preeclamptics (13.00 ± 15.27) versus (57.21 ± 38.08) p < 0.001 respectively (Shehu et al., 2020). In Clinical Center of Vojvodina in Novi Sad, Serbia study, preeclamptic pregnant women had higher values of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) than the non-preeclamptics 45.6 (13.6 – 77.5) vs 29.7 (9.0 -70.5) p < 0.0001 and 634.712 (35.0 – 995.3) vs 519.46 (253.6 – 827.1) p 0.0058 respectively however, mean total antioxidant status (TAS) was lower among the preeclamptics than with the non- preeclamptics 0.97 (0.2 – 5.3) vs. 1.9 (0.35 – 5.03) p 0.0075 respectively (Bogavac et al., 2017). Haem Oxygenase and Other Abnormalities Studies are continuously demonstrating that "haem oxygenase (HO), the haem degradation catalyst," plays a crucial role in the mother and fetus' vascular tasks, as well as placental growth and function (Cudmore et al., 2007; George et al., 2012; George and Granger, 2013).The haem oxyenase is of two forms; HO-2, which is involved in spiral artery invasion (McCaig and Lyall, 2009), and HO-1, which is significantly expressed in non-invasive trophoblastic phenotypes(Bilban et al., 2009). In an animal investigation, a rodent model with low uterine tissue perfusion pressure was given cobalt protoporphyrin (COPP), a HO-1 inducer, which reduced blood pressure and resulted in a pro-angiogenic change in the placenta's VEGF/sFLT1 ratio (George et al., 2011). Natural Killer Cells/Tissues and Abnormal Placentation The involvement of uterine Natural Killer (uNK) in the process that leads in considerable change of endometrial cells is well defined (Bulmer et al., 2010) and it University of Ghana http://ugspace.ug.edu.gh 16 may contribute to the poor placentation seen in preeclampsia. It is not cytotoxic (Koopman et al., 2003; Moffett and Colucci, 2014). The uNK cells determine the extent of placentation, spiral artery modification and trophoblastic invasion (Lash et al., 2006; Moffett-King, 2002). It expresses killer cell Ig-like receptors, (KIR) (Parham and Moffett, 2013) while fetal invasive extra villous trophoblasts express the main KIR ligand, polymorphic human leukocyte antigen-C (HLA-C) and self-major histocompatibility complexes (MHCs) (Apps et al., 2009). The individual separation of maternal KIR and HLA loci (Parham and Moffett, 2013) along with the extra villous trophoblast HLA-C from paternal side to pregnancy leads to a unique combination of KIR (maternal) and HLA-C (fetal) which may influence the success of placentation (Moffett and Colucci, 2014). . Maternal Syndrome Manifestation at the Later Part of Second and Third Trimesters with Associated Excessive Antiangiogenic Factors Imbalance in Circulating Angiogenic Factors Angiogenesis is the growth of more blood vessels from a vascular bed (Folkman and Shing, 1992) and is controlled by an equilibrium between the pro-angiogenesis and anti-genesis factors (Folkman, 1992; Folkman and Shing, 1992). According to Alon et al. (1995), VEGF, PlGF and transforming growth factor-β (TGF-β) make up the pro- angiogenic factors. Vascular endothelial growth factor is required for the proper endothelial cell function, particularly in pitted endothelial in primary organs affected by preeclampsia such as the brain, liver and kidneys (Esser et al., 1998) and is abundantly demonstrated by glomerular podocytes, whose receptors are found on glomerular endothelial cells (Maharaj et al., 2006). University of Ghana http://ugspace.ug.edu.gh 17 PlGF plays a critical role in angiogenesis and binds to VEGFR1/sFLT1 rather than VEGFR2 (De Falco, 2012). Antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFlt1) on the other hand, is made up of Flt1's extracellular ligand-binding domain but lacks the transmembrane and intracellular signaling domains. The solubilized fms-like tyrosine kinase-1 (sFlt1) is made available through the bloodstream, where it attaches to VEGF and PlGF and antagonizes them (Kendall and Thomas, 1993).There is a lot of evidence that sFlt-1 plays a major role in preeclampsia development; high amounts of sFlt-1 were observed in serum or plasma (Koga et al., 2003; Maynard et al., 2003) and preeclamptic placentas had high expression of SFlt-1 and mRNA (Tsatsaris et al., 2003), administration of exogenous sFLT1 delivery to rodents causes hypertension, proteinuria, glomerular endotheliosis, and other symptoms associated with PE (Maynard et al., 2003; Lu et al., 2007). Reduction in sFLT1 levels or antagonizing sFLT1 in preeclampsia animal models improves clinical symptoms (Li et al., 2007; Bergmann et al., 2010; Kumasawa et al., 2011). In preeclamptics, (Maynard et al., 2003; Levine et al., 2004) discovered an elevated circulating levels of sFLT1 with a decrease in free PlGF levels, indicating a protein imbalance between antiangiogenic and proangiogenic proteins. Preeclamptic women's serum and urinary PIGF levels were shown to be low at diagnosis and as the condition progressed, which could be due to both lower expression of PlGF and free PlGF as a result of its attachment to sFLT-1 and an increase in affected women (Levine et al., 2004). The concentration of serum Endoglin (sENG) was significantly higher among pregnant women who developed PE early in pregnancy than in those who developed PE later in pregnancy in an observational descriptive cross sectional study involving 13 early-onset preeclamptics, 13 late-onset preeclamptics and 13 normal pregnant University of Ghana http://ugspace.ug.edu.gh 18 women in the University Hospital and Surabaya hospitals in Indonesia (47.7 ± 40.2, 13.5 ± 9.5, 6.1 ± 1.5 ngmL-1; p = < 0.0001) (Akbar et al., 2017). There was a significant difference in serum VEGF and PlGF values among the preeclamptics and non-preeclamptics (p.05), with preeclamptics having lower serum VEGF and PlGF levels than non-preeclamptics (Nasrolahi et al., 2018). Cim et al. (2017) discovered that in a study involving 40 late-onset preeclamptics at 32 weeks and 40 non-preeclamptics, sENG and SFlt-1 were higher but not significantly higher among the preeclamptics; elevated levels of sENG were noticed in preeclamptics. Among 88 pregnant women who gave birth at Oslo University Hospital, Moe and colleagues discovered that free moving autoantibodies against VEGF and PlGF were significantly declined in preeclamptics in contrast with non-preeclamptics (p value 0.05); independently, only AA-VEGFA and AA-VEGFR-1 were found to be associated with PE and AA-VEGF was also found to be a significant predictor of PE, with an AUC of 0.735 (Moe et al., 2017). In a case-control research, Ding and colleagues discovered significantly elevated values of sFlt-1 and sFlt-1/PlGF, as well as low levels of PIGF (Ding et al., 2018). Adu-Bonsaffoh and colleagues discovered a significant decrease in serum levels of free VEGF among preeclamptics and non-preeclamptics, but not among non-pregnant women, 4.71 pg/ml (3.41, 7.93) and 84.06 pgml-1 (p value 0.001) respectively. Compared to late-onset preeclamptics, early-onset preeclamptics had a significantly reduced free VEGFof 3.89 (2.60, 5.67 pgml-1) with p value 0.001 (Adu-Bonsaffoh et al., 2017b). University of Ghana http://ugspace.ug.edu.gh 19 Inflammatory Cytokines and Immune Cell Alterations The cytokine interleukin -10 (IL-10) promotes T cells to develop into T helper type 2 cells (Th 2). It has been shown to be a significant mitigator of the maternal disease by counterbalancing pro-inflammatory cytokines, AT1-AA, placental reactive oxygen speciesand endothelin-1 (EDN1) (Harmon et al., 2015). According to Weel et al. (2016), several cell types of preeclamptics, including uterine and circulating NKs, are dysregulated in the equilibrium of IL-10 and proinflammatory cytokines. Normal pregnancy has interrelationship with a shift in T-cell phenotype from Th1 to Th2 (Saito and Sakai, 2003; Wegmann et al., 1993) and preeclampsia-related pregnancy has been linked to insufficient trophoblast invasion (Sowmya et al., 2014). Renin-Angiostensin Pathway Downward - Regulation During normal pregnancy, maternal blood volume increases and total resistance decreases, especially in the early stages, and to avoid a drop in blood pressure, the Renin-angiotensin-aldosterone system is turned on, causing sodium and water retention. Moreover, in preeclampsia, intravascular blood volume as well as cardiac output are lowered, and total peripheral aversion was elevated (Verdonk et al., 2014). Despite a decrease in circulating renin and angiotensin II, angiotensin II sensitivity increased during and before the diagnose of PE (Brown et al., 1997; Gant et al., 1973). Autoantibodies to angiotensin II type 1 have been found to recreate the bulk of the key symptoms of preeclampsia; vasoconstriction via endothelin-1163 (ET-1163) activation (LaMarca et al., 2009): endothelial cell mortification and death in the endothelial cells of the umbilical vein (Yang et al., 2014). In response to placental University of Ghana http://ugspace.ug.edu.gh 20 abnormality, there is activation of tissue factor release which contributes to clot formation (Dechend et al., 2000), decrease of trophoblast invasion in human cell culture models (Xia et al., 2003) and rise in the release of reactive oxygen species in culture models (Dechend et al., 2003). Anti-AT1-AA can cause the placenta to produce antiangiogenic factors like sFLT1 and sENG (Parrish et al., 2010). Its activity is stronger in preeclamptics sera, as are CD19+CD5+ cells (surface glycoproteins expressed by Tcells), showing that B lymphocytes contribute to the functioning of the immune system (Herse and LaMarca, 2013). Increased levels of an oxidized angiotensinogen, which is more easily cleaved by renin, have also been linked to the pathogenesis of preeclampsia (Zhou et al., 2010). Hydrogen Sulphide, Cystathionine β-synthase and Cystathionine γ-lyase Downward - Regulation Hydrogen sulphide (H2S) is a gas molecule that creates a signaling effect in the endothelial cells of humans and animals to bring about a vaso-relaxant effects and play a role in in uterine contractions (Papapetropoulos et al., 2009; You et al., 2011; Zhao et al., 2001). H2S generated by the body possesses angiogenic and non- inflammatory qualities effects at the endothelial-leukocyte interface (Papapetropoulos et al., 2009; Zanardo et al., 2006). The enzymes cystathionine-lyase (CSE) and cystathionine-synthase (CBS) are required for the generation of H2 S (Holwerda et al., 2012) and are found in foetal endothelial cells of the stem and chorionic villi with Hofbauer cells expressing CBS mRNA (Holwerda et al., 2012). Cystathionine-synthase mRNA, on the other hand, is down-regulated in early-onset PE (Holwerda et al., 2012). In comparison to healthy pregnancy, Wang and University of Ghana http://ugspace.ug.edu.gh 21 colleagues discovered a reduction in CSE mRNA expression in preeclamptic placental tissue and in women with small for gestational age newborns and this decrease was equivalent to a decrease in H2S levels in the maternal circulation (Wang et al., 2013). Furthermore, in pregnant mice, suppression of enzymes cystathionine-lyase by DL- propargylglycine (PAG) caused hypertension and an increase in circulating fms-like kinase-1, endoglobin, and placental anomalies, whereas administration of GYY4137, which suppresses PAG's action, decreasced circulating sFlt-1 and sENG levels and restored foetal growth (Wang et al., 2013). Deregulation of the enzymes cystathionine-lyase /hydrogen sulphide system also harmed spiral artery remodelling and placental development,according to data from an in vitro investigation. In addition, inhibiting enzymes cystathionine-lyase with PAG lowered Placental growth factor synthesis in placental explants from first-trimester pregnancies (Wang et al., 2013). 2.1.3.2 Risk Factors of Preeclampsia According to research, maternal gynecological history, estimated pre-pregnancy weight and BMI, high blood pressure at first booking, ethnicity/race, marital status/new paternity, maternal previous history of PE and other health conditions, family history of PE and chronic health conditions, seasonality/environmental conditions, lifestyle practices, and nutritional factors all play a role (Mayo Foundation for Medicaal Education and Research, 1998 – 2019). Their links to PE have been demonstrated here in a number of researches. University of Ghana http://ugspace.ug.edu.gh 22 Primiparous/Nulliparous Pregnancy According to findings from after a cross sectional scholarship encompassing 340 expectant mothers who gave birth at East Kalimantan hospital, Indonesia, there is a significant correlation linking primigravidae and the incidence of PE and eclampsia, with a p- value of 0.002 and a prevalence ratio of 1.998 (95% CI = 1.3 – 3.1) with a higher tendency of 1.9 times when compared to multigravid (Fatimah et al., 2017). Primiparity was found to be independently linked with PE OR = 4.51 (95% CI = 2.7652 – 7.3609) with a p value of 0.0001 in a study including 180 preeclamptics and 180 non-preeclamptics at Jaipur, India (Verma et al., 2017). Hercus and fellow researchers in a survey at McEwin Hospital, Australia, observed that mothers with increase birth coupled with longer birth intervals had a significantly higher tendency of developing PE in subsequent pregnancies, with OR = 1.39 (p 0.042) and OR = 2.05 (p = .002) at 3 and 4 years respectively (Hercus et al., 2020). Women with parity of one or more had a higher risk of getting PE in a case study involving 112 cases and 112 controls, with OR = 3.389 (95% CI = 1.936 – 5.934) (Rosmala et al., 2019). Primiparity was a risk factor for PE development (Ferreira et al., 2019). Primiparous women have a higher tendency of developing late-onset PE RRR 0.71 in a retrospective population-based study (You et al., 2018). In a comprehensive review and meta-analysis encompassing fifty-one papers, Meazaw et al. (2020) discovered that primiparous women have a higher tendency of getting PE OR = 2.52 (95% CI =1.19 – 3.86). Primiparous women were shown to be at a higher potential of acquiring PE than non-primaparous women in a hospital-based study in Nairobi County, Kenya University of Ghana http://ugspace.ug.edu.gh 23 AOR=2.1 (95% CI = 1.1–4.2) p 0.031 (Logan et al., 2020). Nulliparous women were found to be at a higher potential of risk developing PE in contrast to non-nulliparous women OR = 1.59 (95% CI = 1.11 – 2.29); AOR = 3.83 (95% CI = 0.72 – 20.40) in a nested case-control study in Hospital Universitario, Bogotá, Colombia (Ayala-Ramrez et al., 2020). Similarly, in a study at Paropakar Hospital in Kathmandu, Nepal, primiparous pregnant women had a higher risk of PE than non primiparous expectant mothers with an adjusted odds ratio of 2.12 and a 95% CI range of 1.25 – 3.60 (Das et al., 2019). To buttress this, a case control study conducted at the Police Hospital in Accra, Ghana, found out that having one child decreased ones tendency of developing PE with odds ratio of 0.5 (95% CI of 0.27 – 0.91) p 0.05 (Otu-Nyarko et al., 2015). Furthermore, another case-control study involving 69 non-preeclamptics and 65 preeclamptics undertaken at Korle Bu Teaching Hospital, found primigravidity to be associated with PE (AOR = 6.6, 95 % CI = 2.4–18.2) (Obiri et al., 2020). Multiple Pregnancies In a study in Norway (SSB), expectant mothers of twin pregnancies were 3 to 4 times higher at risk of having PE than their singleton counterparts OR = 3.78 (95% CI = 3.59 – 3.96). Twin pregnancy remained a risk factor for PE AOR = 4.07 (95% CI= 3.65 – 4.54) even after adjusting for other variables (Laine et al., 2019). Furthermore, Henry and colleagues discovered preterm severe PE was more common in twin pregnancies than in singleton pregnancies (2.4% vs 0.4%, P<0.001), RR = 5.70 (95% CI = 4.47 to 7.26) (Henry et al., 2013). This was also discovered in Endeshaw and colleagues study in Bahir Dar city, Ethiopia where women with multiple gestation University of Ghana http://ugspace.ug.edu.gh 24 have a higher tendency of developing PE than those with single gestation AOR = 4.05 (95% CI = 1.57 – 12.27) (Endeshaw et al., 2016). Furthermore multiple pregnancy was linked with a higher potential of having PE compare with singleton pregnancy Adjusted OR = 5.73 (95 % CI = 1.13 – 29.10) p value 0.04 (Pandey and Pandey, 2017). Das et al. (2019) in a study in Paropakar, Kathmandu, Nepal involving 4820 pregnant women, found pregnant women carrying multiple fetuses to be at a higher tendency for PE than those carrying single foetus AOR = 8.49 (95% CI = 2.92 – 24.72). Estimated Pre-Pregnancy Overweight/Obesity Obesity defined as a BMI of 30 or higher, has been shown to have negative consequences on pregnancy and its outcomes, including preeclampsia (Mayo Foundation, 1998 – 2019). Mohammadi et al. (2019) discovered that overweight and obese pregnant women had an increase chance of getting PE compared to those with normal BMI OR = 1.47 (95% CI = 1.06 – 2.02) and OR = 3.67 (95% CI = 2.57–5.24) respectively. In a case-control study involving 100 preeclamptics and 100 controls conducted in hospital at Dakshina Kannada district, Karnataka, South India, Kumar and colleagues discovered that pregnant women who were overweight had a significant likelihood of developing PE AOR = 7.56 (95% CI = 1.32 – 43.37) p value 0.02 (Kumar et al., 2010). Overweight/obesity were risk factors for preeclampsia OR = 1.81 (95% CI = 1.37 – 2.39) in a study by Yawen and colleagues on pre-pregnancy BMI as well as the likelihood of developing preeclampsia across a subgroup of expectant mothers in University of Ghana http://ugspace.ug.edu.gh 25 Landzhou, China (Yawen et al., 2017). Furthermore, a link was found between pre pregnancy overweight AOR = 1.4 (95% CI= 1.2 – 1.8),obesity AOR =1.8 (95% CI = 1.3 – 2.4) and the risk of preeclampsia (Mrema et al., 2018). Women who were obese class II and III were shown to have a 4 times higher risk of slight to reasonable preeclampsia AOR = 4.0 (95 % CI = 3.7– 4.4) in a population-based cohort research (Sohlberg et al., 2012). Another study in Budi Kemuliaan hospital in Jakarta, Indonesia, found that having a high BMI was linked to PE AOR = 1.09 (95% CI = 1.04 – 1.14) p <0.01 (Savitri et al., 2016). Cuifang et al. (2016) found pregnant women with low BMI to have 28% decreased risk of developing PE compare to normal BMI whilst pooled OR for overweight and obese women were at an increased risk of 1.64 (95% CI = 1.54 – 1.76) and 2.86 (95% CI = 2.56 – 3.19) respectively. Ayala-Ramírez et al. (2020) found pre-gestational underweight, overweight and obese expectant mothers to have a higher tendency for PE development than those with normal BMI AOR = 2.9 (95% CI = 0.2 – 28.36), AOR = 2.37 (95% CI = 0.79 – 7.10) and AOR = 21.0 (95% CI = 1.90 – 232.58) respectively. An open study in Jos , Nigeria; BMI at booking of ≥ 25 kg/m2 was found to be a risk factor for PE RR=3.9 (95% CI = 1.5 – 10.0) (Musa et al., 2018). In a study in Sokoto, Nigeria prevalence of PE was found to be 6% with obesity been a significant predictor (Singh et al., 2014). Verma and colleagues in a study in Jaipur, India found pre-obese and obese expectant mothers to have significantly higher likelihood for PE development than those with normal BMI OR = 3.23 (95% CI = 1.6626 – 6.2925) with p value of 0.0005 and OR = 8.28 (95% CI = 2.4889 – 27.5537) with a p value of 0.006 respectively (Verma et al., 2017). University of Ghana http://ugspace.ug.edu.gh 26 In a study in a municipality in the state of Piauí, Brazil; prevalence of obesity among those who developed PE was 8 (8.6%) (Ferreira et al., 2019). Meazaw and colleagues found high maternal body mass index to be linked with higher tendency of developing PE than those with normal body mass index OR = 1.69 (95% CI =1.17, 2.21) (Meazaw et al., 2020). In a case control study carried out in Bundelkhand Medical College Hospital Sagar Madhya Pradesh, maternal body mass index > 25 kg/m2 was found to be linked with an elevated tendency for PE development AOR = 7.65 (95% CI = 1.32 – 43.47) p 0.02 (Pandey and Pandey, 2017). Shao et al. (2017) in a birth cohort study in China, found overweight/obese pregnant women were at a higher tendency of developing PE (OR = 1.81; 95% CI = 1.37–2.39) compared with those with normal pre-pregnancy body mass index. In a meta-analysis to determine the link amongst overweight/obesity and PE, overweight was found to be associated with PE among 13 random-effect model studies OR = 1.71 (95% CI = 1.52 – 1.91) than with normal body mass index likewise obesity OR = 2.48 (95% CI = 2.05 – 2.90) (He et al., 2020). Canto-Cetina et al (2018) also found overweight or obese expectant mothers to be at a higher likelihood of developing PE compared with those with normal body mass index (Canto-Cetina et al., 2018). In a study in Goma, in the eastern Democratic Republic of Congo, pre-pregnancy overweight and obesity was linked with a higher potential of developing PE compared with those of normal body mass index OR = 2.82 (95% CI = 1.28 – 6.21) p = 0.010 (Richard et al., 2020). Poorolajal and Jenabi in a meta-analysis found pregnant women with excess weight to be at an elevated risk for PE development than those University of Ghana http://ugspace.ug.edu.gh 27 who had normal BMI OR = 1.73 (95% CI = 1.59 – 1.87; 21 studies; I2 = 62.3%) and OR = 3.15 (95% CI = 2.96 – 3.35; 22 studies; I2 = 36.0%) for overweight and obesity respectively (Poorolajal and Jenabi, 2016). In Ghana, a study found obese pregnant women to be at 7 times increase risk (95% CI = 1.9 – 27.7) of developing PE compared with those who had normal BMI (Owiredu et al., 2012). Excessive Gestational Weight Gain Shao and colleagues in a birth cohort study China, found women who gained excessive weight during pregnancy to be at a higher likelihood of developing PE OR = 2.28 (95% CI = 1.70 – 3.05) than those who gained healthy weight (Shao et al., 2017). In a prospective cohort study based on the obstetrical practices of Baystate Health, Massachusetts, USA, pregnant women who gained weight above the Institute of Medicine (IOM) guidelines had a higher tendency for PE development than those who gained within IOM guidelines AOR = 3.33 (95% CI = 1.15 – 9.65) p = 0.02 (Chasan-Taber et al., 2016). Short/Long Inter-Pregnancy Interval Findings from a systematic review and meta-analysis indicated that pregnant women with inter-pregnancy interval of more than 4 years have an increase tendency of developing PE again than those with inter- pregnancy interval of 2 – 4 years AOR = 1.10 [95 % CI = 1.02 – 1.19) I2 0 %] (Cormick et al., 2016). University of Ghana http://ugspace.ug.edu.gh 28 Extremes of Maternal Age Extremes of age is a predictor of PE; that is, ages less than 18 years and more than 35 years (Carson, 2018). In a registry constructed revision involving data in Finland, prevalence of PE was 9.4% among women in their advanced age (> 35years) and 6.4% among women less than 35 years (Lamminpää et al., 2012). A prospective study among 220 Indians in BGH, Jharkhand, Indian found prevalence of PE to be 56.1% among the under 20 years, 40.0% among the 20 – 30 years and a positive correlation for 30 years and above (Neha et al., 2016). In a study in Japan, women who were 45 years and above were at an elevated risk for PE development than those who were 30 – 34 years aRR = 1.86 (95% CI =1.43 – 2.42) and severe PE aRR = 2.03 (95% CI =1.31–3.13) (Ogawa et al., 2017). In a study conducted by Tessema and colleagues in Ethiopia, pregnant women age 35 years or more were found to be at an increased risk of developing PE compared with those who were younger AOR = 4.5 (95% CI = 1.56 – 12.8) (Tessema et al., 2015). In a study in Taiwan, older age was strongly associated with early- onset and vice versa PE RRR = 1.41 (95% CI = 1.29 – 1.54) (You et al., 2018). In Bahir Dar, Ethiopia, older maternal age was linked to a higher risk of developing PE than younger mothers AOR= 4.79 (95% CI = 1.031 – 22.18) (Endeshaw et al., 2016). Goyal et al. (2020) in a matched case control study conducted in associated group of hospitals, Rajasthan, India, found pregnant women age 30 years and above to be at a higher tendency for PE development than their younger counterparts OR = 1.667 (95% CI = 0.992 –2.799) but it was not significant. University of Ghana http://ugspace.ug.edu.gh 29 Furthermore, in a hospital-based unmatched case control study among pregnant women who delivered and were admitted in hospitals in Nairobi County, Kenya, advanced maternal age of 35 – 49 years was linked with an elevated risk of developing PE than those who are younger AOR= 5.9 (95% CI = 1.1 – 33.3) p value 0.042 (Logan et al., 2020). Ayala-Ramírez and colleagues in their study in Bogotá, Colombia, found maternal age of ≥ 35 years to be related with a higher tendency of developing PE than the younger pregnant women AOR = 4.57 (95% CI = 0.94 – 22.06) but it was not significant (Ayala-Ramírez et al., 2020). On the contrary, Das and colleagues in a study found pregnant women 35 years and older to have a higher chance of developing PE compared with those between the ages of 20 – 24 years AOR = 3.27 (95% CI = 1.42 –7.52) (Das et al., 2019) and it was significant. In Ghana, Otu-Nyarko and colleagues found maternal age of 25 years or more to be a predictor of PE OR = 2.42 (95% CI = 1.11 – 5.28) p <0.05 (Otu-Nyarko et al., 2015). Short Parental Height In a study involving 99968 pregnant women and their spouse, the tallest mothers (>172 cm) were at 30% decreased tendency of PE development risk than the shortest women; adjusted OR = 0.74 (CI = 0.66 – 0.82) whilst paternal height was not associated with PE. Findings from an analysis indicated the potential of paternal height to be protective against PE OR = 0.88 (CI = 0.80 – 0.96), but this protection was lost after adjustment for maternal height (Lee and Magnus, 2018). Furthermore, in a study based in Nordic countries, shortest women were at an elevated tendency of developing PE; odds ratio of 1.11 (95% CI1.06 – 1.15) (Sohlberg et al., 2012). University of Ghana http://ugspace.ug.edu.gh 30 Short Duration of Sperm Exposure/Short Cohabitation In an analytic case control study carried out at maternity Hospital in Kashan city, Iran involving primigravid women who delivered at the facility, many preeclamptics had short duration of sperm exposure than the controls (29.2 versus 14.2 for <3 months without barrier methods, AOR = 2.6 (95% CI =1.32 – 5.13) and (45 versus 29.2 for <6 months, AOR = 2.4 (95% CI=1.35 – 4.32) (Sadat et al., 2012). Similarly, Mekie and colleagues in a matched case control involving nulliparous women who delivered in three hospitals of West Amhara Zones, Ethiopia, short duration of cohabitation was identified to be linked with expanded risk for developing PE compared with longer duration of cohabitation PE AOR = 2.13 (95% CI = 1.10 – 4.1) (Mekie et al., 2020). High Maternal Blood Pressure at First Antenatal Clinic Booking Maternal SBP of ≥130 mmHg and DBP of ≥90 mmHg at first time booking at the antenatal clinic significantly increased the chance of getting PE; odds ratio 6.38 (95% CI of 3.03 – 13.33), p value < 0.0001 and odds ratio 3.31 (95% CI of 1.83 – 5.97), p value < 0.0001 respectively (Otu-Nyarko et al., 2015). Non – White Races In a study of 271,569 inpatient delivery hospitalizations in Hawaii, PE rates for non- white race recorded between 2.0 % for Chinese to 4.6 % for Filipinos; native Hawaiians age <35 years and non-obese OR = 1.54 (95 % CI = 1.43 – 1.66), age ≥35 years and non-obese OR = 2.31 (95 % CI = 2.00 – 2.68), other Pacific Islanders age <35 years and non-obese OR = 1.40 (95 % CI = 1.27 – 1.54), age ≥35 years and non- obese OR = 2.18 (95 % 1.79- 2.64), Filipinos age < 35 years and non-obese OR = 1.55 (95 % CI = 1.43 – 1.67), age ≥ 35 years and non-obese OR = 2.26 (95 % 1.67 – University of Ghana http://ugspace.ug.edu.gh 31 2.60) (Nakagawa et al., 2016). Between 2002 and 2008, the Consortium on Safe Labor conducted a study found that non-Hispanic black women had a higher risk of developing mild PE AOR=1.26. Hispanic women and Asian/Pacific Islanders, respectively, had increased odds of remaining normotensive (AOR=1.22 (95 % CI = 1.12 – 1.33) and AOR=1.55 (95 % CI = 1.31–1.84) (Ghosh et al., 2014). Anderson and colleagues found the odds of developing PE to be different among women from different countries; AOR = 1.25 (95 % CI = 0.99–1.27), adjusted odds ratio of 0.56 (95% CI of 0.41–0.76), adjusted odds ratio of 1.51 (CI = 1.16–1.96), and AOR = 1.20 (CI = 0.92–1.56) among Chinese, Mori, Pacific and Indian women respectively in City Hospital, Auckland, New Zealand (Anderson et al., 2012). Breathett and colleagues confirmed this in a study in which PE occurred much more among African Americans than the Caucasians in the National Hospital Discharge Survey (1979–2006) involving 4,644 African Americans and 12,131 Caucasians who had PE and delivered, from a POR of 0.98 (95 % CI = 0.96, 1.0) to a POR of 1.75 (95 % CI = 1.73, 1.78) (Breathett et al., 2014). Furthermore, expectant mothers of the black race had an increased chance of developing PE than expectant mothers of the white race in a study involving expectant mothers of both black and white race based in California (Ross et al., 2019). Low Socioeconomic Status Analysis on data gathered on pregnant women from lower socioeconomic status household indicated a higher tendency of developing PE (odds ratio = 1.26 and 95% CI = 1.01 – 1.57) compared with those from higher socioeconomic households (Choe et al., 2016). University of Ghana http://ugspace.ug.edu.gh 32 Unmarried Women/New Partner In a hospital-based cross-sectional study conducted by Tessema et al. (2015) at Dessie referral hospital in Ethiopia, unmarried women had a higher tendency of developing PE than the married ones. Hercus and colleagues in south Australia observed that women with history of healthy pregnancy had a significantly elevated tendency of developing PE in future pregnancy with new paternity OR = 2.27 p  .015 (Hercus et al., 2020). In a nested case- control study in Bogotá, Colombia, unmarried women had a higher chance of developing PE than the married ones OR = 1.06 (95% CI = 0.65 – 1.73) (Ayala-Ramírez et al., 2020). History of PE and Other Maternal Health Conditions Musa and colleagues found in prospective open-cohort study in the antenatal clinic Jos, Nigeria, that previous history of preeclampsia is a predictor of PE RR=5.1 (95% CI = 2.2 – 12.1) (Musa et al., 2018). Tessema and colleagues found in a study conducted in Ethiopia that women with known high blood pressure have a higher tendency of developing PE than the non-hypertensive AOR = 4.3 (95% CI = 1.33 – 13.9) (Tessema et al., 2015). Kumar et al. (2010) in a study in South India found maternal history of chronic hypertension and diabetes to be significantly linked with PE AOR = 6.69 (95% CI = 1.37 – 32.75) p value 0.02 and PE AOR = 8.66 (95% CI = 1.01 – 76.26) p value 0.05 respectively. Ahmed and colleagues in a study found history of diabetes and hypertension to be significantly associated with PE OR = 5.923 (95% CI = 1.519 – 23.091) p value 0.010 and OR = 7.838 (95% CI = 1.048 – 58.628) p value 0.045 respectively (Ahmed et al., 2018). In a retrospective study involving 42,500 known chronic hypertension patients University of Ghana http://ugspace.ug.edu.gh 33 who had singleton deliveries at two centers in Melbourne, Australia; previous preeclampsia and hypertension duration were most strongly associated with any severity of preeclampsia OR = 5.45(95% CI = 1.89 – 12.71) and OR = 2.4 (95% CI = 1.76 – 4.92) respectively (Brumby et al., 2018). In an age-matched case control study involving 112 cases and 112 controls, participants with known hypertension have a greater tendency of developing PE OR = 5.071 (95% CI = 2.819 – 9.120) (Rosmala et al., 2019). In addition, a retrospective study in Piauí, Brazil, prevalence of chronic hypertension and diabetes mellitus among the preeclamptics were 4 (4.3%) and 8 (8.6%) respectively (Ferreira et al., 2019). Tangren et al. (2018) also in a study at Massachusetts General Hospital, USA, women with recovered acute kidney injury (r-AKI) had a higher rate of PE than those without previous r-AKI (22% versus 9%; P<0.001). As the severity of r-AKI increases the risk of preeclampsia for stages 2 and 3 AKI also increases AOR = 3.5 (95% CI = 2.1 – 5.7) and AOR = 6.5 (95% CI = 3.5 – 12.0) respectively, but not for stage 1 AOR = 1.7 (95% CI = 0.9 – 3.2). Ndoni and colleagues in a retrospective cross sectional study involving data collected from medical records of pregnant women at Tirana, Albania found pre-existing hypertension, renal disease and diabetes mellitus to be 7.8% vs. 2.3% (p = 0.02), 1.9% vs. 1.1% and 5.8% vs. 4.6% respectively (Ndoni et al., 2016). In study in Taiwan, chronic hypertension was strongly associated with early-onset PE RRR 1.71 (95% CI = 1.55 – 1.88) ( You et al., 2018). In a retrospective analysis of countywide records on 271,569 admitted patients who delivered in hospitals in Hawaii, Nakagawa and his colleagues discovered that pre-gestational diabetes and chronic hypertension University of Ghana http://ugspace.ug.edu.gh 34 were independently associated with PE OR = 3.41 (95% CI = 3.02 – 3.85) and OR = 5.98 ( 95% CI = 4.98 – 7.18) respectively (Nakagawa et al., 2016). In a study in UK, chronic hypertension was found to be linked with a higher tendency of developing PE OR = 5.76 (95% CI = 4.93 – 6.73) (Panaitescu et al., 2017). In a multicenter trial, 216 women (28%) out of 774 with chronic hypertension developed superimposed PE; 87 (11%) had superimposed PE with severe features and 129 (17%) had superimposed PE without severe features (Moussa et al., 2017). Findings from systematic review and meta-analysis involving 795221 from 55 countries indicated that chronic hypertension was associated with incidence of 26% for superimposed PE (Bramham et al., 2014). A study in Dr. Soetomo, East Java hospital, Indonesia found stage 2 of chronic hypertension to be associated with urinary protein of +3 (67% vs 21.5%, p = 0.001) and +4 (12.3% vs 0.4%, p = 0.001) (Akhar et al., 2019). Vestgaard and colleagues in a systematic review, found PE to be 17% among diabetes type 1 patients 5 times more than the background population with associated clinical predictors such as diabetic nephropathy (OR = 3.7 – 23.5), microalbuminuria (OR = 3.8 –11.7), diabetic retinopathy (OR 1.9 – 2.9) and pre-existing hypertension (OR = 3.8 –17.1) (Vestgaard et al., 2018). In a study in Bahir Dar city, Ethiopia consisting of 453 expectant mothers family history of preexisting hypertension and diabetes mellitus were linked with increased risk of developing PE AOR=11.16 (95% CI = 5.41 – 41.43) and AOR = 6.17 (95% CI = 2.11 – 20.33) respectively (Endeshaw et al., 2016). University of Ghana http://ugspace.ug.edu.gh 35 Meazaw and colleagues found history of maternal PE/eclampsia was linked with increased danger of developing PE (odds ratio = 5.6 and 95% CI range = 1.82 – 9.28) compared with those who have never developed PE/Eclampsia (Meazaw et al., 2020). In a study in Nairobi County, Kenya, history of hypertension was linked with a higher risk of developing PE AOR = 7.1 (95% CI = 2.6 – 19.3), p = 0.001 (Logan et al., 2020). Gutaj et al. (2017) in Poznan, Poland found prevalence of PE to be 9.7% with duration of disease related with a higher chance of developing PE OR = 1.11(95% CI = 1.03 – 1.12) p 0.009. In Bogotá, Colombia, age of menarche of 12 years or more was found to be linked with a higher risk of developing PE = OR 1.7 (95% CI = 1.18 – 2.46) ; AOR = 1.13 ( 95% CI = 0.44 – 3.90), migraine was found to be related with the elevated risk of developing PE = OR 1.33 (95% CI = 0.65 – 2.71), polycystic ovary was also found to be linked to expanded risk in developing PE OR = 2.07 (95% CI = 0.49 – 8.80), history of PE and intra uterine growth restriction were also related with a higher tendency of of developing PE OR = 6.58 (95% CI = 2.89 – 14.97); AOR = 30.78 (95% CI = 2.65 – 356.73) and OR = 4.54 (95% CI = 1.85 – 11.13); AOR = 11.10 (95% CI = 1.60 – 76.76) respectively (Ayala-Ramírez et al., 2020). In a case control study in Madhya Pradesh, India, chronic hypertension, diabetes and renal disease were found to be connected with a higher risk of developing PE AOR 6.69 (95% CI 1.37 – 32.75) p 0.02, AOR = 8.66 (95% CI = 1.01 – 76.26) p 0.05 and AOR = 5.60 (95% CI = 1.12- 28.04) p 0.04 respectively (Pandey and Pandey, 2017). Das et al. (2019) in a study in Kathmandu, Nepal involving 4820 pregnant women, found pregnant women who were hypertensive and/or gestational diabetics to have a University of Ghana http://ugspace.ug.edu.gh 36 higher tendency of developing PE than non-hypertensive or diabetics AOR = 13.64 (95% CI = 4.45 – 41.81) and AOR = 11.79 (95% CI = 3.20 – 43.41) respectively. In a case control study carried out by Pan and colleagues, matured ovarian teratoma, uterine fibroids and pre-gestational hypothyroidism were establish to be related with high risk for PE with adjusted odds ratios of 7.69 (95% CI = 1.58 – 37.53), 2.24 (95% CI = 1.28 – 3.92) and 5.17 (95% CI = 2.43 –11.00) respectively (Pan et al., 2019). Bernardes and colleagues investigated to determine the risk of recurrence of PE and how the maximum diastolic blood pressure of the previous pregnancies can lead to the development of PE, previous early PE was associated with a risk proportional to that of the maximum diastolic blood pressure recorded in that pregnancy; the recurrence risk for 90 and 100 mmHg and above 110 mmHg were 15% (95% CI = 11.1 – 20.6%) and 26.6% (95% CI = 21.6 – 32.3%) respectively whilst pregnant women who recorded high diastolic blood pressure but no PE in their initial pregnancy were at an expanded risk of 2.2% (95% CI = 2.0 – 2.4%) and 6.3% (95% CI = 5.3 –7.5%) for DBP within the range of 90 to 100 mmHg and above 110 mmHg respectively (Bernardes et al., 2016). In Goma, in the eastern Democratic Republic of Congo, history of maternal PE was connected with an increased tendency of developing PE OR = 12.30 (95% CI = 1.92 – 18.98) p = 0.008 (Richard et al., 2020). Anaemia In Bahir Dar City, Ethiopia, anaemia in the first trimester is a predictor of PE AOR 2.80 ( 95% CI = 1.09 – 7.21) (Endeshaw et al., 2014). Meazaw and colleagues found in fifty- one studies that anaemia during pregnancy was linked with a higher tendency for developing PE with OR = 3.22 (95 % Confidence Interval = 2.70, 3.75) University of Ghana http://ugspace.ug.edu.gh 37 (Meazaw et al., 2020). In Bogotá, Colombia, anaemia was observed to be linked with higher chance for PE OR = 5.00 (95% CI = 0.55 – 45.11) (Ayala-Ramírez et al., 2020). The outcome of a survey by the World Health Organization Global indicated that nulliparous and multiparous pregnant women with severe anemia had a high tendency of becoming preeclamptic AOR = 3.74 (95% CI = 2.90 – 4.81) and AOR = 3.45 (95% CI = 2.79 – 4.25) respectively (Chen et al., 2018). In Ghana, an age-matched case control carried out at Obstetrics and Gynaecology Departments Komfo Anokye Teaching hospital and Ridge Regional hospital (Greater Accra Regional hospital), preeclamptics, mean hemoglobin (Hb) was significantly lower among the preeclamptics (10.01 ± 0.73) than the non preeclamptics (13.76 ± 0.80) (p < 0.001) (Yeboah et al., 2017). Family History of PE and Chronic Disease Conditions Tessema and colleagues in a study in Ethiopia found women having genetically related hypertension and diabetes mellitus to be at an increased risk of developing PE AOR =  7.19 (95% CI = 3.24 – 15.2) and AOR =  2.4 (95% CI = 1.09–5.6) respectively (Tessema et al., 2015). In Jaipur, India, family history of hypertension denoted a significant linked with preeclampsia; AOR = 2.28 (95% CI of 1.27 – 4.09) and p value of 0.007 (Verma et al., 2017). Also Kumar and colleagues found a link between genetically related hypertension and PE in Karnataka, India AOR = 5.48 (95% CI = 1.09 – 27.55) with p value of 0.04 (Kumar et al., 2010). University of Ghana http://ugspace.ug.edu.gh 38 Inheritable PE/eclampsia was found to be linked with a high tendency of developing PE OR =1.68 (95% CI = 1.26, 2.11) in a systematic and meta-analysis carried out by Meazaw et al. (2020). In Bogotá, Colombia, genetically related PE was found to be connected with a higher risk of developing PE = OR 1.51 (95% CI = 0.97 – 2.37) but was linked with a reduced chance of development of preeclampsia when other factors were included in the model; AOR = 0.91 (95% confidence Interval = 0.20 – 4.12), family history of intrauterine growth restriction was a predictor of PE OR = 1.09 (95% CI = 0.53 – 2.24), family history of cardiovascular disease was found to be related with the elevated risk of developing PE OR = 1.20 (95% CI = 0.74 – 1.96), family history of abortions was linked with a higher tendency of PE development risk PE OR =1.98 (95% CI = 1.09 – 3.60) but upon modification, the association was lost adjusted OR = 0.96 (95% CI = 0.17 – 5.15), family history of stillbirth was linked with a higher tendency of developing PE OR = 1.48 (95% CI = 0.65 – 3.38), family history of preterm was connected with a higher risk of developing PE OR = 1.27 (95% CI = 0.76 – 2.12), family history of diabetes was linked with a stronger tendency of developing PE OR = 1.68 (95% CI = 1.12 – 2.52); AOR= 3.41 (95% CI = 1.09 – 10.67) and history of cancer was linked with a decreased chance of developing PE OR = 0.75 (95% CI = 0.47 – 1.20) (Ayala-Ramírez et al., 2020). In a history of genetically-related high blood pressure was found to be linked with a higher potential of developing PE AOR = 5.84 (95% CI = 1.09 – 27.55) p 0.04 (Pandey & Pandey, 2017). Low Levels of Vitamins and Minerals As indicated by discoveries from an EVITA study including 2327 hopeful moms in Pittsburgh, the tendency of developing toxemia diminishes as the Vitamin D fixation University of Ghana http://ugspace.ug.edu.gh 39 builds (50 nmol per L) and afterward levels at values lower than p = 0.05 while those with groupings of <25 nmol/L, 25 -49.9 nmol/L, and 50 - 74.9 nmol/L had an adjusted danger of toxemia of 2.4 (95% CI = 1.2–4.8), 1.1 (95% CI = 0.69–1.7), and 1.3 (95% CI = 0.89–1.8), individually, when contrasted with those with 75 nmol/L (Baca et al., 2016). Among Canadian cohorts, a fundamentally lower 25 hydroxyvitamin D fixation at a mean gestational age of 14 weeks contrasted non-preeclamptics; mean ± SD 25 hydroxyvitamin D 47.2 ± 17.7 versus 52.3 ± 17.2 nmol/L, P < .0001. Pregnant women with 25 hydroxyvitamin D <30 nmol/L contrasted with those with no less than 50 nmol/L had a more serious danger of developing PE AOR = 2.23 (95% CI = 1.29– 3.83) (Achkar et al., 2015). An associate report completed by Zhao and partners discovered that the expectant mothers who became preeclamptic had impressively less 25 hydroxyvitamin D in blood serum contrasted the individuals who didn't. Once more, pregnant women with serum 25 hydroxyvitamin D inadequacy at 23–28 weeks of growth were strongly connected with expanded chances for extreme PE in the wake of adapting to significant confounders AOR = 3.16 (95% CI = 1.77–5.65) (Zhao et al., 2017). Serum 25 hydroxyvitamin D concentrations in early pregnancy were 56% significantly less among the preeclamptics than the controls; mean of 9.79 ± 4.09 ngml-1 (95% CI = 8.71–10.88 ngml-1) vs 22.26 ± 15.28 ngml-1 (95% CI = 20.0 – 24.52 ng/ml) p <0.001. Vitamin D deficient mothers were at 17 times higher risk of developing PE than their counterparts at early pregnancy and at term (p < 0.001; RR = 17.93). Serum 25 hydroxyvitamin D deficiency was seen as an independent risk factor for PE (Jain et al., 2015). University of Ghana http://ugspace.ug.edu.gh 40 Wei and colleagues in a prospective cohort study carried in seventeen urban obstetric hospitals, Canada among pregnant women who were participants in a trial of vitamin C and E supplementation for the prevention of PE; a strong positive correlation was seen in maternal 25(OH)D concentrations between the two gestational age windows (r = 0.69, p < 0.0001), mean maternal 25 hydroxyvitamin D concentrations at 24-26 weeks of gestation were significantly lower in women who subsequently developed PE compared with those who did not (mean ± SD: 48.9 ± 16.8 versus 57.0 ± 19.1 nmol/L, p = 0.03), women with 25 hydroxyvitaminD < 50 nmol/L at 24 – 26 weeks gestation experienced an increased risk of PE AOR = 3.24 (95% CI = 1.37 – 7.69), whereas the association was not statistically significant for maternal 25(OH)D level at 12 – 18 weeks of gestation (Wei et al., 2012). In study in America, the risk of developing PE increased by approximately 3 fold (95% CI = 1.28 – 6.41) for women with vitamin D concentration of < 20 ng per ml (Scholl et al., 2013). Prevalence of low calcium among preeclamptics was 66 (60%) (Saeed et al., 2017). Bodnar et al. (2014) in a case cohort study among women enrolled at 12 U.S. sites in the Collaborative Perinatal Project, found Maternal 25(OH)D 50 – <75 nmolL-1 to be linked with a decrease in the absolute and relative risk of PE and mild PE than 25 hydroxyvitamin D <30 nmolL-1, but the effects were no longer present after adjustment for confounders. For severe PE, 25 hydroxyvitamin D ≥50 nmolL-1 was linked with a decrease of 3 cases per 1,000 pregnancies adjusted RD = −0.003 (95% CI = −0.005 – 0.0002) and a 40% reduction in risk aRR = 0.65 (95% CI = 0.43 – 0.98) than 25hydroxyvitamin D <50 nmol/L. University of Ghana http://ugspace.ug.edu.gh 41 In a study in Qazvin, Iran, mean serum vitamin D level was 27.7 ± 15.3, 22.9 ± 15.9, and 27.6 ± 16.6 for normal, mild PE and severe PE groups respectively (P > 0.05), also vitamin D deficiency was not different between the groups. Calcium deficiency was more frequent among severe preeclamptic group than their counterparts (25.9% vs. 6.6%, p 0.017) and was linked with severe PE OR = 6.7 (95% CI = 1.45 – 30.79) p 0.015 (Hashemipour et al., 2017). In a study by Benachi and colleagues comprising of 83 preeclampsia cases and 319 non preeclamptics, the mean 25 hydroxyviamin D values recorded in the first trimester were 20.1 ± 9.3 ngmL-1 in PE cases and 22.3 ± 11.1 ngmL-1 in non preeclamptic (p = 0.09). The chance for PE with 25 hydroxyvitamin D level ≥30 ngmL-1 in the first trimester was low and insignificant OR = 0.57 (95% CI = 0.30 –1.01) p = 0.09. High levels of 25 hydroxyvitamin D however during the 3rd trimester was linked with a sufficiently low chance of PE OR 0.43 (95% CI = 0.23 –0.80) p = 0.008. For women with 25 hydroxyvitamin D levels <30 ng/mL both in the first and 3rd trimesters (“low-low”) as references, the odds ratio for PE was 0.59 (95% CI = 0.31–1.14) p = 0.12 for “low-high” or “high-low” women and 0.34 (95% CI = 0.13 – 0.86) p = 0.02 for “high-high” women (Benachi et al., 2020). PE was significantly increase in the folic acid group than the control group in crude analyses 17.2% versus 9.9%, relative risk of 1.75 (95 % CI = 1.06 –2.88), p value  0.029. Multivariable analyses nullified this effect, rendering it not statistically remarkable RR = 1.58, p value  0.079 (Corsi et al., 2020). In a nested case - control and meta-analysis, 25 hydroxyvitamin D concentrations were significantly lower in preeclamptics than controls; median (IQR), preeclamptics versus controls: 43.3 (35.5, 55.2) versus 47.5 (37.6, 60.4) nmol/L, p = .014. For women with 25 hydroxyvitamin University of Ghana http://ugspace.ug.edu.gh 42 D <50.0 nmol/L, had a 65% increase in preeclampsia risk (95% CI = 1.02 – 2.69) as compared with women with 25 hydroxyvitamin D concentrations from 50.0 to 74.9 nmol/L. The meta-analysis showed that low 25 hydroxyvitamin D were linked with a significantly increased risk of developing PE by 62% pooled OR = 1.62 (95% CI = 1.36 –1.94) and the risk effect of low 25 hydroxyvitamin D existed in most subgroups (Yuan et al., 2019). In a study in Osun State, Nigeria, mean serum concentrations of zinc, copper, selenium, manganese and magnesium were significantly lower p < 0.05 among preeclamptics than the control group (Akinloye et al., 2010). In addition, Okoror and colleagues in a study found levels of serum Ca2+ to be 7.73 + 1.24 verses 9.17 + 0.77; p <0.001, Ca2+ - Mg2+ ratio 3.36 + 0.60 verses 3.83 + 0.41; p = 0.001 and Mg2+ 2.35 + 0.35 verses 2.41 + 0.16; P=0.469 to be lower among cases. A negative correlation was established between the Serum Ca2+ level and SBP (r = -0.45, p 0.05) and DBP (r =0.50, p 0.010). Hypocalcemia was a risk factor for PE AOR = 7.63 (95% CI = 1.64 – 35.37) (Okoror et al., 2020). Darkwa et al. (2017a) in a study in Accra, Ghana found mean serum magnesium and total calcium levels in preeclamptics to be 0.70 ± 0.15 and 2.13±0.30 mmol/L and mean serum magnesium and total calcium levels among controls to be 0.76 ± 0.14 and 2.13 ± 0.35 mmol/L with significant difference. Furthermore, Darkwa and colleagues also found a significantly decreased p < 0.001 serum sodium levels in preeclamptics mean = 136.13; SD = 4.17 mmol/L compared to normotensive pregnant women (mean = 142.17; SD = 5.66 mmol/L). There was a significantly decreased (p < 0.001) serum potassium levels in preeclamptics (mean = 3.45; SD = 0.54 mmolL-1) than University of Ghana http://ugspace.ug.edu.gh 43 normotensive pregnant women (mean = 3.98; SD = 0.36 mmolL-1) (Darkwa et al., 2017a). A meta-analysis carried out by Fu et al. (2018) results showed that vitamins supplementation could decrease the risk of PE (RR = 0.74, 95%CI = 0.64–0.86), findings of analysis of non-randomized controlled trial (RCT) indicated a significant link between vitamins supplementation with risk of developing PE (RR = 0.60, 95% CI = 0.42 – 0.85) and a vice versa was found for the randomized controlled trial studies. Furthermore, subgroup analysis by vitamin type among RCT studies indicated that vitamin D and multivitamin supplementation could significantly decrease the risk of PE (RR = 0.41, 95% CI = 0.22 – 0.78) and (RR = 0.69, 95% CI = 0.51– 0.93) respectively. Hovedenak and Haram in their literature review on the effect of vitamin and mineral supplementation on pregnancy outcome indicated that calcium, vitamin D and vitamin B6 deficiency as well as low selenium and vitamin C is associated with PE and supplementation of these minerals and vitamins may be beneficial with exception of vitamin E supplementation which findings claim may have harmful effect on pregnancy outcome (Hovdenak and Haram, 2012). From a Cochrane Database Systematic review, calcium supplementation caused a decrease in the average risk of hypertension and the average risk for PE RR0.65, 95% CI = 0.53 to 0.81) and (13 trials, 15,730 women: RR 0.45, 95% CI 0.31 to 0.65) respectively with the impact been strongest among women who are at a potentially high risk ( RR 0.22, 95% CI 0.12 – 0.42), and those with low baseline calcium intake (RR 0.36, 95% CI 0.20 – 0.65) (Hofmeyr et al., 2014). In a clinical preliminary which expected to decide the impact of nutrient Vitamin D enhancement on lessening the University of Ghana http://ugspace.ug.edu.gh https://www.sciencedirect.com/topics/medicine-and-dentistry/vitamin-d 44 likelihood of intermittent toxemia, 72 patients were set in the benchmark group (2.8% had twin pregnancies) while 70 patients were randomized to the intercession bunch (all had singleton pregnancies). The intercession bunch got a 50000 IU pearl nutrient Vitamin D3 once every two weeks while the benchmark group was managed with control treatment until the 36th seven day stretch of pregnancy. The patients in intercession bunch had altogether decrease (p 0.036) likelihood of creating toxemia than patients in the benchmark group. The danger of toxemia for the benchmark group was 1.94 times elevated compared to that for the intercession bunch (95% CI = 1.02 – 3.71) (Sasan et al., 2017). The results of a systematic review and meta-analysis involving twenty-seven RCTs with 28,000 women by Khaing et al. (2017) indicated that calcium, vitamin D and calcium plus vitamin D have the tendency to reduce PE development. In the mean serum level of 25 hydroxyvitamin D in PE group was significantly lower than that in the healthy group (15.27 ± 3.52 vs. 23.84 ± 6.93, p < 0.001) and women deficient in 25 hydroxyvitamin D had an increased tendency of developing PE (odds ratio  = 4.79 and 95% CI  = 1.45 – 9.87) at P = 0.01 (Pashapour et al., 2019). Mardali and colleagues found serum vitamin B12 level lower among preeclamptic women compare with non-preeclamptic (mean, −15.24 pgmL-1 p < 0.015) (Mardali et al., 2020). In a study conducted in Sokoto, Northwestern Nigeria, a significant reduction levels of vitamins A and C were found among the women with PE (1.52 ± 1.68 and 0.14 ± 1.33) p < 0.0001 (Shehu et al., 2020). In a study at Bydgoszcz, Poland, preeclamptics had a lower level of serum 25 hydroxyvitamin D compared with the controls (14.75 vs. 22.10 ng/mL, p 0.0021) and low level of serum hydroxyvitamin D was also found University of Ghana http://ugspace.ug.edu.gh 45 to be a significant predictor on the receiver operating characteristics analysis (AUC = 0.70, p < 0.01) (Domaracki et al., 2016). In a randomized controlled study, mean maternal 25[OH]D level increased significantly among the pregnant women in the group who received 4000IU compared with those in the group 1 who received 400IU (group 2 from 16.3 ± 5 nmol/mL to 72.3 ± 30.9 nmol/mL and group 1 from 17.5 ± 6.7 nmolMl-1 to 35.3 ± 20.7 nmolmL-1) p > 0.0001.The relative risk reduction for attaining ≥75 nmolL-1 before delivery was significantly higher RRR 93