Association of serum uric acid levels on birth weight, in women with hypertension in pregnancy: A retrospective cohort study

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THE ASSOCIATION OF SERUM URIC ACID LEVELS ON BIRTH WEIGHT, IN WOMEN WITH

HYPERTENSION IN PREGNANCY- A RETROSPECTIVE COHORT STUDY

A DISSERTATION SUBMITTED IN PARTIAL FULFILMENT OF THE M.S. BRANCH II (OBSTETRICS AND GYNAECOLOGY

EXAMINATION) DEGREE EXAMINATION OF THE

TAMIL NADU DR. M.G.R.MEDICAL UNIVERSITY, CHENNAI TO BE HELD

IN MAY 2018

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DECLARATION CERTIFICATE

I hereby declare that this dissertation titled ―THE ASSOCIATION OF SERUM URIC ACID LEVELS ON BIRTH WEIGHT, IN WOMEN WITH HYPERTENSION IN

PREGNANCY-A RETROSPECTIVE COHORT STUDY‖ is carried out by me under the guidance and supervision of Dr Jiji Elizabeth Mathew, Prof and Head of Unit V,

Christian Medical College, Vellore.

This dissertation is submitted in partial fulfilment of the requirements of the Tamil Nadu Dr. M.G.R Medical University for the degree of the M.S. Obstetrics and Gynaecology examination to be held in May 2018

Dr Richa Sasmita Tirkey Post Graduate Registrar MS OBG

Department of Obstetrics and gynecology

Christian Medical College, Vellore

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CERTIFICATE

This is to certify that the dissertation titled ―THE ASSOCIATION OF SERUM URIC ACID LEVELS ON BIRTH WEIGHT, IN WOMEN WITH HYPERTENSION IN PREGNANCY-A RETROSPECTIVE COHORT STUDY‖ is the original research work done by Dr Richa Sasmita Tirkey and was carried out by me under co- guidance and supervision towards the partial fulfilment of the requirements of the Tamil Nadu Dr.

M.G.R. Medical University, for the degree of the M.S. Obstetrics and Gynaecology examination to be held in May 2018

Dr Jiji Elizabeth Mathews

Guide Co- guides

Professor and Head of Unit V Dr.Santosh J. Benjamin

Department of Obstetrics and gynecology Dr. Swati Rathore

Christian Medical College, Vellore Dr. B. Antonysami

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CERTIFICATE

This is to certify that the dissertation titled ―THE ASSOCIATION OF SERUM URIC ACID LEVELS ON BIRTH WEIGHT, IN WOMEN WITH HYPERTENSION IN PREGNANCY-A RETROSPECTIVE COHORT STUDY‖ is the original research work done by Dr Richa Sasmita Tirkey and was carried out under the guidance and supervision of Dr Jiji Elizabeth Mathews, Professor and Head of Unit V, Department of Obstetrics and gynecology, Christian Medical College, Vellore towards the partial fulfilment of the requirements of the Tamil Nadu Dr. M.G.R. Medical University, for the degree of the M.S. Obstetrics and Gynaecology examination to be held in May 2018

Dr Annie Regi

Professor and Head of the Department Obstetrics and Gynaecology

Christian Medical College Vellore-632004

Principal

Dr Anna Pullimood

Professor and Head of department Department of Pathology

Christian Medical College,Vellore-632004

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ORIGINALITY CERTIFICATE

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CERTIFICATE

This is to certify that the dissertation titled ―THE ASSOCIATION OF SERUM URIC ACID LEVELS ON BIRTH WEIGHT, IN WOMEN WITH HYPERTENSION IN PREGNANCY-A RETROSPECTIVE COHORT STUDY‖ by the candidate Dr Richa Sasmita Tirkey with registration number 22161405 towards the partial fulfilment of the requirements of the Tamil Nadu Dr. M.G.R. Medical University, for the award of the degree of the M.S. Obstetrics and Gynaecology examination to be held in May 2018.

I personally verified the Urkund .com website for the purpose of plagiarism check.

I found that the uploaded thesis file contains from ‗Introduction‘ to ‗Conclusion‘ pages and the result shows1percentage plagiarism in the dissertation.

Dr Jiji Elizabeth Mathews Guide

Professor and Head of Unit V

Department of Obstetrics and gynecology

Christian Medical College, Vellore

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ACKNOWLEDGEMENT

The dissertation work would not have been possible without the support of many people.

My sincere gratitude goes to my guide Dr. Jiji Elizabeth Mathews, who gave me her support, invaluable guidance and encouragement in completion of my thesis. Her dedication and commitment to work and education is truly inspiring and remarkable.

I am also grateful to my co-guide Dr Santosh Benjamin, Dr Swati Rathore who offered me the necessary strength and support in completion of my thesis.

I am also thankful to Dr Annie Regi, Dr Sridhar, Dr Anuja Abraham, for their guidance and support.

Special thanks to Mr Muthu, in Medical Records department ,Ms Sarfunniza, CHIPS department, Mr Madan in CEU, for their tremendous support in my data collection. I am grateful to my statistician Ms Hepsy Chelliah, for her expert guidance and helping with the analysis of my work.

My gratitude extends to all my friends and seniors for their unmatched help during my entire course and providing me the support in completion of my thesis.

My family cannot go unmentioned for their overwhelming support and prayers

throughout my studies and who endured this long process with me, especially my loving

husband Dr Amit J Tirkey, who always offered me his love and strength every step of

the way. My son, Rishan, who remains for me a continuous source of joy and boundless

energy. In the end, I dedicate my thesis work to the Lord Almighty, truly, ‗Nothing is

impossible with God‘. And to my loving mother, Dr Olive Shiela Tirkey, to whom I

owe everything I am today!

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Table of Contents

INTRODUCTION ... 14

AIM ... 15

OBJECTIVES ... 16

REVIEW OF LITERATURE ... 17

DEFINITION OF HYPERTENSIVE DISORDERS DURING PREGNANCY: ... 17

NORMAL HEMODYNAMIC CHANGES DURING PREGNANCY ... 22

MEASURMENT OF BLOOD PRESSURE AND DEFINING GESTATIONAL HYPERTENSION .. 23

PATHOGENESIS ... 25

UTEROPLACENTAL ISCHEMIA ... 27

CIRCULATING FACTORS CYTOTOXIC TO ENDTHELIAL CELLS IN THE PATHOGENESIS OF HYPERTENSIVE DISORDERS OF PREGANANCY. ... 31

IMMUNOLOGY ... 32

GENETICS ... 32

MATERNAL PATHOPHYSIOLOGY ... 32

Kidney ... 32

Coagulation system ... 33

Liver ... 33

Cerebral effects ... 34

Retinopathy ... 34

PROGNOSTIC SIGNIFICANCE OF SERUM URIC ACID. ... 36

Association of uric acid and changes in the placental vascular system: ... 37

Uric acid as a mediators of inflammation ... 38

Uric acid and damage repair ... 38

Uric acid and renal function ... 38

Uric acid association to development of hypertension ... 39

Uric acid association to development of FGR ... 39

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The Feed-Forward cycle ... 40

Significance of plasma uric acid and hypertension in pregnancy ... 42

Uric acid as a predictor of fetal death in hypertensive disease of pregnancy ... 45

MATERIAL AND METHODS ... 50

RESULTS ... 54

DISCUSSION ... 88

RECOMMENDATIONS ... 92

LIMITATIONS ... 93

CONCLUSION ... 94

REFERENCES ... 95

ANNEXTURE ... 99

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INTRODUCTION

Hypertensive disorders in pregnancy pose a significant problem during antenatal care.

Hypertension during pregnancy has also been studied with increasing maternal and fetal adverse outcomes(1). Various biochemical markers in predicting the severity have been identified (2). Many of these biomarkers are beyond the reach of women in developing countries, where the effects of hypertension in pregnancy are most profound. Uric acid, however is one biomarker which is cost effective and has shown promising results in the prediction and prognostication of hypertension in pregnancy.

In the present study, we attempt to look into the maternal serum uric acid (UA) levels and its association to fetal birth weight, as a marker of poor outcome, in patients with

hypertension. It has been observed in various studies, in the past that the serum uric acid

can predict severity of disease(3) while some studies and reviews have not been able to

confirm this. In the present study, we are taking a fixed variable i.e., fetal growth

restriction of the neonates born to mothers with hypertension during pregnancy and

comparing them in those with normal uric acid levels and high uric acid levels and

looking their outcome. Fetal growth restriction was defined as birth weight less than

10th percentile for the gestation.

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AIM

To compare the association of serum uric acid levels on birth weight for babies in women with

pregnancy induced hypertension. To determine the maternal serum uric acid levels at which

adverse fetal and maternal outcomes are observed.

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OBJECTIVES

1. To see the association of serum uric acid levels on birth weight of babies in women with gestational hypertension.

2. To assess adverse maternal and fetal outcomes in women with gestational hypertension at various uric acid levels.

3. To determine the level of uric acid, at which increasing and maternal/fetal complications are

noted during pregnancy.

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REVIEW OF LITERATURE

Hypertensive disorders in pregnancy are complex and serious. They are known to involve a multi-system pattern with a worldwide incidence of around 10%(4) and contribute significantly to maternal and perinatal morbidity and mortality.(5)

DEFINITION OF HYPERTENSIVE DISORDERS DURING PREGNANCY:

Previously the National High Blood Pressure Program Working group on High blood pressure in pregnancy and ACOG defined hypertensive disorders during pregnancy as follows:(6)

HYPERTENSIVE DISORDERS

IN PREGNANCY

1 Gestational hypertension (GHTN)

New onset hypertension diagnosed after 20 weeks of gestational age, with systolic blood pressure (SBP)

>=140mmHg and diastolic blood

pressure(DBP)>=90mmHg, on two occasions at least 4

hours apart, and resolving within 12 weeks postpartum.

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2 Chronic hypertension Diagnosed before 20 weeks of gestation and not resolving more than 12 weeks post partum.

3 Chronic HTN with superimposed

preeclampsia

Chronic HTN with features that of preeclampsia

4 Preeclampsia With urinary excretion of protein more than or equal to 0.3grams in 24 hours, with BP >=140/90mm Hg in a previous normotensive woman, after 20 weeks of gestational age. In the absence of raised BP it is highly suspected with the following features, headache, blurred vision, abdominal pain or low platelets.

5. Post partum hypertension: diagnosed after delivery anytime from 2 weeks to 6 months

post partum. This is usually mild, and can occur in previously normotensive women also.

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Presently the available classification system has been revised according to the American College of Obstetrics and gynecogologists, and Task Force on hypertension in pregnancy is as below(7):

1. Gestational hypertension (GHTN) and Severe GHTN.

2. Preeclampsia

3. Preeclampsia with severe features,(includes HELLP) 4. Chronic hypertension (CHTN)

5. Superimposed preeclampsia

6. Superimposed preeclampsia with severe features 7. Eclampsia

Gestational hypertension: is defined as a new onset hypertension with systolic BP 140- 159mmHg and diastolic BP 90-109mmHg; after 20 weeks of gestation on 2 occasions and more than 4 hours apart. It will usually resolve within 12 weeks post partum.

Severe GHTN: when BP >= 160/110mmHg on two occasions more than 4 hours apart

while on bed rest, in the absence of any antihypertensive therapy. Normal platelet count,

liver transaminases, and serum creatinine in association with absent maternal symptoms

is also included.

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Preeclampsia without severe features: is defined as GHTN with new onset proteinuria

> 300mg /d, or protein/creatinine ratio of >=0.3, or urine protein of 1+ or more on 2 separate occasions.

Preeclampsia with severe features (HELLP syndrome): is defined as either GHTN or preeclampsia with any one of following features:

Severe features of GHTN/Preeclampsia

Platelet count <100,000/mcgL

Elevated hepatic transaminases >2 times the upper limit of normal

Serum Creatinine >1.1mg/dl

Pulmonary edema Present

Severe upper right quadrant pain If unresponsive to analgesics and unexplained by other causes

Persistence cerebral or visual disturbances

If severe persistent new onset headache

unresponsive to non-narcotic analgesics, altered

mental status or neurological deficits

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Chronic hypertension with superimposed Preeclampsia:

1. Blood pressure >=160/110mmHg on at least 2 occasions despite use of maximum doses of Labetalol (2400mg/day) plus long acting nefedipine (180mg/day)

2. Platelet count <100,000/mcgL

3. Elevated hepatic tranaminases > 2 times

4. Serum Creatinine >1.1 mg/dl (if value <=0.8mg/dl at 20 weeks of gestation) 5. Serum Creatinine >1.4 mg/dl (if value >=0.8mg/dl at 20 weeks of gestation) 6. Pulmonary edema

7. Severe upper right quadrant pain unresponsive to analgesics and unexplained by other causes

8. Severe persistent new onset headache unresponsive to non-narcotic analgesics, altered mental status or neurological deficits.

Eclampsia : Convulsions that is not attributed to other causes, in the setting of

GHTN.(8) At times convulsions may occur in absence of HTN, up to 7 days post

delivery also, this is referred to atypical eclampsia.(9)

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NORMAL HEMODYNAMIC CHANGES DURING PREGNANCY

Blood pressure is the product of cardiac output and total peripheral resistance. (10) Due to active vasodilatation, the peripheral resistance falls during pregnancy. Prostacyclins and nitric oxide are major predisposing factors for vasodilatation and fall in systemic vascular resistance.

The following table shows hemodynamic changes in pregnancy:

Change Amount

Cardiac output Increases 40% 4.5-6.0L/min

Stroke volume Increases 65-70ml

Heart rate Increases 75-80bpm

Systemic vascular resistance Reduces 1350-980dyn seconds/cm ⁵

Blood pressure Reduces 5-10mmHg

Blood volume Increases 2600-3800ml

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MEASURMENT OF BLOOD PRESSURE AND DEFINING GESTATIONAL HYPERTENSION

Blood pressure determination is of fundamental importance in antenatal care. It is measured in sitting position, patient relaxed or after a period of rest, in the right arm with BP cuff positioned at the level of the heart. The cuff should be of right size, covering 2/3 of upper arm, and folded one and half times.

The accuracy of the automated device should be checked, before the measurement can be relied on. The mean arterial pressure is likely to be more accurate than systolic or diastolic, especially when generated by an oscillometric automated device. It is advisable to recheck by mercury sphygnomanometry.

Some common errors and how to avoid them:(10) Source of error Precaution

Rapid deflation Deflate 2-3 mmHg/second

Auscultatory gap Obtain systolic pressure by palpation Threshold avoidance Recheck again

Digit preference Take measurement to nearest 2mmHg

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Recommendations for blood pressure measurement in pregnancy:

1. Instrument: Mercury or aneroid sphygnomanometer or validated automated device 2. Setting: Relaxed, quiet environment preferably after rest

3. Position: Lying or sitting (Cuff at heart level)

4. Arm: left or right, higher value if difference is > 10mmHg

5. Korotkoff sound: First (systolic) and fifth (diastolic), if diastolic pressure s persistently

<40mmHg, use muffling/ make note of 4 ^th sound.

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PATHOGENESIS

The pathogenesis has been observed in 2 stages.(11)

The first is abnormal trophoblastic invasion and uterine spiral artery remodeling, with subsequent placental ischemia, oxidative injury, and trophoblastic debris release. This is usually the asymptomatic phase.

This phase is followed by a trigger of various inflammatory cytokines and release of anti- angiogenic factors resulting in endothelial dysfunction and the clinical signs and symptoms of the disease.(12)

Anti-angiogenic factors, like soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglins (sEng) can cause endothelial dysfunction by sequestering and antagonizing pro-angiogenic molecules such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and transforming growth factor –b .

There are also important inactivation of angiogenic pathway of nitric oxide (NO). NO normally induces vasodilatation and prevents platelet aggregation and inflammatory cell activation. It is also known to inhibit vasoconstriction by endothelin 1 (ET-1) and thromboxane A2. Vasodilatation is further increased due to activation of prostacyclin prostaglandin I2.

All these factors that play a paramount role in establishing adequate utero-placental flow

to the growing fetus are inactivated in GHTN.

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Diagram showing various factors acting at the cellular level in the pathogenesis of preeclampsia

Any defective placentation will lead to the adverse fetal outcome, in the form of FGR

(Fetal Growth Restriction) or high dopplers. Supporting the pathogenic role of placental

ischemia, preeclampsia is more seen in conditions where placental oxygen demand is

more, as in multiple pregnancy, molar pregnancy etc. Also in those with decreased

oxygen transfer due to pre-existing vascular alterations. This supports the fact that

preeclampsia is more common in primigravida where uterine vasculature is less

developed.

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UTEROPLACENTAL ISCHEMIA

Morphology of normal placental bed:

The transformation of the spiral arteries take place in 2 stages. Before the end of first trimester, the cytotrophoblastic shell surrounding the conceptus starts proliferating and forms the tips of the anchoring villi in the placenta. When these reach the myometrial portion of the spiral arterioles, it is then the trophoblastic invasion is said to be complete.

The dramatic changes occurring in the spiral arteries converting them to large, tortuous, low resistance sinusoidal vessels, and the internal elastic lamina is replaced by trophoblast and amorphous matrix containing fibrin. By second trimester another wave of endovascular trophoblastic migration leads to transformation in the utero-placental circulation to low-pressure and high-flow system allowing an adequate blood flow to the fetus. (13)

Morphology of placental bed in gestational hypertension

There is adequate evidence supporting the ‗physiological changes‘ do not or are limited

to only the decidua, and no myometrial invasion takes place, in hypertensive

complicating pregnancies. The utero-placental arteries maintain their musculo-elastic

architecture and also are responsive to vasomotor influences, subsequently vasospasm

and increased sensitivity to vasoconstrictors occurs.

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There is direct relation between uric acid levels and attenuation of trophoblastic invasion into the myometrial portion of the spiral arterioles, therefore uric acid is able to induce placental dysfunction, which is known etiological factor in the development of pre- eclampsia.

Studies have demonstrated that with high uric acid levels there is inhibition of placental system of amino acid transport and hence a causation of intra uterine growth restriction (IUGR).(14)

Figure1 A: Showing normal placentation

Figure1 B: Defective placentation due to impaired trophoblastic invasion.

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Association of hypertensive disorders and fetal growth restriction (FGR)

The decrease in amount of blood flow in the placental circulation leads to a persistent state of utero-placental hypoxia throughout pregnancy. As a result to the hypoxic state, there are a release of multiple anti-angiogenic factors into the maternal circulation leading further endothelial damage.(15) This results in a vicious cycle in the pathogenesis of both preeclampsia and FGR. Syncytial hypoxia, reperfusion injury and apoptosis is seen in preeclampsia, which causes further production of deleterious compounds such as superoxide anion (SO), and reactive oxygen species (ROS). Higher amount of apoptosis is observed in syncytiotrophoblasts of placenta in the presence of FGR complicating pregnancies.(16)

Figure 2. Role of placental syncytium in the pathophysiology of FGR and preeclampsia

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At times the above placental changes may occur in pregnancies complicated by FGR, without co-existing hypertension or preeclampsia. This makes it complex to hence various studies were done to evaluate its association. It was demonstrated that only 15%

of the women with FGR may be having hypertensive disorder in pregnancy(17).

Conversely women with preeclampsia and FGR had more severe hypertension and higher

rates of complications such as placental abruption, disseminated intravascular

coagulation, eclampsia etc.(17)

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CIRCULATING FACTORS CYTOTOXIC TO ENDTHELIAL CELLS IN THE PATHOGENESIS OF HYPERTENSIVE DISORDERS OF PREGANANCY.

Figure 3: The basic cascade of events leading to abnormal placentation in pregnancies complicated by hypertension.

Placental ischemia Microvascular

desease

Abnormal placentation

Increased trophoblastic

tissue

Endothelial activation or injury

Clinical syndrome Tx/PGI2

increases Increase sensitivity to

vasopressors Abnormal

coagulation

Increased permeability

Edema proteinuria thrombosis

hypertension

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IMMUNOLOGY

Normal pregnancy represents a unique state of immune adaptation to paternal antigen.

Immune maladaptation is observed in pre eclampsia. The frequent auto antibodies noted are anti-phospholipid antibody, anti-histone antibody and anti-polynucleotide antibody.

These may play a role in development of fetal growth restriction (FGR) in pre eclampsia.

(18)

GENETICS

The exact interaction between maternal and fetal genomes and mode of inheritance is not known, even though a higher incidence of preeclampsia is noted among girl babies born to eclamptic women as opposed to non eclamptic women. Hence fetal genotype could contribute to development of preeclampsia.(19)

MATERNAL PATHOPHYSIOLOGY

Kidney: The impairment of renal function takes place in two stages. Firstly damage to the tubular function, marked by reduction in uric acid clearance and thus hyperuricemia.

Later on there is impairment of glomerular filtration, and loss of intermediate-weighing

proteins. However proteinuria seems to be a poor predictor of maternal and perinatal

outcome(20). The characteristic renal lesion is glomerular endotheliosis, with swelling of

the endothelial cells, and fibrinoid deposition. However this is not pathognomic of the

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disease itself, and is shown to be a poor predictor.(20) There occus other anatomic changes, like juxtaglomerular hyperplasia, hypertrophy, afferent arteriolopathy, macula densa atrophy, and mild tubulointerstitial fibrosis.(21)

Coagulation system: In pregnancy, the coagulation system is overall in the state of activation. Since the plasma volume rises by 40%, there is marked increase in production of clotting factors and high levels of fibrinogen complexes. Development to gestational hypertension makes the state more hypercoagulable. There is considerable evidence showing that there is early rise in factor VIII antigen:coagulation activity ratio which is directly correlating to disease severity and adverse outcome, also hyperuricemia has been reported to directly contribute to thrombosis.(22) Furthermore increased levels of fibrinopeptides also correlates with to disease progression, and are good marker for accelerated thrombin activity and thrombosis.(23)

Liver : Abnormal liver enzymes have been identified in 20-30% of hypertensive

disorders.(24) This may be a reflection of vasoconstriction and ischemia at the hepatic

vascular bed. Girling et al, 1997(25), demonstrated increased progression to preeclampsia

and adverse outcomes by 54% in the settling of deranged liver enzymes. Histopathology

shows peri-portal deposition of fibrin, haemorrhage, and necrosis. The subcapsular

hematoma or stretching of the Glisson‘s capsule, is characteristic of the epigastric pain in

patients with GTHN and PE.

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Cerebral effects: The most highlighted and serious of the cerebral sequel to occur is Eclampsia. Incidence is 0.6% in GTHN without severe features and is 2 to 3% of women with severe features of preeclampsia not receiving anti-seizure prophylaxis.(26). There are 2 models that explain its pathogenesis, firstly focal cerebral vasospasm, ischemia and decreased perfusion. Secondly the HTN itself causes endothelial damage to intracranial arteries. This leads to extravasation of fluid and cerebral oedema. This has been largely noted in the parietal and occipital lobes

Retinopathy:

Fundoscopy should be an integral part of physical examination. Blindness is a rare complication and can be cortical or retinal in origin. Three-degree classification:(27)

●Mild –as a result of vasospam there is arteriolar narrowing, thickening of vessel wall, arteriovenous nicking, referred to as "nipping".

●Moderate – flame and dot-shaped hemorrhages, hard exudates, cotton-wool spots, and microaneurysms.

●Severe – All of the above plus edema. The presence of papilledema warrants urgent

reducing of the blood pressure.

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Figure 4: A diagrammatic representation of changes occurring in hypertensive

retinopathy

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PROGNOSTIC SIGNIFICANCE OF SERUM URIC ACID.

Uric acid is formed by the purine degradation by xanthine dehydrogenase/xantine oxidase (XDH/XO) by the liver. The metabolism of purine by XO produces free radicals

superoxide (O2 ^- )and which can bind to the endothelium and cause local oxidative injury.

(28)

It is excreted mainly through the kidneys (65%) and intestines (35%). It is known for its excellent antioxidant properties, by reducing nitrosylation of protein tyrosine, and maintaining superoxide dismutase activity.(29) However when values exceed its normal physiological levels, it promotes inflammatory cascade, and endothelial damage.(30) Uric acid, despite being a major antioxidant in the human plasma, both correlates and predicts development of obesity, hypertension, and cardiovascular disease, conditions associated with oxidative stress. While one explanation for this paradox could be that a rise in uric acid represents an attempted protective response by the host, there is evidence that uric acid may function either as an antioxidant (primarily in plasma) or pro-oxidant (primarily within the cell). Also that it is the pro-oxidative effects of uric acid that occur in

cardiovascular disease and may have a contributory role in the pathogenesis of these conditions.(31)

Uric acid levels are dependent on many factors such as protein rich diet

increased cell division, or any defects in purine metabolism and dysfunctional renal

excretion.(32) Estrogen is known to increase the uric acid excretion. It is hence observed

that serum concentrations initially fall in early pregnancy by 25-35%. Other contributing

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factors are increased blood volume and increased glomerular filtration rate It is also noted that concentrations slowly rise to those observed in non-pregnant women by term

gestation (4-6 mg/dL). Kang el showed similar results stating that serum uric acid levels fall in early pregnancy, to 3 mg/dl or below due to reasons mentioned earlier. In third trimester it rises again to 4–5 mg/dl near term.(21)

Dating back to the late 1800s, when hyperuricemia and hypertensive disorders in

pregnancy were first noted, many similar studies came up demonstrating the relevance of uric acid levels in the prediction of severe hypertension. However it still remains a

controversy, regarding the clinical utility of serum uric acid. Recent studies are emerging that shows direct evidence between the high levels of serum uric acid and adverse

maternal and fetal outcomes with gestational hypertension in the absence of proteinuria.(11) (33)

Association of uric acid and changes in the placental vascular system:

The placental vasculature is affected by uric acid. UA lowers the nitric oxide(NO) production, and can modify the trophoblasts leading to the faulty invasion and defective arteriole remodeling.(29) Increasing XO enzymatic activity has been observed in

cytotrophoblastic cells and hence there is an increase in UA levels in preeclampsia. This

causes oxidative injury to endothelial cells.(28) With decrease in the NO levels it is also

responsible for increase in COX-2, an thromboxane activity, leading to compromise in

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placental perfusion and inhibiting fetal intra-uterine growth. Reducing UA may be beneficial in the management to prevent FGR.

Uric acid as a mediators of inflammation

Uric acid stimulate the production of chemokine monocyte chemoattractant protein-1 (MCP-1), and they are dose and time dependent. Pro-inflammatory cytokines like IL-1β, IL-6 and TNF-α(34)(35) are produced by monocytes which are also found to be raised in preeclamptic women.(36) There is positive correlation between TNF-α and maternal uric acid concentrations in preeclamptic patients.(37)

Uric acid and damage repair

Sudden or acute increase in uric acid levels causes an ischemia-reperfusion event which induces endothelial progenitor cell (EPC) mobilization, and helps in repair of damaged vessels. This phenomenon is absent when there is chronic increased levels uric acid.

There is significant fall in the progenitor cells in preeclampsia.(38)

Uric acid and renal function

Renal changes are a consistent finding in patients with preeclampsia. The various numerous renal change mentioned earlier may be uric acid induced (29)and ultimately leads to glomerulosclerosis and subsequent albuminuria and proteinuria. This is

supported by the fact that by lowering UA levels these can be inhibited. Moreover it was

39

observed that the renal changes are more prevalent among the hyperuricemic PE women.(39)

Uric acid association to development of hypertension

As stated earlier since UA plays a role in reduction of NO, it is responsible for altering the vascular tone in hypertensive patients. Hyeruricemia may present as early as 10 weeks, and may preceed the development of hypertension.(40) Bellomo et al reported that with each 1mg/dl rise in UA, at the level of onset of GHTN there was significant association to progression to PE.(41)

Uric acid association to development of FGR

Uric acid is found in higher concentrations in 75% of preeclamptic women altering renal function and is identified as a marker for disease severity.(40) It is further studied that hyperuricemia can be an independent risk factor for the development of FGR,

hypertension, cardiovascular and renal diseases. Uric acid can initiate the inflammatory and redox cascades resulting in utero-placental endothelial damage and insufficiency leading to FGR including still births.(32) Uric acid crystals (monosodium urate) can cause pro-inflamatory changes in the cytotrophoblasts and secretion of IL-1β and IL-6.

The monosodium urate crystal(MSU) cause direct effect by increased apoptosis and

decreased syncytialisation.(42)

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The Feed-Forward cycle

There are various sources of uric acid like maternal vasculature, placenta and the fetus itself. As a part of defective trophoblastic invasion, ischemia- reperfusion to the placenta and oxidative damage happens as discussed earlier. Maternal tissues also experience vasospasm, ischemia and the oxidative stress, which in turn plays a feed-forward cycle and promotes UA production. Moreover hypoxia promotes xanthine

oxidase/dehydrogenase production and thus oxidase form of the enzyme is increased.

Increase in both the substrate and enzyme activity, there is further increase in UA

concentration. Reabsorbtion of uric acid is increased as a part of vasospasm and fluid loss due to endothelial damage in the renal arterioles. Eventually hyperuricemia is

responsible for increased UA production and reduced excretion, forming a feed forward

loop.(43)

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Figure 5: The feed-forward cycle

42

Significance of plasma uric acid and hypertension in pregnancy

Many more recent studies have validated the utility of uric acid in GHTN. A study by Sangeeta el al has shown a strong correlation with uric acid and development of high blood pressure and homocystine .(44)

However, studies by Laughong S K al shows a comparative study of the value of uric acid higher in first trimester for those patients likely to develop preeclampsia along with reduced ureate excretion.(45) The significant rise in UA during pregnancy will correlate with adverse maternal and fetal outcome.(46)

These observations have provoked clinicians to measure UA in order to diagnose preeclampsia and predict complications of mother and the fetus.

However, some studies were not in favour of UA as an important biomarker and rather concluded that for distinguishing preeclampsia with gestational hypertension the positive predictive of serum UA is poor.(47)(48)

Study by Bellomo et al showed that patients presenting after 20 weeks with

hypertension and no proteinuria, go on to develop preeclampsia (45%) and deliver SGA

babies (26%). UA showed an 8–9 fold risk of having preeclampsia and a 1.6–1.7-fold

risk for having SGA infants. His analysis also showed that a UA values of more than

5.2 mg/dl (309 µM) conferred excellent sensitivity, specificity and likelihood ratios for

diagnosis and also for prognostication.(41)(49)

43

All these studies are in favour of doing serumUA for patient with hypertensive disorders in pregnancy, and more importantly in primigravidas.

Increasing evidences is now emerging of UA as an important biomarker in preeclampsia but having a direct contributary role in causation of maternal and fetal

complications.(21)(29)

Uric acid is a potent inhibitor of the endothelial function, induces systemic and renal hypertension in animal models, as it freely enters into the fetal circulation. It has also been found to inhibit VEGF-induced endothelial growth thus blocking the angiogenesis, resulting in SGA infants. UA can inhibit proper trophoblastic growth and may mediate insulin resistance.(45)

The challenges faced because of this important disease does warrant a review of uric acid

as a biomarker and a potent disease modifier.

44

Figure 6: The action of uric acid in the placenta, and its effects on mother and fetus

(32)

45

Uric acid as a predictor of fetal death in hypertensive disease of pregnancy

Redman et al(50) showed that perinatal mortality was significantly high in early onset severe pre-eclampsia with raised UA

The prognosis of the fetus was better indicated by plasma UA than blood pressure measurement. Babies did much better when the blood pressure alone was high without hyperuricemia, rather than those patients who has both elevated

Mild hypertension with high UA still showed the prognosis of the fetus as poor. Thus suggesting that renal functions altering UA may be more significant than presence of hypertension in pre-eclampsia.(50)

Thus it can be studied that hyperuricemia can be used as biomarker for identifying

women at risk of complications and adverse pregnancy outcomes.(45) Hyperuricemia

was defined as a serum uric acid level one standard deviation greater than the appropriate

for gestational age as defined by Lind et al.(51)

46

It was studied that uric acid levels are to be considered elevated in pregnancy based on gestational age, as follows

Gestational age Serum uric acid (mg/dl)

28 - 32 W >4.50

32+1D - 33 W >4.70

33+1D - 34 W >4.93

34+1D - 35 W >4.98

35+1D - 36 W >5.04

36+1D - 37 W >5.40

38 W and over >5.58

High UA levels are associated with increasing maternal and fetal complications. Some studies also did the comparison of birth weight of women with different levels of uric acid. Considering less than 2.5 kg as low birth weight, levels of greater than 5.5 are associated with significant low birth weight. For women with preeclampsia who developed convulsions, there invariably was a further rise in the plasma uric acid levels.

Monitoring of plasma uric acid level in those with preeclampsia may help to predict those

that will develop eclampsia.

47

One driver for urate reabsorption by the kidney is volume contraction, either as a direct stimulus to the tubules or via increased angiotensin II production or sensitivity. This raises the question of whether a relationship exists between plasma volume contraction and serum uric acid in women with preeclampsia, and whether measuring both abnormalities would give greater ability to predict adverse maternal or fetal outcomes than measuring uric acid alone.

Along the same lines, studies have indicated that UA concentrations may predict the progression to PE, whereas preeclamptic women presented higher serum concentrations of this biomarker when compared with normotensive women. It function is highly correlated with SBP and DBP in women who develop hypertension disorder in pregnancy and that the combination of urinary creatinine and SBP in early pregnancy can be considered a predictor of preeclampsia. The concentration of UA is an important biochemical marker of renal dysfunction and has been associated with the development of hypertension.

It was investigated whether first trimester uric acid was associated with the development of the following: gestational hypertension or preeclampsia, these outcomes stratified by presence of hyperuricemia at delivery since this denotes more severe disease, preterm birth or small for gestational age (SGA).(45)

At the same time a prospective observational study carried out in fifty nine healthy

normotensive primigravidas, concluded that single estimation of serum uric acid level,

early in pregnancy is of little value in the prediction of preeclampsia.(52)

48

Keith et al studied that, uric acid levels, although significantly elevated in women with gestational hypertension and preeclampsia as compared to normotensive pregnant

women, are not good prognostic indicators of the severity of the maternal or fetal disease in terms of progression or prediction of HELLP syndrome, or small for gestational age (SGA) babies.(53)

Whereas in a prospective cohort study, it has been sited that maternal hyperuricemia in

normotensive singleton pregnant women is significantly associated with preterm and

SGA delivery and the development of neonatal IVH.(54)

49

The table below shows various studies which are in favor or against the use of uric acid as a biomarker in pregnancy.

Study (Year) Type of study Population of study Conclusion Outcome Number Inclusion

Elaheh Amini et al (2014)

Prospective multicentric cohort

404 Normotensive singleton pregnancies with high uric acid

Maternal hyperuricemia defined as 1SD from appropriate gestational age as defined by Lind et al

Increased fetal adverse outcomes (SGA,IVH)

TL-A Hawkins et al (2012)

Retrospective analysis

1880 Singleton pregnancies with gestational hypertension, no chronic hypertension or renal desease

Uric acid is a marker for adverse maternal and neonatal outcome, even without preeclampsia

Adverse neonatl outcome,(SGA, preterm) maternal outcomes, renal desease

SK Laughon et al (2011)

Prospective cohort 2211 (1997- 2002)

<15weeks gestational age in singleton pregnancies

First trimester hyperuricemia was associated with later preeclampsia.

SGA or Preterm births were not associated with elevated uric acid levels

Birth weight, birth weight centile adjusted with race,sex, gestational age at delivery,SGA,

Koopmans et al (2009)

Updating meta- analysis that already existed

1565 Preeclampsia and hypertensive women from eight studies

Uric acid is useful in predicting adverse maternal outcome and aid in management

Number of induction of labour were high with maternal hyperuricemia

Emmanuel et al (2010)

Prospective cohort 200 Preeclampsia/

eclampsia patients followed up uptill puerperium

Uric acid was

independant marker for persistant hypertension

Serum creatinine, and patients age were also factors for persistant hypertension

S Thangaratinum et al (2006)

Systematic quantitative review

3913 over 18 primary articals

Hypertensive complicating pregnancy

Uric acid cannot predict poor outcome

IUGR, severe HTN, HELLP, eclampsia , LSCS rates

Disha et al , (2012)

Retrospective study

80 Hypertensive complicating pregnancy, mils and severe

High uric acid is associated with FGR,more severe maternal desease

SGA,HELLP,abruption, eclampsia, pulmonary edema.

Robert et al (2006)

Case control 215 GHTN,

Preeclampsia, normal controls

Elevations happen early, may be also secondary to renal functions

Women having hyperuricemia prior to delivery, had increased values throughout pregnancy, with or without preeclampsia.

Bellomo et al, (2011)

Prospective study 206 Nulliparous hypertensive in pregnancy

Uric acid was to be a found to be a reliable predictor

SGA

Richard et al, (2011)

Observational 163 GHTN UA alters insulin

metabolism,block endothelial proliferation hence cause F

GR, by altering fetal angiogenesis

Severity of HTN, SGA, fetal death

Yuquan et al, (2012)

Retrospective cohort study

249 GHTN Initial high levels of UA indicate poorer outcome/progression of desease

One SD elevation of UA

gestationa age wise was

associated 2.3fold increase in

progression .

50

MATERIAL AND METHODS

A retrospective observational cohort study from the electronic Labor Room database, which exists for all women, delivering in our hospital, Christian Medical College Hospital, Vellore.

The study has looked into women with new onset hypertension diagnosed during pregnancy, in the given study period from January 2015 to December 2016.

Among these women, the serum uric acid levels were assessed from their records. If there were multiple serum uric acid levels assessed, each of the values were noted.

Three groups were studied, hypertensive women with high uric acid (HHU), hypertensive with normal uric acid (HNU) and a third group, of normotensive mothers without any risk factors, who have delivered around the same gestational period, as that of the study group. This will not only provide a control group, but also aid to observe prevalence of FGR babies in this population

This will also give us data, whether the population of small for gestational age (SGA) are only due to prematurity among the hypertensive women (because they are delivered early), or there is an underlying pathology played by UA that has already caused a SGA or fetal growth restriction (FGR).

Primary outcome is that of fetal birth weight in the two groups of women. The mean birth weight

in both groups would be noted and those falling below the 10 ^th centile for each week of gestation

would be taken as small for gestational age (SGA). The difference in SGA babies in the two

groups would be compared.

51

Secondary outcomes would be maternal and fetal complications.

Maternal complications include disseminated intravascular coagulopathy (DIC), abruption, HELLP syndrome, eclampsia, renal failure, pulmonary edema etc.

Fetal outcomes include prematurity, birth asphyxia, neonatal ICU admission, neonatal

complications like sepsis, hypoglycemia, metabolic abnormalities, need for ventilator support, etc.

We would also attempt to determine if a particular level of uric acid is associated with more adverse outcomes.

Sample size

A sample of size 638 (319 per group) is needed to detect a 10% of difference in the proportion SGA births between hypertensive mothers with high uric level and normal uric acid level. The proportion of SGA births is 18% and 10% in the hypertensive mothers with high and normal uric acid level, respectively. A similar group of women without gestational hypertension and with normal uric acid level will be compared with the other two groups. So essentially, there will be three groups comprising

1) Hypertensive mothers with normal uric acid level

2) Hypertensive mothers with elevated uric acid level

3) Non hypertensive mothers with normal uric acid level.

52

Statistical methods

Categorical variables were summarised using counts and percentages. Quantitative variables were summarised using mean and standard deviation or median and IQR. Chi square test was used to compare the proportions between categorical variables. The Independent t-test was used to compare the means between two groups. For all the analysis, 5% level of significance was considered to be significant. All the statistical analysis were done using stata/ic v.13.1

Inclusion criteria

The diagnosis of hypertension in pregnancy is based on the NICE guidelines 2010.

This study is done among women with gestational hypertension, pre-eclampsia and eclampsia who delivered between 01/01/2015 to 31/12/2016.

Among these women, the serum uric acid levels were assessed from their records. If there were multiple serum uric acid levels, each of the values was noted.

As uric acid levels are known to vary with gestational age, the gestational age at which the

samples were taken were noted. Using gestational age specific charts from previous studies, as

reference values, it was determined if the given value was above or below the cut-off for that

gestation.

53

Exclusion criteria

 Gestational age < 22 weeks

 Major fetal anomaly

 Multiple gestation

 Chronic hypertension

 Other systemic causes of hypertension- renal causes, collagen vascular diseases, etc.

There were hypertensive complicating pregnancies in the study period. After excluding those with gestational age less than 22 weeks, major fetal anomalies, multiple gestations, and other pre-existing maternal risk factors such as chronic hypertension, renal disease, collagen vascular disease etc, the above women were separated into two groups. The study group was the one with hypertension with high uric acid levels. This was to compare with a group of women with gestational hypertension and normal uric acid levels. The levels were determined from earlier studies, which are gestational age specific. We would also study a similar number of pregnant women without hypertension or any other major risk factor. The birth weight in normal

pregnancies during the same gestational period was assessed. This will give us an idea about the

baseline incidence of small for gestational age in our population. They were the same number, so

as to make the comparisons with the study group at same gestational age.

54

RESULTS

Our study included patients with new onset hypertension during period from January 2015 to December 2016 in our institute. Out of total 28,945 deliveries, after having excluded the essential/chronic hypertension, hypertension due to secondary causes, renal disease, antiphospholipid antibody syndrome, collagen vascular disease etc, 3382 were found to be complicated with primary hypertensive disorders of pregnancy. This

amounts to 11.6%, which is almost similar to the incidence of the disease as per literature mentioned earlier.

The study group which fulfilled our study criteria was 896 out of which 295 women with

hypertension with high uric acid (HHU), 306 women with hypertension with normal uric

acid (HNU), and a third group of 295 normotensive women were taken. The controls

were matched for gestational age.

55

Figure 7. Distribution of patients all three study groups.

HHU- Hypertension with high uric acid= 295 women HNU- Hypertension with normal uric acid=306 women Normotensive control= 295 women

HHU, 295

HNU, 306

Normotensive 295

56

Table 1: Demographic and clinical characteristics: Age, BMI High UA

(N = 295)

Normal UA (N = 306)

Normotensive Control (N = 295)

P-value

Age

<20years 21-31years

>32years

24(8.2) 227 (77.5) 42 (14.3)

16 (5.3) 240 (28.7) 49 (16.1)

33 (11.2) 228 (77.3) 34 (11.5)

0.067

BMI (Kg/m ² )

<18.5 18.5-24.99 25-29.99

>30

2 (0.7) 38 (13.9) 98 (35.9) 135 (49.5)

3 (1.0) 40 (13.3) 105 (35.0) 152 (50.7)

11 (3.7) 105 (35.6) 127 (43.1) 52 (17.6)

<0.001

Age: Most of the population in our study belonged to age between 21-31 year old.

Women with hypertension were older than the normotensive women. Hypertensive

women were more likely to be obese, however there was no difference between the

normal UA group and high UA group.

57

Table 2 Demographic association in terms gestational age High UA

(N = 295)

Normal UA (N = 306)

Normotensive Control (N = 295)

P-value

Gestational age at diagnosis Second trimester(<28weeks) Third trimester(after 28 weeks)

16 (5.4) 279 (94.6)

1 (0.3) 305 (99.7)

15 (5.1) 280 (94.9)

<0.001

In the high uric acid group more women were likely to be less than 28 weeks

Table 3 Demographic associations in relation to Gravida status

Gravida HTN with high UA

HTN with normal UA

Normotensive Control

Total

1 202

(68.47%)

179 (58.50%)

136 (46.10%)

517 (57.70%) More than 1 93

(31.53%)

127 (41.50%)

159 (53.90%)

379 (42.30%)

Total 295

(100%)

306 (100%)

296 (100%)

896 (100%) P value <0.001

Women with high uric acid were more likely to be primigravida. This was seen more than

the women with normal UA and normotensive group.

58

Figure 8: Association of Parity and the study groups

Most number of study population were parity 0, this included primigravida as well as all early pregnancy loss.

227

55

12

1 215

77

12

2 161

104

22

5

0 1 2 3

Num ber o f pa tient s

parity -->

Parity

HUA

NUA

Control

59

Medical associated risk factors- Maternal Table 4: Anemia

Anemia HTN with high UA

HTN with normal UA

Normotensive Control

Total

Yes 62

(27.31%)

51

(21.98%)

89

(51.45%)

202 (31.96%)

No 165

(72.69%)

181 (78.02%)

84

(48.55%)

430 (68.04%)

Total 227

(100%)

232 (100%)

173 (100%)

632 (100%) P value<0.001

Hypertensive with high UA had 27.31% of women who were anemic, and 21.98% of normal uric acid women were having anemia complicating pregnancy.

Table 5 Gestational diabetes mellitus:

GDM HTN with

high UA

HTN with normal UA

Normotensive Control

Total

Diet 40

(17.62%)

52

(22.41%)

01 (0.58%)

93

(14.72%)

OHA 08

(3.52%)

10 (4.31%)

03 (1.73%)

21 (3.32%)

Insulin 13

(5.73%)

06 (2.59%)

0 19

(3.01%)

No 166

(73.13%)

164 (70.69%)

169 (97.69%)

499 (78.96%)

Total 227

(100%)

232 (100%)

173 (100%)

632 (100%) P value<0.001

Gestational diabetes mellitus was seen in association with hypertensive complicating

pregnancy, most of them were controlled on diet, for all the three study groups.

60

Table 6. Association of past dates with study group Past dates HTN with

High UA

HTN with normal UA

Normotensive Control

Total

Yes 07

(3.08%)

18 (7.76%)

08 (4.62%)

33 (5.22%)

No 220

(96.92%)

214 (92.24%)

165 (95.38%)

599 (94.78%)

Total 227

(100%)

232 (100%)

173 (100%)

632 (100%) P value <0.073

Few of the women only were past dates, as termination of pregnancy offered to them

depending upon the severity if hypertension.

61

Table7: Other maternal medical risk factors and the prevalence of these in each of the study group

Risk factor HTN with High UA

HTN with normal UA

Normotensive Control

Total P value

Hypothyroidism 29

(12.78%)

24

(10.34%)

17 (9.83%)

70

(11.08%)

<0.587

Hyperthyroidism 1

(0.44%)

1

(0.43%)

0 2

(0.32%)

<0.685

Bronchial asthma 1

(0.44%)

0 3

(1.73%)

4

(0.63%)

<0.084

Seizure disorder 2

(0.88%)

4

(1.72%)

7

(4.05%)

13 (2.06%)

<0.079

Heart disease 3

(1.32%)

0 4

(2.31%)

7

(1.11%)

<0.083

Grand multipara 0 1

(0.43%)

3

(1.73%)

4

(0.63%)

<0.085

Short stature 20 (8.81%)

12 (5.17%)

14 (8.09%)

46 (7.28%)

<0.289

Liver disease 2

(0.88%)

0 3

(1.73%)

5

(0.79%)

<0.147

HBsAg positive 2

(0.88%)

2

(0.86%)

4

(2.31%)

8

(1.27%)

<0.352

62

PRIMARY OUTCOME

Table 8: Distribution of cases according to the Gestational age, between the three groups

HHU (N = 295)

HNU (N = 306)

Normotensive Controls (N = 295)

P-value

<28 weeks 16 (5.4) 1 (0.3) 15 (5.1)

<0.001 28-32w 33 (11.2) 6 (2.0) 36 (12.2)

32+1—33w 15 (5.01) 3 (1.0) 17 (5.8) 33+1—34w 22 (7.5) 6 (2.0) 24 (8.1) 34+1---35w 27 (9.2) 8 (2.6) 25 (8.5) 35+1---36w 30 (10.4) 21 (6.9) 27 (9.2) 36+1---37w 32 (10.9) 32 (10.5) 34 (11.5) 37+1---38w 38 (12.9) 72 (23.5) 41 (13.9) 38w and over 82 (27.8) 157 (51.3) 76 (25.8) Total 295 (100) 306 (100) 295(100)

Distribution of cases according to gestational age between three groups were as above

63

Table 9: Association of uric acid, and number of fetal growth restriction (FGR) in each group

FGR HTN with

highUA

HTN with normal UA

Normotensive Control

Total

Yes 49

16.61%

21 6.86%

13 4.41%

83 9.26%

No 246

83.39%

285 93.14%

282 95.59%

813 90.74%

Total 295

100%

306 100%

295 100%

896 100%

P value <0.001

A total of 83 babies were found to be affected by growth restriction with birth weight

<10 ^th centile. 49 were in high uric group, 21 in normal uric acid group, and 13 in

normotensive group. Sensitivity 70%, Specificity 54%, Negative predictive value 56%,

Positive predictive value 16%.

64

Table 10. Number of births who were FGR( below the 10%tile), according to gestational age, in all the three groups.

Gestational age HHU Birth

weight<10%tile (N = 49)

HNU Birth weight

<10%tile (N = 21)

Normotensive Control Birth

weight<10%tile (N = 13)

<28 weeks 3 (6.1) 0 (0.0) 0 (0.0)

28-32w 5 (10.2) 1 (4.8) 1 (7.7)

32+1—33w 2 (4.1) 0 (0.0) 1 (7.7)

33+1—34w 4 (8.2) 1 (4.8) 0 (0.0)

34+1---35w 4 (8.2) 2 (9.5) 0 (0.0)

35+1---36w 5 (10.2) 2 (9.5) 0 (0.0) 36+1---37w 5 (10.2) 4 (19.1) 0 (0.0) 37+1---38w 9 (18.4) 4 (19.1) 0 (0.0) 38w and over 12 (24.5) 7 (33.3) 11 (84.6)

Total 49 (100) 21 (100) 13 (100)

P -value <0.83 <0.03

The number of babies with FGR (below 10%tile) between the high and normal uric acid

groups were not statistically significant but were clinically significant at each of the

above gestational age .

65

Table 11. Mean birth weight among gestational hypertensive mothers

Gestational age UA cut off taken as high

HHU Median (min,

max) (N = 295)

HNU

Median (min, max) (N = 306)

<28 weeks >4.5 530 (220, 800) 1000

28-32w >4.5 1120 (440, 3210) 990 (670, 1590) 32+1—33w >4.70 1370 (1020, 1700) 1800 (1560, 1980) 33+1—34w >4.93 1590 (810, 2330) 1760 (1200, 2260) 34+1---35w >4.98 1760 (1450, 2420) 1870 (1420, 2440) 35+1---36w >5.04 1965 (1300, 2810) 2300 (1260, 2800) 36+1---37w >5.40 2170 (1620, 3110) 2500 (1710, 3040) 37+1---38w >5.58 2735 (1900, 3780) 2780 (1560, 3690) 38w and over >5.58 2985 (1570, 4700) 2980 (2180, 4260)

Among the hypertensive mothers, the average fetal birth weight according to uric acid

cut-off and gestational age are given in table 11

66

Table 12. The mean birth weight among hypertensive compared to normotensive control group

Gestational age UA cut off taken as high

HHU

Median (min, max) (N = 295)

Normotensive (control) Median (N = 295)

HNU

Median (min, max) (N = 306)

<28 weeks >4.5 530 (220, 800) 620 1000

28-32w >4.5 1120 (440, 3210) 940 990 (670, 1590)

32+1—33w >4.70 1370 (1020, 1700) 1120 1800 (1560, 1980) 33+1—34w >4.93 1590 (810, 2330) 1700 1760 (1200, 2260) 34+1---35w >4.98 1760 (1450, 2420) 2000 1870 (1420, 2440) 35+1---36w >5.04 1965 (1300, 2810) 2360 2300 (1260, 2800) 36+1---37w >5.40 2170 (1620, 3110) 2400 2500 (1710, 3040) 37+1---38w >5.58 2735 (1900, 3780) 2490 2780 (1560, 3690) 38w and over >5.58 2985 (1570, 4700) 2420 2980 (2180, 4260)

Birth weights seen among the population of high uric acid group(HHU), hypertension in

normal uric acid (NNU) and normotensive control group.