COMPARISON OF 24 HOUR URINARY PROTEIN AND URINARY DIPSTICK VS URINARY SPOT PROTEIN ...repository-tnmgrmu.ac.in/3958/1/220600116nabishabegam.pdf · 2017. 11. 15. · DECLARATION I,

COMPARISON OF 24 HOUR URINARY PROTEIN AND

URINARY DIPSTICK VS URINARY SPOT PROTEIN

CREATININE RATIO IN PRE-ECLAMPSIA

Dissertation submitted for

MS (OBSTETRICS & GYNAECOLOGY)

BRANCH - II

THE TAMILNADU DR.MGR MEDICAL UNIVERSITY

CHENNAI

OCTOBER 2015

BONAFIDE CERTIFICATE

This is to certify that the dissertation entitled “COMPARISON

OF 24 HOUR URINARY PROTEIN AND URINARY DIPSTICK VS

URINARY SPOT PROTEIN CREATININE RATIO IN PRE-

ECLAMPSIA” is a bonafide record work done by Dr.A.Nabisha

Begam under my direct supervision and guidance, submitted to The

Tamil Nadu Dr. MGR Medical university in partial fulfillment of

university regulations for M.S Obstetrics and Gynaecology.

Dr. SHOBHA MD, DGO Professor

Institute of Obstetrics & Gynaecology

Madras Medical College Chennai.

Dr. BABY VASUMATHI MD, DGODirector

Institute of Obstetrics & Gynaecology Madras Medical College

Chennai.

Dr. R. VIMALA, MD Dean

Madras Medical College Chennai.

DECLARATION

I, Dr.A.Nabisha Begam, solemnly declare that the dissertation

titled “COMPARISON OF 24 HOUR URINARY PROTEIN AND

URINARY DIPSTICK VS URINARY PROTEIN CREATININE

RATIO IN PRE-ECLAMPSIA” has been prepared by me . I also

declare that this bonafide work or a part of this work was not submitted

by me for any award, degree ,diploma to any other university either in

India or abroad.

This is submitted to The Tamil Nadu Dr. MGR Medical

University, Chennai in partial fulfillment of the rules and regulations for

the award of M.S Degree (Obstetrics and Gynaecology) held in October

2015.

Place:

Date: DR.A.NABISHA BEGAM

ACKNOWLEDGEMENT

I am extremely thankful to Dr. BABY VASUMATHI MD DGO

Director Institute of Obstetrics and Gynaecology, for granting me

permission to undertake this study.

My sincere thanks and gratitude to Prof. DR SHOBHA MD,DGO

Institute of Obstetrics and Gynaecology, for her expert guidance and

support for the completion of this study.

I am grateful to all unit chiefs in Institute of Obstetrics and

Gynaecology, for their valuable suggestions in preparing this dissertation.

My hearty thanks to all the Assistant professors. Institute of

Obstetrics and Gynaecology, for their immense help during this study.

Thanks to my fellow Postgraduates, House Surgeons and my

Family Members who assisted me throughout this study.

I acknowledge the co-operation of the patients without whom this

study would not have been possible.

CONTENTS

S. NO.

TOPIC PAGE

NO.

1. INTRODUCTION 01

2. AIM OF THE STUDY 03

3. MATERIALS AND METHODS 04

4. REVIEW OF LITERATURE 06

5. STATISTICS 63

6. DISCUSSION 96

7. CONCLUSION 98

8. BIBLIOGRAPHY 99

9.

ANNEXURES

PROFORMA

MASTER CHART

ETHICAL COMMITTEE CERTIFICATE OF

APPROVAL

PLAGIARISM SCREENSHOT &

DIGITAL RECEIPT

Introduction

1

INTRODUCTION

Hypertensive disorder of pregnancy complicates approximately 15-

20% of pregnancies of which preeclampsia occurs in 2-8%. Preeclampsia

accounts for 15-20% of maternal mortality and a high amount of maternal

morbidity . It is a major pregnancy complication causing preterm birth

which is often iatrogenic, intrauterine growth restriction, abruption and

intrauterine fetal demise which contribute significantly to perinatal

mortality and morbidity.

Estimation of proteinuria is essential for making diagnosis, to

assess the severity of disease and also for predicting feto maternal

outcome in preeclamptic pregnancies. For estimating the amount of

protein in urine collection of 24 hour urinary sample is taken as gold

standard, but it is time consuming, cumbersome and inconvenient.

Routine simple dipstick urine analysis has low sensitivity high

false positive and false negative results. Also its results are being

influenced by maternal hydration status, diurnal variation, presence of

infection, exercise etc,.

2

So we can use random urinary spot protein creatinine ratio instead

of 24 hour urinary protein to detect significant proteinuria. In this method

urinary protein concentration is divided by GFR independent urinary

creatinine concentration. Therefore it is a useful reference.

Aim of the study

3

AIM OF THE STUDY

Comparing the results of 24 hour urinary protein, urinary dipstick

and urinary spot protein creatinine ratio.

To study the relationship between the 24 hour urinary protein and

random urinary spot protein creatinine ratio in pre eclampsia.

To determine the ability of random spot protein creatinine ratio for

prediction of significant proteinuria.

Materials and Methods

4

MATERIALS AND METHODS

This study was conducted in 100 antenatal women with

preeclampsia, who got admitted in antenatal ward, Institute of Obstetrics

and Gynaecology, Madras Medical College, Chennai during the time

period between August 2014 to January 2015.The study type is cross

sectional. Ethical committee clearance was obtained from the institution

to undergo this study.

After getting the informed consent ,all women were examined.

A detailed history was taken, general physical and systemic including

obstetric examination was done. A urinary dipstick was done and in the

women who showed 1+ proteinuria or more, quantitative tests for

proteinuria carried out.

The tests were carried out as follows: the patients were instructed

to collect the 24 hours urine starting from the second urine sample in the

morning till the first urine sample next day morning. An another sample

was collected on the next day for spot protein/ creatinine ratio estimation.

Amount of proteinuria is estimated by using turbimetric (sulphosalicylic

acid) method . Normal values for protein excretion, negative if the 24

hour urinary protein is <300 mg/24 hours, protein creatinine ratio

<0.3,clinically significant proteinuria if urinary protein is ≥300 mg/24

5

hours and protein creatinine ratio≥ 0.3.The ISSHP (International Society

for the Study of Hypertension in Pregnancy) defined significant

proteinuria as;

1. 24 hour urinary protein ≥300mg/day

2. Random protein creatinine ratio≥30mg/mmol.

The data thus collected were analysed using appropriate statistical

methods.

INCLUSION CRITERIA:

This study will be carried on 100 randomly selected admitted

antenatal cases with pre eclampsia of more than 20 weeks gestation.

EXCLUSION CRITERIA:

1. Urinary tract infection.

2. Pre existing renal or vascular disease.

3. Chronic hypertension

4. Diabetes mellitus.

Review of Literature

6

REVIEW OF LITERATURE

GENERAL ASPECTS:

Pre eclampsia is a disease involving multiple systems such as renal,

hepatic, neurological, coagulation and cardiovascular system etc.

.Globally the incidence of the disease is between 5 to 8%. Pre eclampsia

is often thought of as a disorder with two components, an abnormal

placental implantation with endothelial dysfunction.

INCIDENCE:

The incidence of preeclampsia in nulliparous ranges from 3-10%.In

multiparous it is variable but lesser than that for nulliparous. It is because

the incidence is markedly influenced by race and ethnicity.

RISK FACTORS:

1.Age

Young and nulliparous women < 20 years

Maternal age older than 35 years

2.Race

It is high in African and American ethnicity(3%) compared with

white women (1.8%)

3.Obesity

BMI Incidence of pre eclampsia

<20 4.3%

>35 13.3%

7

The possible explanations are increased cytokine mediated

inflammation , increased oxidative stress , increased shear stress,

dyslipidemia and increased sympathetic activity

4. Prolonged interpregnancy interval > 10 years

5. Family history of preeclampsia

6. Obstetric factors

a) Previous history of preeclampsia

b) Multifetal gestation

c) Hydropsfetalis

d) Abnormal uterine artery Doppler at 18-24 weeks

7. Preexisting medical disorders

a) Diabetes Mellitus

b) Chronic Hypertension

c) Renal Disease

d) Thrombophilias

e) Autoimmune disease

8. Environmental factors

Smoking decreases the risk of preeclampsia

8

PATHOGENESIS:

Preeclampsia has been known as ‘’The Disease of Theories”

because the exact course of events that cause the clinical syndrome is not

clear. Pregnancy is seen as a “Stress Test” for the vascular system of

mother and women those who develop preeclampsia is due to failure of

this test.

TWO STAGE THEORY OF PREECLAMPSIA:

(RED MANN ET AL)8

In stage one there is faulty endovascular trophoblastic remodeling

of uterine arteries during first half of pregnancy results in placental

hypoxia.

In stage two there is systemic release of placental factors because

of oxidative stress that causes systemic inflammatory response and

endothelial activation culminating in preeclampsia syndrome.

9

OTHER THEORIES PROPOSED:

1. Impaired trophoblastic invasion

2. Immunological maladaptation

3. Exaggerated inflammatory response

4. Vascular endothelial damage

5. Increased oxidative stress

6. Coagulation abnormalities

7. Angiogenic imbalance

8. Genetic factors

IMPAIRED TROPHOBLASTIC INVASION:

The basic pathology in pre eclampsia is impaired trophoblastic

invasion. It may result either from defective invasion or trophoblastic

cell death induced after normal invasion. As a result of this, remodelling

of spiral arterioles got affected. The process of interstitial trophoblastic

invasion of both the deciduas basalis and the myometrium starts at the

centre and spreads towards the margin. During the first few weeks of

pregnancy some of the interstitial trophoblasts enter the lumina of spiral

arterioles in the superficial decidual compartment near placental decidual

junction later on deeper in the myometrial compartment.Based on the

studies it is found that there is a time interval of one month between

10

endovascular trophoblastic invasion of decidual and myometrial segments

respectively. Based on these the existence of two successive waves of

endovascular invasion with a temporary halt at decidual myometrial

junction. Normal spiral artery remodeling involves five steps:

Step 1 Endothelial vacuolization.

Step 2 Early media disorganisation and weakening of elastica.

Step 3 Appearance of endovascular trophoblast in the arteriolar

lumen

Step 4 Incorporation of endovascular trophoblast into the vessel

wall.This process is associated with fibrinoid deposition

Step 5 Endothelial repair and intimal thickening

In preeclampsia the deeper myometrial arterioles do not lose their

endothelial lining and musculoelastic tissue. So their mean external

diameter is reduced which impairs placental blood flow. This diminished

perfusion and hypoxic environment result in stage two changes.

IMMUNOLOGICAL MALADAPTATION:

Loss of immune tolerance or immune dysregulation is an another

theory for preeclampsia syndrome .

11

During implantation the extra villous trophoblast invade the

maternal decidua which is infiltrated by abundant NK cells, macrophages

and CD3 TCells. These trophoblastic cells are allogenic which express

three class I molecules HLA-G,HLA-E and HLA-C. Among these three

HLA-G and HLA-E show very limited polymorphism .Only HLA-C is

highly polymorphic. Among the identified NK receptors it is the KIR

family (Killer Immunoglobulin like Receptors )will bind with HLA-

C.This particular combination of maternal KIR with paternal HLA-C has

a main influence on the production of chemokines by NK cells. So

preeclampsia will arise as a result of unfavourable combination of

maternal KIR and paternal HLA-C.

EXAGGERATED INFLAMMATORY RESPONSE:

The two main point of contact between maternal and fetal immune

system are

1. The systemic immune response between maternal blood and

syncytiotrophoblast

2. The local immune response between maternal decidua and extra

villous trophoblast

The syncytiotrophoblast is entirely devoid of MHC expression

.Normally CD4+ Th cells differentiate into Th1 and Th2 .Th1 cells

produce IFN-gamma associated with inflammatory response .Th2 cells

12

produce IL-4&5.Normally there is a shift towards Th2 differentiation . In

preeclampsia an imbalance in Th1 /Th2 ratio is proposed with deviation

toward Th1 response .This causes exaggerated systemic inflammatory

response in preeclampsia.

VASCULAR ENDOTHELIAL DAMAGE:

Maternal serum and placental levels of sFlt-1(soluble fms like

tyrosine kinase-1) are increased in preeclampsia. It is synthesized from

the placenta in response to ischemia which binds with VEGF and

PLGF.As a result of this the levels of VEGF and PLGF are reduced

which ultimately affects endothelial function.

13

OXIDATIVE STRESS:9

Inadequate antioxidant response after initiation of maternal blood flow in

intervillous space

Faulty trophoblastic invasion and partial remodeling of spiral arterioles

Placental hypoperfusion

Placental hypoxia and increased shear stress

Increased expression of xanthine oxidase and NADPH oxidase

Increased superoxide generation

Chronic oxidative stress

Apoptosis and necrosis of trophoblast

Release of placental factors into circulation

Increased endothelin

Decreased nitric oxide

Altered TXA2/PGI2 ratio

14

COAGULATION ABNORMALITIES:

Significant alterations in prostanoid production occurs in women

with preeclampsia. An imbalance in production of vasodilator

prostaglandin (PGI2) and vasoconstricting prostaglandin (TXA2) is

suggested.

ANGIOGENIC IMBALANCE:

In preeclampsia there is dispropotion between circulating

proangiogenic (VEGF, PLGF-decreased) and anti angiogenic (sFlt1 and

soluble endoglin increased) substances.

GENETICS:

The hereditary predisposition is a result of complex interaction of

several inherited genes both maternal and paternal. Those are

1. MTHFR gene

2. Factor V Leiden gene

3. Angiotensinogen gene

4. HLA gene

5. NOS3 gene

6. Prothrombin gene

7. ACE gene

15

ATYPICAL PREECLAMPSIA:6

Preeclampsia or eclampsia may develop in a women without either

hypertension or proteinuria.

CRITERIA

1. GHTplus one or more of the following

Symptoms of preeclampsia

Hemolysis

Thrombocytopenia (<1 lakh /cu mm)

Elevated liver enzymes two times the upper limit of normal

2. Gestational proteinuria plus one or more of the following

Symptoms of preeclampsia

Hemolysis

Thrombocytopenia (<1 lakh /cu mm)

Elevated liver enzymes two times the upper limit of normal

3. Early signs and symptoms of preeclampsia –eclampsia at <20

weeks

4. Late postpartum preeclampsia-eclampsia> 48 hour

16

CLINICAL FEATURES OF PRE-ECLAMPSIA:

The following are imminent symptoms:

Occipital or frontal headache

Blurring of vision

Severe right hypochondriac pain or epigastric pain

Nausea or vomiting.

Generalised puffiness, edema of face, hands or feet.

Reduced urine output.

Convulsions.

Chest pain or dyspnoea.

CLASSIFICATION:

Hypertensive disorders of pregnancy classified into four well defined

groups:

1. Gestational Hypertension

2. Preeclampsia, Eclampsia

3. Chronic Hypertension

- Essential

- Secondary

4. Preeclampsia superimposed on chronic hypertension

17

DEFINITION :

I) NICE – 2010 GUIDELINES2

Pre eclampsia:

De novo hypertension developing after 20 weeks of gestation

returning to normal at postpartum with properly documented proteinuria.

Severe Pre-Eclampsia:

Pre-eclampsia with severe hypertension and / or with symptoms,

and / or biochemical and / or hematological impairment.

II) ACOG : 2012 3

Gestational hypertension:

Development of hypertension after 20 weeks.

Previously normotensive.

SBP > 140mmHg

(or)

DBP > 90mmHg

Persistent for 4 hours.

Returns to normal by 6 weeks postpartum.

18

Pre-Eclampsia:

Gestational Hypertension + New onset of any of the following

Proteinuria.

≥300mg/day (or)

Protein creatinine ratio 0.3

Dipstick ≥ 1+

Thrombocytopenia.

Altered liver function.

Renal insufficiency.

Pulmonary edema.

Cerebral disturbances

Visual impairment

Chronic HT “ Suspected” superimposed Pre-eclampsia

New onset proteinuria

Sudden increase in Pre-existing proteinuria

Sudden increase in blood pressure if

o Previously well controlled (or)

o Escalation of BP medications.

19

NICE guidelines divided hypertension into mild, moderate and severe for

management purposes.

Systolic BP

mm Hg Diastolic BP

Mm Hg

Mild hypertension 140-149 90-99

Moderate hypertension 150-159 100-109

Severe hypertension ≥160 ≥110

Pre-Eclampsia 5

Mild Pre-eclampsia Severe Pre-eclampsia

i) Hypertension :

BP ≥ 140/90 mmHg on 2

occasions atleast 6 hours apart

ii) Proteinuria:

i) Dipstick ≥1+

ii) Urine Protein :

Creatinine ratio ≥0.3

iii) 24 hrs urinary protein

≥300mg /24 hr

i) BP of ≥160mmHg

Systolic or ≥ 110mgHg of

Diastolic on 2 occasions 6hrs

apart.

ii) Proteinuria ≥ 5g in 24 hours

iii) Oliguria < 500ml/24 hrs

iv) Cerebral visual disturbance

v) Epigastric pain ,nausea,

vomiting

vi) Pulmonary edema

vii) Impaired liver function

viii) Thrombocytopenia

ix) Eclampsia

x) IUGR / FGR

[ Sibai BM et al]

20

ACOG 2012 Presidential Initiative:

Pre-eclampsia is never mild. It is a progressive disease.

Rapid progression is possible at any stage.

- If early onset

- Co-morbidities.

Gives a false sense of security

So task force recommends that

o Pre-eclampsia without severe features (Pre-eclampsia)

o Pre-eclampsia with severe features (severe Pre-eclampsia)

Laboratory abnormalities in Pre-eclampsia:

Renal Changes:

Renal blood flow and glomerular filtration rate are increased in

normal pregnancy. In Pre-eclampsia because of Vasoconstriction and

glomerular endotheliosis there is 25% reduction in GFR.

Hyperuricemia is seen in women with severe pre-eclampsia. It is

associated with decreased renal tubular secretion, glomerular

endotheliosis and increased oxidative stress because of increased activity

of xanthine oxidase. Renal failure is uncommon in pre-eclampsia unless it

is associated with HELLP or sepsis. The upper limit of normal of serum

creatinine is 1.2mg/dL and BUN is 15mg/dL.

21

Changes in liver function test:

Liver is affected only in 10% of women with severe pre-

eclampsia. Mild elevation of serum transaminases. (AST & ALT Levels

>70IU is significant) is common. Bilirubin especially the indirect fraction

raised in HELLP syndrome. The levels return back to normal by 5th

postpartum day.

Hematological Abnormalities:

Pre-eclampsia is associated with decreased hemoglobin and

hematocrit due to decreased plasma volume. The most common

hematological problem is thrombocytopenia which correlates with the

severity of the disease. Fall in fibrinogen levels (<200mg/dl) is unusual in

the absence of abruption. PT and aPTT should be done only if the

platelet count is <1 lakh/cumm.

Management of mild Pre-eclampsia:

Depends upon

a) Severity of Pre-eclampsia

b) Gestational age of the fetus

c) Maternal and fetal status

d) Presence (or) absence of labour

e) Level of neonatal services available

22

A) Gestational age ≥ 37 weeks

Patients with mild Pre-eclampsia at ≥ 37 weeks should be

delivered. There is no benefit in continuing pregnancy.

The HYPITAT Trial9(Hypertension and Pre-eclampsia Intervention

Trial at Term) showed that women with gestational hypertension or mild

Pre-eclampsia had better maternal outcome and same neonatal outcome

with induction at ≥ 37 weeks compared with expectant management.

Maternal Outcome

Induction

n=377 Expectant

n=379 RR

(95% CI)

Composite Adverse outcome 31% 44% 0.71 (0.59-0.86)

HELLP 1% 3%

Pulmonary Edema 0 1%

Abruptio placentae 0 0

Eclampsia 0 0

Maternal ICU 2% 4%

Severe systolic HTN 15% 23% 0.63 (0.46 – 0.86)

Cesarean Delivery 14% 19% 0.75 (0.55-1.04)

23

HYPITAT Randomized Trial9

Neonatal Outcome

Induction

% Expectant

%

Composite adverse outcome 6 8

Perinatal deaths 0 0

Apgar <7 at 5 mins 2 2

Cord pH <7.05 3 6

NICU Admission 3 2

RDS 0.25 0.25

(Koopmans et al Lancet 2009)

B) Gestational age between 24 and 36 weeks:

Depends upon.

Maternal Evaluation:

Ask for symptoms of severe Pre-eclampsia

Check for BP 4 times a day

Daily body weight, urinary dipstick evaluation

Laboratory evaluation hematocrit with platelet count, LFT (AST,

ALT), Serum creatinine, BUN and Serum Uric Acid, 24 hrs urinary

protein and spot protein creatinine ratio.

24

Fetal evaluation:

Daily fetal movement count

Biweekly NST and AFI

Fetal biometry every 3 weeks

Umbilical and cerebral Doppler fortnightly.

If the initial evaluation is negative the risk of progression is

minimal. So continue expectant management till 37 weeks.

If the evaluation shows any abnormality termination of pregnancy

can be considered after a course of steroids.

Role of Anti-Hypertensives:

a) NICE guidelines suggest that start anti-hypertensives in women

with moderate hypertension with aim to keep BP <150/80-

100mmHg.

b) Mild hypertension with other markers of severe disease.

c) Mild hypertension with co-morbid conditions.

Role of corticosteroids for lung maturity:

If the gestational age is <34 weeks, give Inj. Betamethasone 12mg

intramuscularly two doses 24 hours apart.

25

RCOG green top guidelines15 shows single course of antenatal

steroids reduce the risk of

Neonatal death by 31%

RDS by 44%

Intraventricular hemorrhage by 46%

(Grade A recommendation evidence level 1++)

Delivery:

Induction of labour with prostaglandins and vaginal delivery

attempted.

Continue anti-hypertensive treatment.

Maintain BP <150/100mmHg

Epidural analgesia / anesthesia is the procedure of choice.

Active management of 3rd stage to avoid PPH. Ergometrine is

contraindicated.

SEVERE PRE-ECLAMPSIA MANAGEMENT

The main objectives of our management are:

a) Seizure prevention

b) Hypertensive control

c) Delivery of the baby

26

A) Seizure Prevention:

ACOG recommendations3 are all women with severe pre eclampsia

should have MgSO4 prophylaxis. MgSO4 is a peripheral anticonvulsant

acts by blocking the neuromuscular transmission by decreasing acetyl

choline release. The Magpie trial10 2002(Magnesium sulphate for

prevention of eclampsia) shows 58% risk reduction of eclampsia with

magnesium sulphate.

The Multinational Eclampsia Trial Collaborative Group study11

summarized that MgSO4 is associated with lower incidence of recurrent

seizures.

It can be given intravenous (or) intramuscular.

Intravenous regimen

Loading dose : 4 or 6g iv over 20 mins (20%)

Maintenance dose (50%) 1-2gm iv per hour.

If convulsions recur 2g slow iv.

Intramuscular regimen: (Pritchard’s regime)

Loading dose:

a) Intravenous : 20ml of 20% MgSO4 4gm slow iv

b) Intramuscular : 10ml of 50% MgSO4 (5gm) in each buttock

27

Maintenance dose:

5gm (50% MgSO4 10ml) deep intramuscular in alternate buttock

every 4 hours.

It should be continued till 24 hours after delivery (or) after last

convulsion whichever is later

Therapeutic level should be maintained at 4-8 mEq/Lit.

Monitoring for magnesium toxicity:

Urine output should be atleast >30ml / hr.

Patellar reflex should be present.

Respiration rate > 14 breaths / minute

Plasma Magnesium Concentration

Effect

8-10mEq/lit Absent patellar reflex

First sign of impending toxicity

>12mEq/lit Respiratory depression and

paralysis

28

ANTIDOTE:

10ml of 10% solution of calcium gluconate intravenous over 3

minutes.

Acute Management of Severe Hypertension:(ACOG 2012)

When the systolic BP is ≥160mmHg or diastolic BP ≥110mmHg

and persistent for 15 min it is called severe hypertension.

Treatment

1) IV Labetalol

First drug of choice

Combined alpha and beta adrenergic blocker

Intravenous bolus dose 20-40mg (Maximum 300mg/hr)

Continuous IV infusion (1-2 mg/min)

2) IV bolus doses of Hydralazine:

Direct arteriolar smooth muscle dilator

Intravenous bolus dose starting at 5mg increasing by 5mg

every 20 minutes (Maximum 25mg)

3) Oral Nifedipine:

10-20mg repeated every 20 minutes maximum upto 60mg.

29

Delivery of the fetus:

If the gestational age is ≥34 weeks deliver immediately.

If the gestation age is <24 weeks, it is better to allow early delivery

in these patients because expectant management carries a high maternal

and perinatal mortality and morbidity.

Sibai et al (1985)5 reported that expectant management causes

16.7% eclampsia and HELLP syndrome and ATN in 5% of individuals.

The overall perinatal mortality was 87%.

Gestational age between 25 weeks and 33 weeks:-

A systematic review suggests that expectant management of severe

Pre-eclampsia at these gestational age may give some additional benefit

for the fetus at the expense of additional maternal risk. But however an

another study named MEXPRE Latin study disproves this concept.

Following guidelines to be practiced during expectant management.

Hospitalisation

Daily weight, input output chart

Daily fetal movement count

Antihypertensive treatment to be continued

Course of steroids

30

Lab investigations every other day

Daily NST

AFI twice weekly

Umbilical and MCA Doppler twice every week

Ultrasound for fetal growth once in 2 weeks

Sibai and barton (2007)12

Expectant management to be discontinued in the following

settings:

Maternal:

Apperance of imminent symptoms

Signs of pulmonary edema

Hypertension refractory to treatment

Urine output <500ml/24 hours (or) Sr. Creatinine> 1.5mg/dl

Persistent thrombocytopenia <1 lakh/cu.mm.

When abruption is suspected.

Fetal:

Severe fetal growth restriction <5th centile for GA.

Umbilical artery Doppler shows diastolic flow reversal

persistant severe oligo (AFI <5cm).

Fetal demise

Biophysical profile < 4 done 6 hours apart

31

Delivery:

Mode of delivery depends on gestational age, fetal conditions and

favourability of bishop’s score.

Vaginal delivery is preferred by induction of labour with

prostaglandins.

Continuous electronic fetal monitoring is must during labour to

diagnose fetal distress or hyperstimulation.

In case of cesarean delivery regional anesthesia is the anesthesia of

choice, if there is no contraindications such as coagulopathy or

thrombocytopenia.

COMPLICATIONS OF PRE-ECLAMPSIA:

1. HELLP Syndrome

WEINSTEIN coined the term HELLP as a unique variant of pre-

eclampsia.

Hemolysis

Abnormal peripheral blood smear (burr cells,schistocytes)

Elevated bilirubin > 1.2 mg/dl

Low serum haptoglobin

Increased LDH > twice the upper limit of normal (>600IU/l)

Elevated Liver enzymes:

Elevated AST, ALT > 72 IU/L

Low Platelet Count <1 lakh/mm3

32

MISSISSIPPI CLASSIFICATION:

For assessing the severity

Class I : Severe Thrombocytopenia <50000/mm3

Class II : Moderate thrombocytopenia

Platelet count 50000 to 100000/mm3

Class III : Mild thrombocytopenia

Platelet count 100000 to 150000/cumm

TENNESSEE SYSTEM:13

Classifies HELLP as

Complete

Incomplete

All three parameters Abnormal

One/two of the three as Abnormal

(AST/ALT, LDH, Platelets) (AST/ALT, LDH, Platelets)

It carries 1% risk of maternal mortality as a consequence of

abruptio placentae with DIVC, acute renal failure and pulmonary edema.

33

Maternal Morbidity:

1) Disseminated intravascular coagulation - 10-15%

2) Abruptio placentae - 10-15%

3) Acute renal failure - 5-8%

4) Pulmonary edema - 6-8%

5) Adult respiratory distress syndrome - 1─2%

6) Death - 1%

The HELLP syndrome develops either antepartum (70%) or

Postpartum (30%) (Sibai and associates).This postpartum HELLP mostly

occurs within 48 hours of delivery. Among this 80% associated with

antenatal pre-eclampsia and 20% is not associated with pre-eclampsia.

Increased incidence of pulmonary edema and acute renal failure is seen in

HELLP patients who are not having antenatal pre eclampsia.

Differential Diagnosis:

Cholecystitis

Appendicitis

Acute fatty liver of pregnancy

Hemolytic Uremic Syndrome

Hepatic Encephalopathy

Systemic lupus erythematosus

34

Treatment consists of crystalloids, antithrombotics, Steroids and

infusion of fresh frozen plasma.

If gestational age is >34 weeks immediate delivery is indicated or

else the pregnancy can be terminated after a course of steroids. Vaginal

delivery is a consideration. If it does not happen 12 hours after induction

consider cesarean section.

Platelets to be transfused if count is <50000/cumm. At present,

steroids for the treatment of HELLP is not recommended.4

Consider general anesthesia if the platelet count is <75000/cumm.

Platelets to be transfused when the count falls <40000/cumm

Keep a sub fascial drain during closure.

During postpartum platelet count will reach a nadir in 24-48 hours.

But an upward trend will be seen by 4th postpartum day in patients those

who are recovering without any complications.

35

PULMONARY EDEMA:

It is the most common complication of severe pre-eclampsia and

eclampsia, usually occurs in the postpartum period. It is usually as a

result of aggressive use of crystalloids for intravascular volume

expansion in a patient with oliguria.

It typically presents as respiratory distress such as dyspnea,

tachypnea and cough with expectoration of pink frothy sputum. On

examining the patient there will be a fall in oxygen saturation and

bilateral diffuse crepitation on auscultation.

Treatment consists of propped up position, nasal oxygen by mask

and furosemide 20-40mg iv every 6th hourly. There is usually a dramatic

response to furosemide with profuse diuresis and improvement of

respiratory symptoms.

ACOG (2002)3 recommends central venous pressure monitoring

only in severe pre-eclamptic women with cardiac disease or renal disease

or in cases of refractory hypertension.

36

ACUTE RENAL FAILURE:

Oliguria in severe pre-eclampsia is generally due to hypovolemia

and responds to increasing the rate of intravenous fluid administration.

Once the women is not responding to fluid challenge it is necessary to

review the pathophysiology of oliguria.

Severely hypertensive women with increased hematocrit needs

treatment with vasodilators whereas normotensive or mildly hypertensive

with low hematocrit needs aggressive diuresis.

In rare cases oliguria is renal in origin due to ATN. This usually

occurs in the setting of pre-eclampsia with severe abruption and DIVC.

These patients may require dialysis but” recovery is the rule.”

INTRACRANIAL HEMORRHAGE:

Intracranial bleeding is the leading cause of death in pre-

eclampsia.

The following things are attributed:

a) Underestimation of severity of disease.

b) Failure to use anti hypertensives to extreme elevations of blood

pressure.

c) Discharge from the hospital before obtaining adequate control of

hypertension.

37

In an analysis Stroke in association with pre-eclampsia and

eclampsia was that the correlation of this event is the systolic BP, not the

diastolic BP, so they suggested to start anti-hypertensive when the

systolic BP reaches 150mmHg.

Most patients got admitted in the hospital in a comatose stage

following the onset of headache and convulsions at home. The diagnosis

is confirmed by CT/MRI. It carries a very poor prognosis. Here

“Recovery is the exception rather than the rule”.

POSTPARTUM CARE:

BP should be closely monitored 4 times a day for first 2 days. Once

in a day for 2 weeks start antihypertensives if BP is > 150/100mmHg.

Dosage can be reduced if it falls below 130/80mmHg. Anti-hypertensives

can be stopped if normal BP is maintained for 48 hours.

Educate the women regarding occurrence of postpartum eclampsia

and pulmonary edema.

She has to be re-evaluated at 6 weeks postpartum.

38

CONTRACEPTION:

PPIUCD may be safely inserted in these women (or)

Progestin only pills (or)

Progestin only injectables can be prescribed at 6 weeks postpartum.

(or) Low dose OC pills in these individuals is considered as WHO

category-2.

IUCD can be inserted at 12 weeks postpartum

(or) Barrier method of contraception may be advised.

PREVENTION:

I) Primary prevention

II) Secondary prevention

I) PRIMARY PREVENTION

A) Pre-pregnancy:

Lengthier sexual relationship preceding first pregnancy.

Ideal BMI before conception.

Periconceptional folic acid and Vit B12 these supplements

operate via lowering maternal homocysteine levels.

If patient is a known diabetic / hypertensive adequate control

several months before conception.

39

B) Prenatal – Prediction of Pre-Eclampsia

It helps in stratifying women as high risk group so that intensive

surveillance can be done.

TESTS RELATED TO EXAMPLES

I) Placental perfusion a) Roll over test

b) Isometric hand grip test

c) Angiotensin II infusion test

d) Mean arterial pressure in

midtrimester

II) Fetoplacental Unit –

Endocrine dysfunction

Increased HCG, AFP, Estriol, Low PAPP-A

Low inhibin

III) Renal dysfunction Serum Uric Acid, Microalbuminuria,

Hypocalciuria

IV) Endothelial

dysfunction/ oxidative

stress

CRP, Hyperhomocysteinemia,

Antiphospholipid antibodies,

Plasminogen activator inhibitor (PAI)

(PLGF)

(VEGF)

Soluble FMS – like Tyrosine Kinase

Receptor -1 (sFLT-1)

Others Antithrombin III , Free fetal DNA

40

Angiotensin Sensitivity Test:

Degree of sensitivity to angiotensin II increased several weeks

before clinical symptoms.

Roll Over Test:

Positive test denotes elevation of 20mmHg or more in BP when the

patient rolls over from lateral decubitus to supine position.

Mean Arterial Pressure in Midtrimester:

Elevation of midtrimester MAP >90mmHg was proposed but it is a

better predictor of gestational hypertension than of pre eclampsia.

Urinary Calcium:

Pre-eclampsia is associated with hypocalciuria. If the 24 hr urinary

calcium is <12mg/dl it has 85% of positive predictive value and 91% of

negative predictive value. This test done in selected patients with high

apriori risk.

Urinary artery Doppler:14

It is done at 22-24 weeks of gestation. Significance of pulsatality

index >95th percentile with bilateral notching in uterine artery is

a. Pre eclampsia with FGR occurs in 69%.

b. Pre eclampsia without FGR occurs in 24%.

41

II) SECONDARY PREVENTION:

Following things are suggested

Lifestyle modification:

Diet and Exercise

Salt restricted diet

Nutritional Supplements:

Calcium supplementation

Magnesium / Zinc supplementation

Garlic

Antioxidant Vitamins C & E

Medications:

Nitric Oxide donors

Low molecular weight heparin

Diuretics

Progesterone

Anti-hypertensive medications

But ACOG is currently not recommending these supplements as

there is no evidence available.

42

Role of Low Dose Aspirin:16

Many trials have evaluated the role of Low Dose Aspirin for

prevention of pre eclampsia. There was a meta analysis named The

Perinatal Antiplatelet Review of International Studies (PARIS)

Collaborative Group which analyse the safety and efficacy of aspirin in

pre eclampsia prevention. The results of this analysis showed that Low

Dose Aspirin decreases the risk of Pre eclampsia by 19% and fetal death

by 16%.

43

NICE CLINICAL GUIDELINES 2011 RECOMMENDATIONS

Hypertensive disease during previous pregnancy

Chronic kidney disease

Autoimmune disease such as SLE or APLA.

Type 1 or type 2 diabetes

Chronic hypertension

These individuals are at high risk for pre eclampsia. They

should take aspirin 75 mg OD daily from 12 weeks till delivery.

Moderate risk factors:

a) Primi

b) Elderly > 40 years

c) Prolonged birth interval >10 years

d) Pre conceptional BMI > 35kg/m2

e) Positive family history of pre eclampsia

f) Multiple gestation

If >1 moderate risk factor is present take 75mg aspirin OD from 12

weeks to birth.

44

RISK OF RECURRENCE OF HYPERTENSIVE DISORDERS OF

PREGNANCY (NICE Clinical Guidelines 2010):2

Women with previous history of GHT,

Risk % in future

pregnancies

1. GHT 16% to 47%

2. Pre eclampsia 2% to 7%

Women with previous history of Pre eclampsia

Risk % in future

pregnancies

1. GHT 13% to 53%

2. Pre eclampsia 16%

3. Pre eclampsia with complications such as severe pre eclampsia, HELLP, Eclampsia or led to birth <34 weeks

25%

4. Pre eclampsia led to birth <28 weeks 50%

LONG TERM MATERNAL OUTCOME:

Chronic hypertension (4fold )

Ischemic heart disease

Stroke

Venous thromboembolism

Preeclampsia is a screening test for future health.

45

KIDNEY IN PRE-ECLAMPSIA

In a normal pregnancy the kidneys undergo considerable vascular

changes. So in preeclampsia the renal system is very important in both

the pathogenesis and pathological sequelae of the disease.

The classical pathological change associated with pre-eclampsia is

“glomerular capillary endotheliosis” which was described by Spargo et al

in 1959.

In the early stage of disease there is intracapillary hypercellularity

results in capillary dilatation or “ballooning effect”. Then later in the

disease the capillaries are longitudinally expanded and attain a “cigar-

shaped” morphology. This increased capillary cellularity may push some

of the loops into the proximal tubule – a phenomenon known as

“pouting”.

As a result of this the glomeruli are effectively obstructed giving

rise to the bloodless appearance. In severe cases the mesangial cells may

infiltrate the basement membrane and ultimately make the membrane

thick.

46

Renal hemodynamics in normal pregnancy & Preeclampsia:

Renal blood flow increased substantially in human pregnancy. It is

reported that Effective Renal Plasma Flow (ERPF) and Glomerular

Filtration Rate (GFR) increase by 50-55% and 40-60% respectively.

These are as a consequence of renal vasodilatation of both the afferent

and efferent arteriole without concomitant elevation in glomerular

pressure. The stimulus for gestational renal vasodilatation is mediated via

nitric oxide pathways. The ovarian hormone relaxin also plays an

important role.

In pre-eclampsia on an average there is a 32% reduction in GFR

and a 24% reduction in ERPF compared to normal pregnancy. It is due to

selective increase in efferent arteriolar resistance.

Lindheimer (1999) and Moran et al (2003)7

Comparison of renal hemodynamics

Normal Pregnancy Pre-eclampsia

pregnancy

GFR ml/min 133 90

ERPF ml/min 649 487

FF% 20.4 18.7

47

Renal involvement in pre-eclampsia:

Serum Creatinine:

It is often used as a measure of renal function but it has poor

sensitivity because the levels may remain within the normal range till

>50% renal function is compromised. Also it levels are affected by

diurnal variation and dietary factors. So as an alternative 24 hour

creatinine clearance is used. It relies upon creatinine freely filtered at the

glomerulus and minimal tubular secretion. In pregnancy the level rises

from 92ml/min to maximum 125ml/min as a result of increased renal

perfusion. The average serum creatinine during pregnancy is 0.6mg/dl

and value >0.8mg/dl is suspicious.

Serum Urea (or) Blood Urea Nitrogen:

The levels are influenced by GFR, tubular re-absorption, dietary

protein intake etc.

Mean Serum levels of Urea & Creatinine in pregnancy:

Non-

pregnantI

trimesterII

trimester III

trimester

S. Creatinine Umol/Lit. 73 65 51 47

S. Urea 4.3 3.5 3.3 3.1

48

Serum Uric Acid:

Although hyperuricemia does not predict the development of pre-

eclampsia, the levels of uric acid correlates well with fetal and maternal

morbidity and severity of the renal lesion.

The causes of hyperuricemia has not been established definitively.

The proposed mechanisms are

a) Decrease in GFR

b) Decreased tubular secretion

c) Increased re-absorption

d) Increased placental production secondary to ischemia and

trophoblast breakdown.

e) Increased expression of Xanthine oxidase activity .

Serum Cystatin C:

This is a newer indicator of GFR which is independent of age,

gender and muscle mass. The levels are rised in pre-eclampsia and the

increased serum cystatin C correlate well with the severity of glomerular

endotheliosis. So it is emerging as a promising marker of renal

impairment in pre-eclampsia.

49

Proteinuria:

Renal handling of protein:

In the normal healthy pregnant female glomerulus is relatively

impermeable to large protein and permeable to smaller protein <30Ao.

These filtered protein is re-absorbed in proximal tubules and some of

them excreted in urine. In pregnancy both the total protein excretion and

urinary albumin excretion are increased after 20 weeks gestation upper

limit 300mg/24 hr and 20mg/24 hr respectively.

So the normal renal handling of protein depends upon

a) Integrity of the glomerular barrier

b) Proximal tubular re-absorption

Hence proteinuria is a consequence of diminished integrity of

glomerular barrier (or) defective tubular re-absorption.

So the degree of proteinuria seen in pre-eclampsia particularly

when the reduced GFR is taken into account is explained by loss of

charge selectivity. As a result the protein load delivered to the proximal

tubule increases which rapidly saturates the reabsorption transport

mechanisms.

50

METHODS OF PROTEINURIA ESTIMATION:

I) ESTIMATION OF 24 HOUR URINARY PROTEIN:

This is the gold standard test for proteinuria estimation. But the

following limitations to be considered.

Collection is cumbersome

Needs admission of the patient

Requires about one day (time consuming) for collection

Subjected to errors such as collection and storage

The patient compliance is poor

There will be a delay in diagnosing the severity of the disease.

METHOD:

Patients were instructed to collect urinary sample for 24 hours

(from morning 6 am after discarding the first sample to next day morning

6 am including the first morning sample). In our lab quantitative

estimation of proteinuria was done by turbimetric method using

sulphosalicylic acid.

The advantage is this can be easily performed . It will detect other

proteins such as globulin and Bence Jones protein in addition to albumin.

51

Total 24 hour urinary volume is measured and the adequacy of

sample was cross checked with creatinine in the sample to the predicted

creatinine concentration.

0.5 ml of urinary sample is taken to this 2 ml of 3% sulphosalicylic

acid is added. It forms a white turbitidy depends on the amount of

protein. It is measured using Auto Colorimeter Model No:1000 at Optical

Density 640 nm. Eg) If OD is 0.05 the amount of protein is 8 mg/ dl

likewise a standard method is followed.

Total 24 hour Urinary Protein= Urinary Protein Concentration mg/dl × 24 hr urinary volume in ml ----------------------------------------------- 100

II) URINARY DIPSTICK ANALYSIS:

Most common method for screening of proteinuria.

Advantages:

Inexpensive

Easily performed

Rapid results

Does not require trained personnel.

52

Disadvantages:

Results are being influenced by maternal hydration status.

Diurnal variation of protein excretion

Exercise

In the presence of infection

Urinary contaminates such as blood, phosphates etc.

In our hospital we are using Rapi Scan Reagent strips for urine

analysis which gives the results in 60 seconds.

Grades of Proteinuria:

0 Absent

Trace =0.15 to 0.3 g/L

1+=>0.3g/L

2+=>1g/L

3+=>3g/L

4+=>5g/L

III) URINARY SPOT PROTEIN CREATININE RATIO:

It is done in next morning random sample. Here the diurnal

variation of urinary specific gravity due to changing GFR affects the

urinary protein concentration at different times of the day. To avoid this

urinary protein concentration is divided by GFR independent spot urinary

creatinine level.

53

Advantages:

Can be ordered on OP basis.

Results available in a short time.

METHOD OF ESTIMATION:

Urinary protein concentration is measured by Sulphosalicylic acid

method.

Estimation of urinary creatinine is based on Jaffes principle.

On addition of picric acid to the urinary creatinine at alkaline pH it

forms a orange colour creatinine alkaline picrate. The magnitude of

change in colour is measured using colourimeter at 492nm. The

creatinine concentration is calculated by calibrating against solution of

known creatinine.

Urinary PCR is calculated by dividing urinary protein

concentration by urinary creatinine concentration.

54

1) SAPNA V AMIN ET AL[2014]17

The objective of this study is to evaluate the efficacy of urinary

spot protein creatinine ratio and urinary dipstick analysis for prediction of

24 hour proteinuria in hypertensive disorders of pregnancy.

This study was conducted at Kasturba Hospital, Manipal. In this

study totally 102 pregnant women who were fulfilling the inclusion

criteria were studied. For all those women pre admission urinary dipstick

and urinary PCR were performed on a random urine sample. After

admission 24 hr urinary sample was collected and proteinuria estimated.

Of these 102 patients 78 patients [76.5%] had significant proteinuria ie

≥300mg/24 hour. Urinary dipstick method showed 59% sensitivity and

67% specificity for prediction of significant proteinuria, where as urinary

PCR was showing 82% sensitivity and 12.5% false positive rate for cut

off value of 0.45.So this study suggestion that Urinary PCR is a reliable

investigation to assess proteinuria.

55

02) SHAZIA MAJID KHAN ET AL (2014)18

A comparison of spot urine protein creatinine ratio vs 24 hours

urinary protein excretion in women with pre-eclampsia.

This study was conducted at Sheikh Zayed Medical College,

Pakistan.

The objective is to evaluate the diagnostic accuracy of spot urine

protein-creatinine ratio for the diagnosis of proteinuria among patients

with pre-eclampsia taking 24 hours urinary protein concentration

≥300mg/24 hrs as gold standard. This was a cross sectional study. Totally

551 patients with pre-eclampsia were included. Spot protein creatinine

ratio ≥0.3 was cut off for proteinuria.

Diagnostic accuracy was detected by determining sensitivity,

specificity. Results showed that spot urinary protein creatinine ratio has

95.8% sensitivity, 94.8% specificity and 91.6% diagnostic accuracy.

So this study concluded that spot urinary protein / creatinine ratio

can provide excellent discrimination between patients with and without

significant proteinuria. So this test can be used as an alternative for 24

hours urinary protein.

56

03) REVANKAR MANOHAR VIJAYA ET AL[2013]19

A correlative study of 24 hour urinary protein and random

urinary protein creatinine ratio in hypertensive pregnant women.

A total of 50 pregnant women with gestational hypertension and

pre eclampsia were selected and conducted for 2 years at Govt Lady

Goschen Hospital, Mangalore. The patients were instructed to collect the

24 hr urine and a single voided urine sample was obtained soon after 24

hour collection. Both values were estimated. A fair correlation coefficient

[r2=0.902] was observed between these two which was statistically

significant at p<0.001.

04) SANCHEZ – RAMOS L AND ASSOCIATES [2013]

Urinary protein creatinine ratio for the prediction of

significant proteinuria in patients at risk for pre eclampsia.

This is a meta analysis to investigate the diagnostic accuracy of the

protein creatinine ratio from random urine samples to confirm the

presence of proteinuria. Eligible studies published between Jan 1996 to

April 2010 was retrieved. Accuracy of this ratio was estimated and it is

compared with 24 hr urinary collection.

57

Totally 24 trials with 3186 aggregate participants were included.

Pooled sensitivities and specificities were 91% and 86.3% respectively.

Pooled positive likelihood ratio and pooled negative likelihood ratio was

6.7 and 0.10 respectively.

From this analysis authors have concluded that random urinary

protein creatinine ratio provides useful evidence to rule out the presence

of significant proteinuria. A cut off value of >0.3 is associated with the

best accuracy.

05) NAZLI HOSSAIN AND ASSOCIATES [2013]20

Spot protein creatinine ratio and 24 hour urinary protein

excretion – Diagnostic accuracy in women with pre eclampsia.

This was a prospective study done at department of OBG Civil

hospital Karachi.

Total of 85 women with pre eclampsia were enrolled in the study.

Four were excluded due to incomplete data. The mean age of the women

28+-4.62 years range[18-35] years. The mean PCR was 1.14 +1.87 mg/dl

[0.03to9.73]. The correlation co-efficient for the protein creatinine ratio

against the 24 hour urinary protein excretion was r=0.81, p<0.001

58

The area under the curve is 0.90[0.834-0.965]. The cutoff point of

0.14 was identified as the best threshold to detect protein excretion of

300mg/24 hours with a sensitivity 82% and specificity 79%, positive

predictive value 81.1% and negative predictive value 79%.

This study concluded that there was a strong correlation between

spot protein creatinine ratio and 24 hour urinary protein excretion.

06) AMITA SHARMA ET AL [2013] 21

Diagnostic accuracy of spot urine protein creatinine ratio and

its comparison with 24 hr urinary protein for pre eclampsia

prediction.

This study was conducted at department of OBG GSVM medical

college Kanpur.

Logistic regression analysis and ROC curve analysis have been

used to analyse data and the results are compared. There was a strong

correlation between the spot protein creatinine ratio and 24 hr urinary

protein excretion [Pearsons correlation coefficient r2=0.71;p<0.0001].

The optimal spot protein creatinine ratio cut off point was 0.25 for

300mg/24 hr urinary protein with 69% sensitivity and 75% of

specificity.

59

So urinary spot protein creatinine ratio can be used as an

alternative method for proteinuria evaluation.

07) ESLAMIAN L AND ASSOCIATES [2011] 23

Random urine protein creatinine ratio as a preadmission test in

hypertensive pregnancies.

This study was conducted to evaluate the value of random urinary

spot protein creatinine ratio in detection of significant proteinuria.

Random urinary samples and routine 24 hr urine collection were collected

from 100 hypertensive pregnant woman. Reliability of this ratio was

assessed using ROC curve and 24 hr urinary protein has been taken as

standard.46% patients had significant proteinuria. Area under ROC curve

to predict proteinuria was 0.926[95% CI ;p<0.001].

A cut off value of 0.22 is taken as best for prediction of significant

proteinuria with sensitivity, specificity, positive predictive value and

negative predictive value of 87%,92.6%,90.% and 89.3% respectively.

The conclusion of this study was random urinary protein creatinine

ratio is a simple , inexpensive and excellent alternative for 24 hr urinary

protein.

60

08) SHAHBAZIAN ET AL [2008] 22

A comparison of spot urinary protein creatinine ratio with 24

hr urinary protein in women with pre eclampsia.

This study was conducted at department of obstetrics and

Gynaecology, Imam Khomeini Hospital, Ahwaz, Iran.

A total of 81 pregnant women with pre eclampsia were

prospectively studied for proteinuria. In this study urinary spot PCR was

determined in mid stream sample and 24 hr urine collected on the next

day and the amount of protein excretion measured. The ROC curve

analysis was used to determine the best discriminator value of urinary

protein creatinine ratio.

There was a strong correlation found between the spot PCR and 24

hr urinary protein[r=0.84,p<0.001].The optimal spot PCR cut off point

was 0.2 for 300mg/24 hr protein. The sensitivity , specificity, positive

predictive value and negative predictive value of this value are

91.2%,87.8%, 94.4% and 96.8% respectively. The spot protein creatinine

value less than 0.19 yielded a sensitivity of 100% for exclusion of pre

eclampsia.

The conclusion of this study was urinary spot PCR has significant

correlation with 24 hr urinary protein.

61

09) BANSALBHAVANA ET AL (2007)25

Comparison of protein / creatinine ratio in single voided urine

sample with 24 hours urine protein for estimation of proteinuria in

pregnancy induced hypertension.

This study was conducted in Dayana Medical College and

Hospital, Ludhiana.

50 hospitalised pregnant women with suspicion of pregnancy

induced hypertension with more than 20 weeks gestational age are

included in this study. Urine sample for 24 hours urine protein followed

by next voided spot sample for protein/creatinine ratio were collected.

Linear regression was used to determine the correlation between 24 hours

urinary protein and protein/creatinine ratio.

This study result showed that there was a significant correlation is

found between these two (r2=0.83, P=0.000). It also showed statistically

significant linear relationship. This study concluded that urinary protein /

creatinine ratio appears to be an excellent alternative to 24 hours urinary

protein. A level above 0.2 is a good indicator of significant proteinuria.

62

10) JOSEPH EIGBEFOH AND ASSOSIATES [2006] 24

Protein creatinine ratio in random urine specimens for

quantification of proteinuria in pre eclampsia.

The purpose of this study is to determine the urine protein

creatinine ratio correlates with the 24 hr value to confirm the diagnosis

of preeclampsia. Totally 86 patients with hypertensive disorders of

pregnancy were included and 24 hr urinary sample was collected. A

protein creatinine ratio and a urinary dipstick test for protein was done on

a random sample on the next day.

The sensitivity and false negative value of this ratio and urinary

dipstick are 92%,8% and 81% ,19%.The specificity and false positive

values of both urinary PCR and dipstick are 86%,14% and

47%,53%.Thus urinary dipstick has the risk associated with making

decisions based on a positive dipstick reaction .So this study concluded

that protein creatinine ratio is reliable and accurate for proteinuria

estimation correlating well with 24 hr urinary protein much more reliable

than dipstick test in clinical practice.

Statistics

63

STATISTICS

Age group * Urinary PCR significance

Crosstab

Urinary PCR significance

0 1 Total

Age group

1

Count 8 5 13

% within Age group 61.5% 38.5% 100.0%

% within Urinary PCR significance

42.1% 6.2% 13.0%

% of Total 8.0% 5.0% 13.0%

2

Count 8 58 66

% within Age group 12.1% 87.9% 100.0%


42.1% 71.6% 66.0%

% of Total 8.0% 58.0% 66.0%

3

Count 3 18 21

% within Age group 14.3% 85.7% 100.0%


15.8% 22.2% 21.0%

% of Total 3.0% 18.0% 21.0%

Total

Count 19 81 100

% within Age group 19.0% 81.0% 100.0%


100.0% 100.0% 100.0%

% of Total 19.0% 81.0% 100.0%

Chi square=17.618 P=0.000<0.001 significant.

64

Chi-Square Tests

Value df Asymp. Sig.

(2-sided)

Pearson Chi-Square 17.618a 2 .000

Likelihood Ratio 13.944 2 .001

Linear-by-Linear Association 8.197 1 .004

N of Valid Cases 100

2 cells (33.3%) have expected count less than 5.

The minimum expected count is 2.47.

In 100 study patients 13 patients belong to <20 years.66 patients

belong to 20 to 30 years of age, 71.6% of significant PCR was found in

this age group. Otherwise 87.9% of patients between 20 to 30 years of

age had significant urinary PCR.P value was 0.000<0.001.So there was a

statistical significant association found between the age group and urinary

PCR in our study.

65

The same result was shown as bar diagram.

66

Gestational Age group * Urinary PCR significance

Crosstab


0 1 Total

Gestational Age group

1

Count 6 35 41

% within Gestational Age group

14.6% 85.4% 100.0%


31.6% 43.2% 41.0%

% of Total 6.0% 35.0% 41.0%

2

Count 8 39 47


17.0% 83.0% 100.0%


42.1% 48.1% 47.0%

% of Total 8.0% 39.0% 47.0%

3

Count 5 7 12


41.7% 58.3% 100.0%


26.3% 8.6% 12.0%

% of Total 5.0% 7.0% 12.0%

Total

Count 19 81 100


19.0% 81.0% 100.0%


100.0% 100.0% 100.0%

% of Total 19.0% 81.0% 100.0%

Chi square=4.633 P=0.099 Not significant.

67

Chi-Square Tests


(2-sided)







Among 100 study patients 41 patients were upto 30 weeks

gestation.47 patients were between 31 to 35 weeks gestation.12 patients

were more than 35 weeks. Since P =0.099, there is no statistical

significance exists between PCR significant and not significant patients

with respect to gestational age in our study.

68

The bar chart shows the relationship between gestational age group and urinary PCR.

69

Gravida * Urinary PCR significance

Crosstab


0 1 Total

Gravida

1

Count 9 52 61

% within Gravida 14.8% 85.2% 100.0%


47.4% 64.2% 61.0%

% of Total 9.0% 52.0% 61.0%

2

Count 9 25 34

% within Gravida 26.5% 73.5% 100.0%


47.4% 30.9% 34.0%

% of Total 9.0% 25.0% 34.0%

3

Count 1 4 5

% within Gravida 20.0% 80.0% 100.0%


5.3% 4.9% 5.0%

% of Total 1.0% 4.0% 5.0%

Total

Count 19 81 100

% within Gravida 19.0% 81.0% 100.0%


100.0% 100.0% 100.0%

% of Total 19.0% 81.0% 100.0%

Chi square= 1.951 P=0.377 Not significant.

70

Chi-Square Tests

Value df Asymp. Sig. (2-

sided)






The minimum expected count is .95.

In 100 study patient 61 patient were primi.39 patients were multi.

64.2% of significant urinary PCR was seen in primigravida or 85.2% of

primi had significant urinary PCR value. P value was 0.377. There was

no statistical significance between obstetric score and urinary PCR in our

study.

71

The bar chart shows the association between obstetrics score and

urinary PCR.

72

Previous History of Pre Eclampsia Gravida * Urinary PCR significance

Crosstab


0 1 Total

Previous history of

pre eclampsia

0

Count 10 12 22

% within Previous history of pre eclampsia

45.5% 54.5% 100.0%


100.0% 41.4% 56.4%

% of Total 25.6% 30.8% 56.4%

1

Count 0 17 17


.0% 100.0% 100.0%


.0% 58.6% 43.6%

% of Total .0% 43.6% 43.6%

Total

Count 10 29 39


25.6% 74.4% 100.0%


100.0% 100.0% 100.0%

% of Total 25.6% 74.4% 100.0%

Chi square = 10.392, P value = 0.001

73

Chi-Square Tests


(2-sided) Exact Sig. (2-sided)

Exact Sig. (1-sided)


Continuity Correctionb 8.145 1 .004


Fisher's Exact Test .002 .001

Linear-by-Linear Association

10.125 1 .001

N of Valid Cases 39

1cells (25.0%) have expected count less than 5.


In this study group of 100 patients 39 were multi. Among them 17

patients had positive previous history of pre eclampsia.58.6% of

significant urinary PCR was found in this group or all the 17 patients with

the positive previous history had 100% significant urinary PCR.P value is

0.001.There is statistical significant association found between the

previous history of pre eclampsia and urinary PCR in our study.

74

The bar chart shows the relation between urinary PCR and

previous history of pre eclampsia.

75

Urinary dipstick significance * 24 hr urinary protein significance

Crosstab

24 hr urinary protein significance

0 1 Total

Urinary dipstick significance

0 Count 0 26 26

% of Total .0% 26.0% 26.0%

1 Count 20 54 74

% of Total 20.0% 54.0% 74.0%

TotalCount 20 80 100

% of Total 20.0% 80.0% 100.0%

McNemar test :p=0.461

Kappa statistics:=-0.292

Chi-Square Tests

Value Exact Sig. (2-sided)

McNemar Test .461a


Binomial distribution used.

Symmetric Measures

Value Asymp. Std.

Errora Approx.

Tb Approx.

Sig.

Measure of Agreement

Kappa -.292 .043 -2.964 .003

N of Valid Cases

100

Not assuming the null hypothesis.

Using the asymptotic standard error assuming the null hypothesis.

76

The bar chart shows the association between urinary dipstick and

24 hour urinary protein.

77

Single Table Analysis DIP STICK VS.24 HOUR

Positive Negative Total

Positive

54 20 74

73% 27% 100%

67.5% 100%

Negative

26 0 26

100% 0% 100%

32.5% 0%

80 20 100

80% 20% 100%

100% 100%

Parameter Estimate Lower - Upper

95% CIs Method

Sensitivity 67.5% (56.64, 76.76¹ ) Wilson Score

Specificity 0.0% (0.0, 16.11¹ ) Wilson Score

Positive Predictive Value 72.97% (61.91, 81.77¹ ) Wilson Score

Negative Predictive Value 0.0% (0.0, 12.87¹ ) Wilson Score

Diagnostic Accuracy 54% (44.26, 63.44¹ ) Wilson Score

From the above we infer that urinary dipstick is having 54%

diagnostic accuracy with respect to 24 hr urinary protein and also the

measure of agreement is fair (Mc Nemar 0.461,Kappa test =0.292)

78

Urinary PCR significance * 24 hr urinary protein significance

Crosstab

24 hr urinary protein significance

0 1 Total


0 Count 19 0 19

% of Total 19.0% .0% 19.0%

1 Count 1 80 81

% of Total 1.0% 80.0% 81.0%

TotalCount 20 80 100

% of Total 20.0% 80.0% 100.0%

McNemar p=1.0000

Kappa Statistics =0.968

Chi-Square Tests

McNemar Test Value Exact Sig. (2-sided)

N of Valid Cases 100 1.000a


Symmetric Measures

Measure of Agreement Value Asymp. Std.

Errora Approx.

Tb Approx.

Sig.

Kappa .968 .032 9.686 .000




79

The bar chart shows the relation between urinary PCR and 24 hour

urinary protein.

80

Diagnostic or Screening Test Evaluation SPOT VS 24 HOUR


Positive

80 1 81

98.8% 1.2% 100%

100% 5%

Negative

0 19 19

0% 100% 100%

0% 95%

80 20 100

80% 20% 100%

100% 100%


95% CIs Method

Sensitivity 100% (95.42, 100¹ ) Wilson Score

Specificity 95% (76.39, 99.11¹ ) Wilson Score


Negative Predictive Value 100% (83.18, 100¹ ) Wilson Score


McNemar test =1.000

Kappa test =0.968

The measure of agreement between urinary PCR and 24 hour

urinary protein is almost perfect. From the above table we infer that

urinary PCR is having 99% diagnostic accuracy ,100% sensitivity and

95% specificity with respect to 24 hour urinary protein.

81

Urinary dipstick significance * Urinary PCR significance

Crosstab


0 1 Total

Urinary dipstick significance

0

Count 0 26 26

% within Urinary dipstick significance

.0% 100.0% 100.0%


.0% 32.1% 26.0%

% of Total .0% 26.0% 26.0%

1

Count 19 55 74


25.7% 74.3% 100.0%


100.0% 67.9% 74.0%

% of Total 19.0% 55.0% 74.0%

Total

Count 19 81 100


19.0% 81.0% 100.0%


100.0% 100.0% 100.0%

% of Total 19.0% 81.0% 100.0%

McNemar test p =0.371 Kappa statistics =-0.281

Chi-Square Tests

Value Exact Sig. (2-sided)

McNemar Test .371a



Symmetric Measures

Measure of Agreement Value Asymp. Std.

Errora Approx.

Tb Approx.

Sig.

Kappa -.281 .043 -2.871 .004




82

Bar chart shows the relationship between urinary dipstick and

PCR.

83

Dip vs pcr Results Diagnostic or Screening Test Evaluation


Positive

55 19 74

74.3% 25.7% 100%

67.9% 100%

Negative

26 0 26

100% 0% 100%

32.1% 0%

81 19 100

81% 19% 100%

100% 100%


95% CIs Method

Sensitivity 67.9% (57.12, 77.06¹ ) Wilson Score

Specificity 0.0% (0.0, 16.82¹ ) Wilson Score


Negative Predictive Value 0.0% (0.0, 12.87¹ ) Wilson Score


McNemar =0.371

Kappa test =0.281

Urinary dipstick shows 55% diagnostic accuracy and 67.9%

sensitivity with respect to urinary PCR in our study.

84

Group Statistics


N Mean Std.

Deviation Std. Error

Mean P

Systolic BP

1 81 157.33 12.296 1.366 0.000

0 19 141.89 2.536 .582

Diastolic BP

1 81 101.83 7.370 .819 0.000

0 19 92.11 2.536 .582

Age

1 81 27.56 5.445 .605 0.219

0 19 24.37 5.747 1.318

Independent Samples Test

Levene's Test for Equality of Variances

t-test for Equality of Means

F Sig. t df

Systolic BP

Equal variances assumed

26.279 .000 5.426 98

Equal variances not assumed

10.396 97.410

Diastolic BP


21.414 .000 5.653 98


9.678 84.943

Age


1.533 .219 2.273 98


2.197 26.120

85



Sig. (2-tailed)Mean

Difference Std. Error Difference

Systolic BP

Equal variances assumed .000 15.439 2.845


.000 15.439 1.485

Diastolic BP



.000 9.722 1.005

Age



.037 3.187 1.451



95% Confidence Interval of the Difference

Lower Upper

Systolic BP Equal variances assumed 9.792 21.085

Equal variances not assumed 12.491 18.386

Diastolic BP Equal variances assumed 6.309 13.135

Equal variances not assumed 7.725 11.719

Age Equal variances assumed .404 5.970

Equal variances not assumed .206 6.168

86

One-Sample Statistics

N Mean Std. Deviation Std. Error

Mean

Age 100 26.95 5.616 .562

Systolic BP 100 154.40 12.665 1.267

Diastolic BP 100 99.98 7.730 .773

24 hr urinary volume 100 2.517 .5444 .0544

24 hr urinary protein 100 2178.99 2033.845 203.385

Urinary PCR 100 2.1859 2.02942 .20294

One-Sample Test

Test Value = 0

t df Sig. (2-tailed) Mean Difference

Age 47.985 99 .000 26.950

Systolic BP 121.910 99 .000 154.400

Diastolic BP 129.336 99 .000 99.980

24 hr urinary volume 46.237 99 .000 2.5173

24 hr urinary protein 10.714 99 .000 2178.990

Urinary PCR 10.771 99 .000 2.18590

87

One-Sample Test

Test Value = 0


Lower Upper

Age 25.84 28.06

Systolic BP 151.89 156.91

Diastolic BP 98.45 101.51

24 hr urinary volume 2.409 2.625

24 hr urinary protein 1775.43 2582.55

Urinary PCR 1.7832 2.5886

Group Statistics

Previous history of

pre eclampsia N Mean

Systolic BP 1 17 162.35

0 21 146.86

Diastolic BP 1 17 103.41

0 21 93.43

Age 1 17 27.88

0 21 27.48

24 hr urinary volume 1 17 2.431

0 21 2.538

24 hr urinary protein 1 17 3647.00

0 21 572.76

Urinary PCR 1 17 3.6300

0 21 .5448

88

Group Statistics

Previous

history of pre eclampsia

Std. Deviation Std. Error

Mean

Systolic BP

1 14.954 3.627

0 5.313 1.159

Diastolic BP

1 8.330 2.020

0 2.767 .604

Age

1 3.551 .861

0 3.945 .861

24 hr urinary volume

1 .4786 .1161

0 .5852 .1277

24 hr urinary protein

1 2227.967 540.361

0 641.415 139.968

Urinary PCR

1 2.22786 .54033

0 .64442 .14062

89


Levene's Test for Equality of Variances


F Sig. T df

Systolic BP


15.989 .000 4.428 36


4.070 19.276

Diastolic BP


42.568 .000 5.166 36


4.735 18.866

Age


.100 .754 .330 36


.334 35.552



1.892 .178 -.606 36


-.620 35.991



28.658 .000 6.039 36


5.507 18.154

Urinary PCR


28.594 .000 6.058 36


5.526 18.174

90



Sig. (2-tailed)

Mean Difference

Std. Error Difference

Systolic BP


.000 15.496 3.500


.001 15.496 3.808

Diastolic BP


.000 9.983 1.933


.000 9.983 2.109

Age


.743 .406 1.232


.741 .406 1.218



.548 -.1069 .1763


.539 -.1069 .1726



.000 3074.238 509.075


.000 3074.238 558.195

Urinary PCR


.000 3.08524 .50928


.000 3.08524 .55833

91




Lower Upper

Systolic BP

Equal variances assumed 8.398 22.594


7.534 23.458

Diastolic BP



5.568 14.399

Age

Equal variances assumed -2.092 2.904


-2.065 2.877


Equal variances assumed -.4645 .2507


-.4569 .2431




1902.226 4246.251

Urinary PCR



1.91303 4.25745

92

Regression

Dependent Y Urinary_protein

Independent X Urinary_PCR Urinary PCR

Sample size 100

Coefficient of determination R2 0.9571

Residual standard deviation 423.5148

Regression Equation

y = 35.8547 + 980.4361 x

Parameter Coefficient Std. Error 95% CI t P

Intercept 35.8547 62.4146 -88.0050 to 159.7144 0.5745 0.5670

Slope 980.4361 20.9739 938.8141 to 1022.0581 46.7456 <0.0001

Analysis of Variance

Source DF Sum of Squares Mean Square

Regression 1 391938452.38 391938452.38

Residual 98 17577752.61 179364.82

F-ratio 2185.15

Significance level P<0.001

93

Graph shows linear relationship between 24 hour urinary protein

and spot urinary protein creatinine ratio.

Correlation

Variable Y Urinary_Protein

Variable X Urinary_PCR Urinary PCR

Sample size 100

Correlation coefficient r 0.9783

Significance level P<0.0001

95% Confidence interval for r 0.9679 to 0.9854

0 1 2 3 4 5 6 70

1000

2000

3000

4000

5000

6000

7000

Urinary PCR

urin

ary_

prot

ein

94

ROC curve

Variable Urinary_PCR Urinary PCR

Classification variable hr_urinary_protein_significance

Sample size 100

Positive group : hr_urinary_protein_significance = 1 80

Negative group : hr_urinary_protein_significance = 0 20

Urinary PCR

0 20 40 60 80 1000

20

40

60

80

100

100-Specificity

Sens

itivi

ty

Sensitivity: 100.0 Specificity: 100.0 Criterion : >0.3

95

Area under the ROC curve (AUC)

Area under the ROC curve (AUC) 1.000000

Standard Errora 0.000

95% Confidence intervalb 0.963783 to 1.000000

Significance level P (Area=0.5) <0.0001

a DeLong et al., 1988

b Binomial exact

Youden index

Youden index J 1.0000

Associated criterion >0.3

Criterion values and coordinates of the ROC curve

Criterion Sensitivity 95% CI Specificity 95% CI +LR -LR

≥0.1 100.00 95.5 - 100.0 0.00 0.0 - 16.8 1.00

>0.3 100.00 95.5 - 100.0 100.00 83.2 - 100.0

0.00

>6.3 0.00 0.0 - 4.5 100.00 83.2 - 100.0

1.00

Discussion

96

DISCUSSION

In this study 100 admitted antenatal cases of pre eclampsia with

urinary dipstick value ≥1+ were selected.

General physical and obstetric examination was done for all.

24 hr urinary sample and a next morning random sample for

urinary PCR was collected from all the patients.

Amount of proteinuria was estimated by turbimetric method using

sulphosalicylic acid and urinary creatinine was calculated by jaffes

method.

24 hour urinary protein ≥300mg/24 hr or urinary Protein Creatinine

Ratio ≥0.3 is taken as significant proteinuria.

Among 100 study patients 80 had significant proteinuria. 66% of

the patient were in the age group of 20 to 30 years, among them 87.9%

were significant for urinary PCR.

61% were primi,39% were multi. Among multi 43.6% of patients

were positive for previous history of pre eclampsia. All of them had

significant urinary PCR.

97

The sensitivity and positive predictive value of dipstick is 67.5%

(95% CI, 56.64 - 76.76) and 72.97% (95% CI, 61.91-81.77) respectively.

The diagnostic accuracy is 54% with respect to 24 hour urinary protein.

The sensitivity and positive predictive value of urinary dipstick is

67.9% (95%CI, 57.12-77.06) and 74.32% (95% CI, 63.35-82.9)

respectively. The diagnostic accuracy is 55% with respect to urinary

PCR.

On comparing the 24 hour urinary protein with urinary protein

creatinine ratio the sensitivity and specificity of urinary PCR is 100% and

95% respectively. The positive and negative predictive value is 98.77%

and 100% respectively. The diagnostic accuracy is 99%.

Measure of agreement tests McNemar test =1.000, Kappa statistics

p= 0.968 show perfect agreement. Co-efficient of determination (r2) is

0.9571 which infers a very good correlation between 24 hour urinary

protein and urinary spot protein creatinine ratio.

Youden Index and Area under the ROC Curve =1 which implies

100% accuracy for PCR significant group with respect to 24 hour urinary

protein. In the ROC Curve the value of 0.3 has maximum sensitivity and

specificity.

Conclusion

98

CONCLUSION

From our study we concluded that random urinary spot protein

creatinine ratio has a significant linear correlation with 24 hour

urinary protein in pre eclampsia.

Since the measure of agreement between these two is perfect

urinary spot protein creatinine ratio can be used as an excellent

alternative for the time consuming 24 hour urinary protein

estimation in patients with pre eclampsia.

Also urinary dipstick alone has a poor sensitivity and specificity in

diagnosing proteinuria of pre eclampsia.

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Annexures

PROFORMA

1. NAME

2. AGE

3. IP.NO.

4. OBSTETRIC FORMULA

5. LAST MENSTRUAL PERIOD

6. EXPECTED DATE OF DELIVERY

7. GESTATIONAL AGE

8. DIAGNOSIS

9. SINCE WHEN

10. TREATMENT

11. 24 HOUR URINARY VOLUME

12. 24 HOUR URINARY PROTEIN

13. URINARY DIPSTICK VALUE:

14. SPOT PROTEIN CREATININE RATIO VALUE:

15. PREVIOUS HISTORY OF PRE ECLAMPSIA: YES/NO

MASTER CHART

Documents

COMPARISON OF 24 HOUR URINARY PROTEIN AND URINARY DIPSTICK VS URINARY SPOT PROTEIN ...repository-tnmgrmu.ac.in/3958/1/220600116nabishabegam.pdf · 2017. 11. 15. · DECLARATION I,