A Prospective Study for the Prediction of Pre Eclampsia With

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A PROSPECTIVE STUDY FOR THE PREDICTION OF PRE ECLAMPSIA WITH

SERUM PROLACTIN LEVEL

A PROSPECTIVE OBSERVATIONAL STUDY

Dissertation submitted to

THE TAMILNADU Dr. M.G.R. MEDICAL UNIVERSITY

In partial fulfillment of the requirement For the award of

M.S.DEGREE- BRANCH – II OBSTETRICS AND GYNAECOLOGY

GOVT. KILPAUK MEDICAL COLLEGE KILPAUK, CHENNAI

OCTOBER-2017

BONAFIDE CERTIFICATE

This is to certify that the dissertation entitled “A PROSPECTIVE

STUDY FOR THE PREDICTION OF PRE ECLAMPSIA WITH

SERUM PROLACTIN LEVEL” is the bonafide original work done by

Dr. M. INDHUJA under the guidance of Dr. K.L. MALARVIZHI MD,

DGO., DNB., Professor and Head of the Department of Obstetrics and

Gynaecology, KMCH, Chennai in partial fulfillment of the requirements for

MS Obstetrics and Gynaecology branch II examination of the Tamilnadu

Dr.MGR Medical university to be held in OCTOBER 2017. The period of postgraduate study and training from JULY 2014 to OCTOBER 2017.

Prof.DR.K.L.MALARVIZHI M.D D.GO ., DNB., Professor and Head Department of Obstetrics and Gynaecology, Government Kilpauk Medical College and Hospital, Chennai-600010.

Prof. Dr. P.VASANTHAMANI M.D, DGO, MNAMS, DCPSY, MBA., The Dean, Government Kilpauk Medical College and Hospital, Chennai - 600010.

DECLARATION

I solemnly declare that this dissertation “A PROSPECTIVE

STUDY FOR THE PREDICTION OF PRE ECLAMPSIA WITH

SERUM PROLACTIN LEVEL” was prepared by me at Government

Kilpauk Medical College and Hospital, Chennai, under the guidance and supervision of Dr.K.L.MALARVIZHI MD, DGO., DNB., Professor and

Head of the Department, Department of Obstetrics and Gynaecology,

Government Kilpauk Medical College and Hospital, Chennai.

This dissertation is submitted to The Tamil nadu Dr. M.G.R.

Medical University, Chennai in partial fulfillment of the University regulations for the award of the degree of M.S. (Obstetrics and

Gynaecology).

Place: Chennai

Date: (Dr. M.INDHUJA)

ACKNOWLEDGEMENT

I start my thesis in the name of almighty God. I thank him for giving me the privilege to learn from such eminent professors and assistant professors in my department.

I express my sincere thanks to Professor DR VASANTHA MANI,

M.D, DGO, MNAMS, DCPSY, MBA., The Dean, Kilpauk Medical

College for allowing me to conduct the study using the available facilities.

I convey my heartfelt gratitude and sincere thanks to my HOD and my guide Dr.K.L. MALARVIZHI, MD., DGO., DNB., Professor & Head of the Department, Department of Obstetrics and Gynaecology, Kilpauk

Medical College, who with her immense knowledge and professional expertise has provided guidance and encouragement throughout the study and in the preparation of this dissertation.

I am grateful to all my assistant professors, colleagues and my friends for their advice and suggestions. I express heartfelt thanks to my husband, my parents who have been a constant source of encouragement and for instilling in me the sense of commitment. Last but not the least I thank all my patients, who formed the backbone of this study.

(Dr. M. INDHUJA)

CONTENTS

S. TITLE PAGE NO. No. 1. INTRODUCTION 1

2. REVIEW OF LITERATURE 58

3. AIM OF THE STUDY 63

4. MATERIALS & METHODS 64

5. STATISTICAL ANALYSIS 70

6. DISCUSSION 82

7. SUMMARY 84

8. CONCLUSION 86

9. BIBLIOGRAPHY 87

10. ANNEXURES

 ABBREVIATIONS

 PATIENT INFORMATION SHEET  MASTER CHART

Introduction

INTRODUCTION

“What makes the BP in pregnancy to rise

Is still a mystery for many a wise

How can we find a method of cure

When the causative factor still remains obscure”

Pre eclampsia is a multi system disorder specific to pregnancy and puerperium which manifest by hypertension and proteinuria after 20weeks of gestation and resolves by 12 weeks after delivery.

According to WHO estimates

Current world wide maternal death is about 216

Every day, approximately 830 women die from preventable causes related to Pregnancy and childbirth.99% of all maternal deaths occur in developing Countries. Maternal mortality is higher in women living in rural areas and among poorer communities. Young adolescents face a higher risk of complications and death as a result of pregnancy than other women. Skilled care before, during and after childbirth can save the lives of women and newborn babies. Between 1990 and 2015, maternal mortality worldwide dropped by about 44%.Between 2016 and

2030, as part of the Sustainable Development Goals, the target is to

1 reduce the global maternal mortality ratio to less than 70 per 100 000 live births.

CAUSES OF MATERNAL DEATH WORLDWIDE IS

 Obstetric haemorrhage 25%

 Infection 15%

 Unsafe abortion 13%

 Hypertensive disorders of pregnancy 12%

 Obstructed labour 8%

 Other direct causes 8%

 Indirect causes 20%

CAUSES OF MATERNAL MORTALITY

hemorrhage infection unsafe abortion hypertension obstructed labour other direct cause

8% 8% 25% 12%

13% 15%

A HISTORICAL OVERVIEW OF PREECLAMPSIA-ECLAMPSIA

Preeclampsia is a multisystem disorder of pregnancy whose aetiology remains unknown. Although management is evidence based, past hypotheses and scientific contributions have influenced the understanding of pathophysiology of preeclampsia and guided its management.

THE PREECLAMPSIA TIMELINE:

 ANCIENT TIMES

 MIDDLE AGES AND RENAISSANCE

 18TH - 19TH CENTURY

 20TH CENTURY

 21ST CENTURY

DURING THE ANCIENT TIMES:

THEORIES ON DISEASE CAUSATION:

Preeclampsia was described in early 4th and late 5th century by

Hippocrates.

But it was mainly considered to be due to the imbalance between 4 humors which caused fluid overload causing preeclampsia symptoms. Also the theory of wandering womb was suggested. According to this theory

the uterus wandered outside the pelvis in search of moisture; thus affecting the liver, kidneys , stomach ,spleen and lungs in the process.

TREATMENT:

Because the disease was believed to be due to imbalance between 4 humors, the treatment was aimed at restoring the balance by:

 Bloodletting (phlebotomy)

 Purging

 Altering the diet

According to Hippocrates, to maintain this balance the woman should be pregnant, lactating or menstruating. He believed in all the above processes the excess fluid is lost in the form of blood and milk.

DISEASE CLASSIFICATION:

It was not recognised as a disease. Hippocrates only suggested that headache accompanied by heaviness and convulsions during pregnancy is bad.

A PICTURE OF HIPPOCRATES

A PICTURE OF PHLEBOTOMY

MIDDLE AGES AND RENAISSANCE:

THEORIES ON DISEASE CAUSATION:

During middle ages the progress of medicine was slowed down due to spread of religion. Between 700CE and 1200CE there was no significant progress. During renaissance acceleration in medical progress occurred. In

1537 Pope Clement VIII granted permission to teach anatomy by human dissection which helped in understanding of the anatomy of pelvic organs better.

French physician Francois Marceau established obstetrics as a specialty. He was the first to systematically describe eclampsia and said that it occurred mostly in primigravida. He thought that the eclampsia symptoms were due to retained lochia or intrauterine fetal death, which caused cerebral congestion, headache and convulsions.

TREATMENT:

Treatment was influenced by Christian beliefs and charms were remedies during middle ages. During renaissance, Mauricio suggested 2-3 phlebotomies during pregnancy.

DISEASE CLASSIFICATION:

Gabelchoverus classified 4 types of epilepsy as,

Epilepsy arising from:

 Head

 Stomach

 Pregnant uterus

 Chilled extremities

In 1619 the word ECLAMPSIA first appeared in VARANDAEUS‟

“TREATISE ON GYNAECOLOGY”

A PICTURE OF Dr. FRANCOIS MAURICEAU

18TH- 19TH CENTURY:

THEORIES ON DISEASE CAUSATION:

In 18th century, Boissier de Sauvages distinguished eclampsia from epilepsy. He believed that the convulsions occurred due to the body trying to free itself from morbid elements. Dr. Thomas Denman focused on death due to convulsions in pregnancy.

According to Denman:

Increasing size of uterus

Greater pressure on blood vessels

Regurgitation of blood to cerebral vessels

Cerebral congestion

Convulsions

A PICTURE OF Dr. THOMAS DENMAN

In 1849 Dr. William Tyler Smith challenged this theory because he believed that pregnancy was a state of fullness in circulation and many cases of convulsions would be observed if such congestion caused convulsions.

According to him, the cause are;

 Any excessive mechanical or emotional stimulus applied to spinal

centres.

 Blood letting

 Variations in atmosphere, wind and temperature

 Irritation to uterus, uterine passages and intestines

 Presence of toxins due to retention of wastes

A PICTURE OF Dr. WILLIAM TYLER SMITH

In 1881, the discovery of sphygmomanometer by Dr. Siegfried

Samuel revolutionized the view of preeclampsia-eclampsia though preeclampsia was classified as hypertensive disorder only later in 1897 byVaquez and Nobecourt.

TREATMENT:

Till early 1800’s bloodletting was considered the treatment. Later opiates and hastening of delivery when the woman is physiologically ready was considered by Denman.

With theory of disease causation focus shifted on microbes.

DISEASE CLASSIFICATION:

Bossier de Sauvages noted severe haemorrhage, various sources of pain and vermicular infestations associated with eclampsia.

In 1797 Demanet noted association between oedema and eclampsia.

In 1843 John Lever discovered albumin in urine of eclampsia women.

In 1843 Dr. Robert John described the imminent symptoms of eclampsia like headache, temporary loss of vision, severe stomach pain, oedema of hands, neck and face.

As a result of these contributions the concept of preeclamptic state was identified.

A PICTURE DESCRIBING “PREECLAMPTIC STATE”

20TH CENTURY:

THEORIES ON DISEASE CAUSATION:

Although the researches failed to identify the aetiology, the pathophysiology was better understood. In 1960, dramatic difference in placenta of preeclampsia and a normal one was identified. It was

12 discovered that placental trophoblasts failed to invade the uterine spiral arteries in preeclampsia, causing vasospasm and placental insufficiency.

In 1983 a parasitic worm called hydatoxi lualba was said to be the cause. But it was ruled out as starch powder from gloves and cellular debris caused the worm like appearance in H&E.

In 1989, Dr. Robert and colleagues hypotheses preeclampsia as an endothelial disorder where the ischemic placenta releases damaging factors into maternal circulation causing ENDOTHELIAL DYSFUNCTION. This lead to activation of coagulation cascade and loss of fluid from intravascular space.

TREATMENT:

At the end of 19th century and at the beginning of 20th century two very diverse approaches were followed.

1. Doctors in Germany and Netherlands followed aggressive

management like cesarean section. But it was associated with very

high maternal mortality rates.

2. Physicians like Tweedy and Stroganoff of Russia advocated

conservative management. Physicians were to abstain from

induction or hastening of labour as it itself may lead to convulsions.

Forceps use was allowed. They treated eclampsia and ignored

pregnancy. Morphine and chloral hydrate were used to decrease

frequency of convulsions and to sedate the patient.

3. Magnesium sulphate use became popular in 20th century. It was first

used by Horn in 1906 for treating preeclampsia – eclampsia. But

intravenous use of magnesium sulphate for treating this condition

was popularized by Dr.Lazard and Dr.Dorsett in 1920.

4. Since 1960, the management of preeclampsia had improved very

much.

5. Routine antenatal care became the best surveillance method.

Patients with signs and symptoms were hospitalized and monitored

They were allowed for vaginal delivery or cesarean section depending on their condition.

DISEASE CLASSIFICATION:

Till 1976, preeclampsia – eclampsia were named as ―TOXEMIA OF

PREGNANCY‖. Later they were classified as ―HYPERTENSIVE

DISORDERS OF PREGNANCY‖.

21ST CENTURY:

THEORIES OF DISEASE CAUSATION:

At present many theories are suggested like:

1. IMMUNOGENIC INTOLERANCE THEORY:

 Proposed by Leeman and Fontaine in 2008

 Intolerance between fetoplacental unit and maternal tissue.

E.g.: ENDOGLIN PROTEIN involved in trophoblastic infiltration

expresses anti-angiogenic factors causing vasospasm.

2. TWO STAGE MODEL PREECLAMPSIA:

 Proposed by Roberts and Hubel in 2009.

 STAGE 1: Reduced placental perfusion due to abnormal

location of placenta and subsequent remodelling interferes

with maternal factors causing maternal syndrome.

 STAGE 2: The maternal syndrome is characterized by

occlusive micro thrombi affecting multiple organs,

hypertension, proteinuria and Oedema

3. PLACENTAL TOXINS ( cytokines ,angiogenic factors etc ) are not

tolerated by some women leading to preeclampsia.

The following picture shows these theories :

DIAGNOSIS OF HYPERTENSION:

 Systolic BP > 140mmHg

 Diastolic BP >90 mmHg

At least two measurements, should be taken, in the same arm, 6 hours apart but within a week period and the average should be considered.

High systolic and diastolic BP have been associated with adverse foetal and maternal outcome .

Identifying increase in blood pressure from booking or preconception blood pressure, instead of relying on absolute value, was considered useful in diagnosing .

Measurement of Proteinuria:

All pregnant women must be checked for proteinuria. Urinary dipstick testing might be used for screening patients for proteinuria (due to easy availability, convenience and low cost.)

Grading for proteinuria is

TRACE - 0.1mg/dl

1+ - .3mg/dl

2+ - 1mg/dl

3+ - 3mgdl

4+ - 10mg/dl

There may be inter observer variations with visual dipstick assessment. This can be alleviated by the use of automated dipstick readers, which can reduce both false positive and negative rates. If the woman has hypertension, a proteinuria of 1+ is diagnosed as pre eclampsia

Diagnosis of Clinically Significant Proteinuria:

Urinary excretion of 300mg or more of protein in 24 hours urine collection or persistent 30mg/dl in random clean catch sample on atleast 2 occasions collected 6 hours apart is defined as clinically significant protein uria , this corresponds to urine protein /creatinine ratio of 30mg/mmol after ruling out urinary tract infection.

URINE SPOT PCR

This is an alternative to 24 hours urine protein, spot protein to creatinine ratio of more than .3 indicates significant protein uria .

DIFFERENT TYPES OF CLASSIFICATION OF

PREGNANCY

National High Blood Pressure Education Program (NHBPEP)

Working Group, the classification is as follows :

2. Pre- eclampsia

3. Preeclampsia 1. Gestational superimposed hypertension on chronic hypertension Classification

5. Chronic hypertension with 4. Eclampsia pregnancy

 Gestational hypertension

 Chronic hypertension

 Preeclampsia

 Eclampsia

 Super imposed preeclampsia (on chronic hypertension)

Gestational hypertension:

The characteristics of gestational hypertension are follows:

 BP of 140/90 mm Hg or more for the first time during pregnancy

 Proteinuria is nil

 Bp returns to normal in less than 12 weeks' postpartum

 Final diagnosis can be made only in the postpartum period

Chronic hypertension:

Hypertension which is diagnosed before 20 weeks of gestation and which remains persistent after 12 weeks of post partum period.

Blood Pressure of 140/90 mm Hg or greater before pregnancy or diagnosed before 20 weeks' of gestation age after ruling out mole and secondary cause of hypertension.

Preeclampsia/eclampsia

Preeclampsia is defined as blood pressure measurement of 140/90 mm Hg or more beyond 20 weeks of gestation in women with previously normal blood pressure and who have proteinuria (≥0.3 g protein in 24-h urine specimen).

Superimposed preeclampsia:

Superimposed pre eclampsia is defined as,

(1) New onset proteinuria (≥300 mg/24 h) in a woman with hypertension

who had no proteinuria before 20 wks gestation

(2) A sudden rise in proteinuria or blood pressure, or thrombocytopenia

with a platelet count of less than 100,000/mm3, in a woman with

hypertension and proteinuria before 20 weeks of gestation.

Eclampsia.

It was an extremely Severe form of pre eclampsia characterized by sudden onset of generalized tonic and clonic form of convulsions or coma in pregnancy or post partum unrelated to other cerebral condition.

National Institute for Health and Care Excellence (NICE, UK): classification of severity:

 Mild: systolic BP 140 to 149mmHg and /or diastolic BP 90 to

99mmHg

 Moderate: : systolic BP 150 to 159mmhg and /or diastolic BP> 100

to 109 mmHg

 Severe: : systolic BP >160mm/hg and /or diastolic BP >110mm/hg

AMERICAN CONGRESS OF OBSTETRICIANS AND

GYNECOLOGISTS (ACOG) CLASSIFICATION OF SEVERITY

1.PREGNANCY INDUCED HYPERTENSION

PRE ECLAMPSIA

Mild pre eclampsia

Severe pre eclampsia

ECLAMPSIA

2. PREGNANCY AGGREVATED HYPERTENSION

Super imposed pre eclampsia

Super imposed eclampsia

Co incidental hypertension

RISK FACTORS

 Genetic factors  Partner factors  Age and parity  Pregnancy factors  Underlying medical condition  Others

AETIO PATHOGENESIS OF PRE ECLAMPSIA

The key features are abnormal trophoblastic invasion ,in appropriate endothelial activation, exaggerated inflammatory response.

Abnormal troblastic invasion

Inappropiate endothelial activation

Exaggerated inflammatory responce

Its hypothesized as two stage disorder

PRIMARY STAGE - Abnormal trophoblastic invasion

In normal pregnancy

Invasion of endovascular trophoblastic cells

Small muscular elastic spiral arteries

Large tortuous channels

Large amount of blood in to the intervillous space and are resistant to vasomotor agent.

This physiologic changes are incomplete in patients with pre eclampsia and the trophoblastic invasion does not enter in to myometrial part of spiral arteries leading to incomplete trophoblastic invasion. This lead to decreased utero placental perfusion and increased response to vaso motor agents.

SECONDARY STAGE-ENDOTHELIAL ACTIVATION AND

EXAGGERATED IMMUNE RESPONSE.

Episodes of placental hypoxia and reperfusion leads to oxidative stress apoptosis and necrosis release of placental debris to maternal circulation leading to endothelial disruption and hyper inflammatory response with the production of multi organ failure signs and symptoms.

VASCULAR ENDOTHELIAL ACTIVATION

This is due to activation of leucocytes from maternal circulation due to placental factors leading to oxidative stress by the formation of free radicals and lipid peroxides which modifies endothelial nitric oxide synthase and increase permeability leading to edema and protein uria.

ANGIOGENIC IMBALANCE

Imbalance between angiogenic and anti angiogenic substance by the trophoblastic tissue at uteroplacental interphase is noted in patients with pre eclampsia and its correlated within disease severity. Increase in soluble

Fms like tyrosine kinase and decrease in vascular endothelial growth factor(VEGF )and placental like growth factor(PLGF).

soluble Fms like thyrosine kinase

VEGF AND PLGF

GENETIC FACTORS

It is due to interaction of multiple genes inherited from both maternal and paternal sides. This theory suggests fetal genes increase transfer of nutrients to fetus and increase in blood pressure and maternal genes decrease the transfer and lowers the blood pressure .

INCREASED PRESSOR RESPONSE

Women destined to have pre eclampsia has increased vascular reactivity to angiotensin2 and nor epinephrine.

NITRIC OXIDE

It is produced by endothelial cells from L-arginine which is a vaso dilator. Women with pre eclampsia is associated with decreased endothelial nitric oxide synthesis.

PROSTOGLANDINS

It has also been said prostanoids also play a role in the pathogenesis of pre eclampsia .In normal pregnancy there is almost decreased or blunted response to vasomotor influence due to increased production of endothelial prostacyclin.

In pre eclampsia there is decreased production of PGI2 and there is increased production of thrombaxne A2 from the platelet simultaneously.

This lead to decrease in prostacyclin to thromboxane A2 ratio and corresponds to increased sensitivity to vaso pressor response.

INCREASED THROMBOXANE DECREASED PROSTACYCLIN I2 A2

PREECLAMPSIA

NOTE

Soughan et al described pre eclampsia as maternal pre eclampsia and placental pre eclampsia.

Maternal pre eclampsia.

This is due to hyper response to inflammatory substance due to some underlying chronic medical condition such as obesity, diabetes, hypertension , auto immune disorders to a point of decompensation which will manifest as pre eclampsia.

Placental pre eclampsia.

This is due to incomplete invasion of spiral arteries by trophoblast cells leading to abnormal placentation. Thus all pre eclamptic women need not have abnormal placenta ion and all abnormal placenta ion need not be

29 a risk factor for developing pre eclampsia. Abnormal placentaion is also found in intra uterine growth retardation, pre term labor and pre mature rupture of membranes.

Normal and abrnormal invasion of trophoblast in normal and abnormal placentation.

MATERNAL CHANGES OF PRE ECLAMPSIA

Hemodynamic changes in pre eclampsia

After reviewing literature, the most common hemodynamic change is increase in cardiac output rather than increase in peripheral vascular resistance in mild pre eclampsia. When the mild pre eclampsia turns to severe pre elapse there is decrease in cardiac output and elevated peripheral vascular resistance leading to rise in both systolic and diastolic pressure. when there is high cardiac output and high peripheral vascular resistance result in traumatic intravascular haemolysis (micro angiopathic haemolytic anaemia )

Mild pre eclampsia Severe pre eclampsia

CO CO

PVR PVR

EDEMA:

Severe proteinuria causes fluid shift into the extracellular space.

Hence the intracellular space is depleted and thus there is a relative hypovolemia.

Thus an abnormal hematotcrit is an indicator of hypovolemia and its severity correlates with low birth weight, perinatal mortality and prematurity.

Physiological oedema of pregnancy is due to raised intracapillary hydrostatic pressure.

But the pathological oedema of preeclampsia is due to INCREASED

PERMEABILITY TO PLASMA PROTEINS AND REDUCTION IN

PLASMA COLLOID ONCOTIC PRESSURE.

SIGNS AND SYMPTOMS:

 Pathological edema appears suddenly. More often in the face and

periorbital regions.

 Presents as accelerated weight gain ( >1kg/week for 2 – 3 weeks or

>2 kg/week in 1 week).

CHANGES IN INTRAVASCULAR VOLUME:

HEMOCONCENTRATION IS THE HALLMARK OF SEVERE

PREECLAMPSIA AND ECLAMPSIA.

The physiological expansion of plasma volume in normal pregnancy is about 40% and is highest about 30 weeks and remains stable until term.

COMPLICATIONS:

ANTEPARTUM:

 Growth restriction

 Oligohydramnios

 Preterm labour

POSTPARTUM:

The hematocrit and hemoglobin decreases and plasma volume increases because:

 Decreased vasospasm

 Excessive blood loss during delivery

 Mobilization of extracellular fluids into intravascular compartment

In treating these patients with severe preeclampsia – eclampsia it must be remembered that they are unduly sensitive to both fluid therapy and blood loss. And the management must balance both.

CHANGES IN PERIPHERAL VASCULAR RESISTANCE:

It is found that women who are normotensive during pregnancy show progressive resistance to pressor agent ANGIOTENSIN II AND

CATECHOLAMINES throughout gestation, in contrast to women destined to develop preeclampsia.

GESTATIONAL DOSE REQUIRED TO RAISE AGE OF 26 – 24 WEEKS DIASTOLIC BP BY 20mm Hg

Normotensives 12 – 14 ng/kg/min of angiotensin II

probable preeclamptics 8 – 9 ng/kg/min of angiotensin II

Probable superimposed Response is Similar to preeclamptics preeclampsia

HEMATOLOGICAL ABNORMALITIES:

The most common hematological abnormality is MILD

THROMBOCYTOPENIA (7% - 10% of cases).

Overt thrombocytopenia i.e. platelet count <1,00,000/ϻl indicates severe disease.

Lower the platelet count, higher is the maternal and fetal morbidity and mortality.

In most cases delivery is advisable as platelet count continues to fall and improves only a day after delivery. Reaches normal level by 3-5 days postpartum in 90% cases.

Changes similar to mild intravascular coagulation can occur like :

1. Decrease in factor VIII plasma clotting factor.

2. Increases fibrinogen levels.

But investigations like partial and activated thromboplastin time are required only in case of abruption placenta.

HELLP SYNDROME:

Most serious haematological complications of preeclampsia characterized by:

 Haemolytic anaemia

 Elevated Liver enzymes

 Low Platelets

PATHOGENESIS:

Manifestation of microangiopathic haemolysis due to endothelial disruption with platelet adherence and fibrin deposition.

The HELLP syndrome precedes the appearance of consumptive coagulopathyand DIC.

HELLP SYNDROME

HEMOLYTIC ANEMIA:

Presence of hemolysis is accounted by:

 IN SERUM: elevated lactate dehydrogenise

 IN PERIPHERAL SMEAR: schizocytosis, spherocytosis and

reticulocytosis

DIAGNOSIS:

Diagnosis is of HELLP needs:

1. Confirmation of hemolysis by elevated LDH or peripheral smear

findings.

2. AST or ALT >70 IU/L.

3. Platelet count below 100000 /ϻl

A large population study suggests existence of association between

Leiden factor V mutation and severe preeclampsia. To a lesser extent associated with MTHFR C6771 mutation.

It was also found that women with thrombophilia had increased risk of severe preeclampsia. Hence screening for thrombophilia for women developing preeclampsia before 32 weeks can be useful in preventing recurrence in subsequent pregnancies

BRAIN CHANGES:

Acute and severe hypertension

Cerebrovascular auto regulation failure

Vasospasm, ischemia, tissue infarction,cytoxic oedema.

SIGNS AND SYMPTOMS:

 Hyperreflexia and clonus – they are hallmarks of severe

preeclampsia and due to neurological irritability

 Eclamptic seizures are GRAND MAL in character with tonic-clonic

phases.

 Vasospasm of frontal cortex – frontal headache ( unreleived by

analgesics)

 Constriction in visual cortex – visual disturbances and cortical

blindness.

 Most common hypertension related maternal mortality is due to

CEREBROVASCULAR ACCIDENTS

RENAL CHANGES:

In normal pregnancy, renal perfusion and glomerular filtration rate are increased.

In preeclampsia:

5 times increase in renal afferent arteriolar resistance

Reduced renal blood flow

Decreased renal perfusion

Decreased glomerular filtration rate

PATHOLOGY:

Hallmark renal lesion in preeclampsia is characterized by swollen intracapillary endothelial cells in the glomeruli called as GLOMERULAR

ENDOTHELIOSIS.

In electron microscopy it is seen as swelling, vacuolization, deposition of osmophilic material in the cytoplasm of endothelial cells. By immunoflourescence the osmophilic material reacted with antibodies against fibrinogen and fibrin.

Glomerular Endotheliosis

Swelling of damaged endothelial cells, leads to partial closure of many of the capillary lumens (large arrows). Mitosi within an endothelial cell (small arrow) is a sign of cellular repair.

Preeclampsia is associated with increase in concentration of uric acid and diminished excretion of urinary calcium.

Glomerular endotheliosis

Blocks filtration barrier

Diminished effective renal plasma flow

Reduced glomerular filtration

Acute renal failure is a rare complication of preeclampsia (1 in

10000).

Most commonly due to ACUTE TUBULAR NECROSIS due to bilateral cortical necrosis.

Acute renal failure in preeclampsia is invariably induced by coexisting hemorrhagic hypotension due to obstetric haemorrhage and without adequate blood replacement.

HEPATIC CHANGES:

Excessive fibrin deposition in hepatic sinusoids

Obstruct blood flow to the liver

Hepatic vasoconstriction mediated hypoxemia

Release of hepatic enzymes

 Hepatic capsule distension

 Hepatocellular damage

 Periportal haemorrhages

 Sub capsular hematoma

SUB CAPUSLAR HAEMATOMA IN HELLP SUNDROME

SCREENING TEST FOR PRE ECLAMPSIA

A variety of biochemical and biophysical markers implicated in pathology and pathophysiology of pre eclampsia has been proposed for its prediction .but to the utmost disappointment of many workers there is no reliable valid and economical screening test available for the prediction of pre eclampsia.

MID TRIMESTER BLOOD PRESSURE

The absence of fall in mid trimester blood pressure has been noted in many patients who develop pre eclampsia .

Women mean Arterial pressure > 90 mmHg has 3 fold risk of developing pre eclampsia.

HAND GRIP TEST .

An increase in diastolic pressure of more than 20mmHg during hand grip exercise test at 28 to 32 weeks had a positive predictive value of 20 to

30%.

ANGIOTENSION II INFUSION TEST

Women requiring less than 8ng/dl minute of Angiotension II to raise

BP by 20mm Hg has a positive predictive value of 20 to 40% for developing pre elampsia.

ROLL OVER TEST

A test in which women lies on her left side for 15 minutes after which blood pressure is recorded .she then rolls into the supine position and after five minutes blood pressure is recorded .A rise in diastolic BP of more than 20mmHg has a positive predictive value of pre eclampsia of 33%.

URIC ACID

Uric Acid of more than 5.9 mg/dl had a positive predictive value of

33%. for the development of pre eclampsia.

CALCIUM METABOLISM.

24 hour urine calcium less than 12 mg/dl positive value of 91%.

URINARY KALLIKREIN EXCRETION

Kalikrien is an important regulator of blood pressure and iis diminished excretion due to reduced level in circulation is a predictor of pre eclampsia.

FIBRONECTIN

Women with fibronectin value of more than 400ng/dl is more prone to develop pre eclamsia

PLACENTAL PEPTIDES

Inhibin A ActivinA are promising in the search for early pregnancy markers of pre elampsia

DOPPLER VELOCIMETRY

Doppler measurement of Uterine Artery impedence in the second trimester is an early screening test .

PLASMA P SELECTIN

Plasma p selectin as the earliest predictor of pre eclampsia is under study.

PROLACTIN AS A PREDICTOR OF PRE ECLAMPSIA

My study is about whether prolactin has a role in pathogenesis of pre eclampsia and whether it can be used a predictor of pre eclampsia in second trimester.

PROLACTIN

Prolactin (PRL),luteotropichormone or luteotropin,is a protein that is best known for its role in enabling mammals, usually females, to produce milk. Prolactin is secreted from the pituitary gland in response to eating, mating, estrogens treatment, ovulation and nursing.

Prolactin is secreted in pulses in between these events. Prolactin plays an essential role in metabolism, regulation of the immune system and pancreatic development. It is associated with human milk production.

Prolactin also acts in a cytokine-like manner and as an important regulator of the immune system. It has important cell cycle-related functions as a growth, differentiating and anti-apoptotic factor. As a growth factor, binding to cytokine-like receptors, it influences hematopoiesis, angiogenesis and is involved in the regulation of blood clotting through

47 several pathways. The hormone acts in endocrine auto crine paracrine manner through the prolactin receptor and a large number of cytokine receptors.

REGULATION OF SECRETION

Pituitary prolactin secretion is regulated by endocrine neurons in the hypothalamus. The most important ones are the neuro secretory tubero infundibulum (TIDA) neurons of the arcuate nucleus that secrete dopamine

(aka Prolactin Inhibitory Hormone) to act on the D2 receptors of lactotrophs causing inhibition of prolactin secretion.

Thyrotropin-releasing factor (thyrotropin-releasing hormone) has a stimulatory effect on prolactin release, however prolactin is the only adenohypophyseal hormone whose principal control is inhibitory.

It stimulates the mammary glands to produce milk (lactation), increased serum concentrations of prolactin during pregnancy cause enlargement of the mammary glands and prepare for milk production, which normally starts when the levels of progesterone fall by the end of pregnancy and a suckling stimulus is present. A key regulator of prolactin production is estrogens that enhance growth of prolactin-producing cells

49 and stimulate prolactin production directly, as well as suppressing dopamine.

In decidual cells and in lymphocytes the distal promoter and thus prolactin expression is stimulated by cAMP. Responsivness to cAMP is mediated by an imperfect cAMP–responsive element and two

CAAT/enhancer binding proteins (C/EBP). Progesterone upregulates prolactin synthesis in the endometrium and decreases it in myometrium and breast glandular tissue. Breast and other tissues may express the Pit-1 promoter in addition to the distal promoter.

Extra pituitary production of prolactin is thought to be special to humans and primates and may serve mostly tissue specific paracrine and autocrine purposes.

It has been hypothesized that in vertebrates such as mice a similar tissue specific effect is achieved by a large family of prolactin-like proteins controlled by at least 26 paralogous PRL genes not present in primates.

Vasoactive intestinal peptide and peptide histidine isoleucine help to regulate prolactin secretion in humans. Prolactin follows diurnal and ovulatory cycles. Prolactin levels peak during REM sleep and in the early morning. Many mammals experience a seasonal cycle. During pregnancy,

50 high circulating concentrations of estrogen and progesterone increase prolactin levels by 10- to 20-fold.

Estrogen and progesterone inhibit the stimulatory effects of prolactin on milk production. The abrupt drop of estrogen and progesterone levels following delivery allow prolactin which temporarily

remains high to induce lactation.

Sucking on the nipple offsets the fall in prolactin as the internal stimulus for them is removed. The sucking activates mechanoreceptors in and around the nipple. These signals are carried by nerve fibers through the spinal cord to the hypothalamus, where changes in the electrical activity of neurons that regulate the pituitary gland increase prolactin secretion. The suckling stimulus also triggers the release of oxytocin from the posterior pituitary gland, which triggers milk let-down: Prolactin controls milk production (lactogenesis) but not the milk-ejection reflex; the rise in prolactin fills the breast with milk in preparation for the next feed.Levels can rise after exercise, high-protein meals sexual intercourse, breast examination[ minor surgical procedures, following epileptic seizures or due to physical or emotional stress. In a study on female volunteers under hypnosis, prolactin surges resulted from the evocation, with rage, of humiliating experiences, but not from the fantasy of nursing.

PHYSIOLOGICAL FUNCTION OF PROLACTIN

1. Prolactin provides the body with sexual gratification after sexual

acts. The hormone counteracts the effect of dopamine, which is

linked to sexual arousal. This is thought to cause the sexual

refractory period. The amount of prolactin can be an indicator for

the amount of sexual satisfaction and relaxation.

2. Elevated levels of prolactin decrease the levels of sex hormones

estrogen in women and testosterone in men. Prolactin within the

normal reference ranges can act as a weak gonadotropin, but at the

same time suppresses GnRH secretion. The exact mechanism by

which it inhibits GnRH is poorly understood. Physiologic levels of

prolactin in males enhance luteinizing hormone-receptors in Leydig

cells, resulting in testosterone secretion, which leads

to spermatogenesis.

3. Prolactin also stimulates proliferation of oligodendrocyte precursor

cells. These cells differentiate into oligodendrocytes, the cells

responsible for the formation of myelin coatings on axons in

the central nervous system.

4. It helps in pulmonary surfactant synthesis of the fetal lungs at the

end of the pregnancy and immune tolerance of the fetus .

5. Prolactin promotes neurogenesis in maternal and fetal brains.

prolactin is produced in anterior pituitary, decidua, myometrium,

breast, lymphocytes, leukocytes and prostate.

Hypersecretion is more common than hyposecretion.

Hyperprolactinemia is the most frequent abnormality of the anterior pituitary tumors, termed prolactinomas. Prolactinomas may disrupt the hypothalamic – pituitary gonadal axis as prolactin tends to suppress the

53 secretion of GnRH from the hypothalamus and in turn decreases the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone

(LH) from the anterior pituitary, therefore disrupting the ovulatory cycle.[28] Such hormonal changes may manifest as amenorrhea and infertility in females as well as impotence in males. Inappropriate lactation

(galactorrhoea) is another important clinical sign of prolactinomas.

STRUCTURE AND ISOFORMS

The structure of prolactin is similar to that of growth hormone and placental lactogen. The molecule is folded due to the activity of three disulfide bonds.

Significant heterogeneity of the molecule has been described, thus bioassays and immunoassays can give different results due to differing glycosylation, phosphorylations and sulfation, as well as degradation.

The non-glycosylated form of prolactin is the dominant form at is secreted by the pituitary gland.

The three different sizes of prolactin are:

Little prolactin .the predominant form. It has a molecular weight of appxoximately 22-kDa.] It is a single-chain polypeptide of 198 amino acids and is apparently the result of removal of some amino acids.

 Big prolactin—approximately 48 kDa It may be the product of

interaction of several prolactin molecules. It appears to have little, if

any, biological activity.

 Big big prolactin approximately 150 kDa. It appears to have a low

biological activity. The levels of larger ones are somewhat higher

during the early postpartum Period

Serum prolactin level

Nonpregnant First Second Third Units Female Trimester Trimester Trimester ng/mL 0 – 20 36 - 213 110 - 330 137 – 372

Pmol/L 0 – 859 1,565 - 9,261 4,783 - 14,347 5,957 - 16,174

Serum prolactin level

THE ROLE OF PROLACTIN IN THE

PATHOGENESIS OF PRE ECLAMPSIA.

1. It causes elevated BP by modulating the activity of endothelial nitric

oxide synthetase.

2. It causes retension of fluids and electrolytes leading to increased BP.

3. It causes increased response to vaso pressor agent.

4. It causes imbalances in angiogenesis and anti angiogenesis leading

to pre eclampsia.

5. It has direct effect in elevation of arterial pressure during pregnancy.

Review of Literature

REVIEW OF LITERATURE

Timalsina et al conducted a non randomized case control study of which

54 cases and 60 controls out of which 41 had mild preeclampsia and 13 had severe pre eclampsia . The study showed that median concentration of prolactin was significantly higher in pre eclampsia when compared to normal healthy pregnant women.

Alfredo ullareo et al conducted a study with an objective to determine the relationship among preeclampsia, serum and urinary prolactins levels, and excretion of anti angiogenic prolactin fragments in urine.

Study design used was cross-sectional design. Urinary prolactin and serum PRL levels, and the presence of prolactin isoforms were determined in pregnant women: 210 healthy pregnant as controls , 121with gestational hypertension, 68 with mild preeclampsia, and 147 with severe preeclampsia .

Results:

Urinary prolactin concentrations were significantly (P <0.001) higher in preeclampsia (11.99 ng/mg creatinine) than in healthy pregnancy

(0.20 ng / mg creatinine) and gestational hypertension (0.19ng/mg

58 creatinine), and were even higher in severe pre eclampsia compared with mild preeclampsia (21.20 vs. 2.77ng/mg creatinine), respectively; P <

0.001).

Antiangiogenic PRL fragments (14–16 kDa) were detected in 21.6% of urine Samples from women with severe pre eclampsia but in none from other groups.

Patients with multi organ failure such as hemolysis, elevated liver enzymes, low platelet count syndrome, eclampsia , placental abruption, acute renal failure, and pulmonary oedema exhibited highest urinary prolactin concentrations (P <0.028) and frequency of antiangiogenic prolactin fragments in urine (P <0.036). High serum prolactin levels were associated with severe preeclampsia independently of gestational age, proteinuria, and prolactinuria (P<0.032).

Conclusions: Preeclampsia is characterized by increased urinary prolactin excretion. Urinary prolactin concentrations and their isoforms appear to be suitable markers to assess the severity of preeclampsia and occurrence of adverse outcomes. PRL and /or its isoforms might be involved in the pathophysiology.

Albert S. Changa, Ruriko Granta, Hirofumi Tomitaa, Hyung-Suk

Kima et al conducted a study shows Prolactin alters blood pressure by

59 modulating the activity of endothelial nitric oxide synthase Increased levels of prolactin cleaved form with molecular weight have been associated with pre eclampsia .

To study the effects of prolactin on blood pressure , they generated male mice with a single-copy transgene that enables inducible hepatic production of prolactin and its cleavage product. The Tg is driven by the indole-3-carbinol(I3C)-inducible rat cytochrome P4501A1 promoter.

When the Tg mice were fed normal chow (NC),plasma prolactin concentrations were comparable to those in female WT mice in the last third of pregnancy, and BP was lower than in WT Mice (average of 100 mm Hg vs average of 110 mm Hg). When the Tg mice were fed chow containing IC3, plasma prolactin concentrations increased three fold, BP increased to130 mm Hg, and cardiac function became markedly impaired.

IC3 chow did not affect the WT mice. Urinary excretion of nitrite/nitrate and the amount of Serum-phosphorylated endothelial nitric oxide (NO) synthase (eNOS) were significantly greater in the Tg mice fed NC than in

WT mice, as they are during pregnancy. However, when I3C was fed, these indicators of nitric oxide production became significantly less in the

Tg mice than inWT mice. The effects of increased plasma prolactin were abolished by a genetic absence of endothelial nitric oxide synthase. Thus, a four fold increase in plasma prolactin is sufficient to increase BP

60 significantly and to markedly impair cardiac function, with effects mediated by NO produced by eNOS. From the study they have concluded pregnant women with abnormally high prolactin levels may need special attention. and concluded that prolactin has a role in pathogenesis of pre eclampsia by modulating the activity of endothelial nitric oxide.

Alfredo Leaños-Miranda et al., conducted a study- Circulating

Factors and serum Prolactin as Predictors of Adverse Outcomes in Women

With Preeclampsia. Angiogenic They assessed whether these biomarkers are associated with an increased risk of adverse maternal and perinatal outcomes in preeclamptic women.. They studied 501 women with preeclampsia attended at a tertiary care hospital. Serum concentrations of soluble fmslike tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and soluble endoglin (sEng), as well serum PRL levels, were determined by enzymed-linked immunosorbent assay.

Antiangiogenic PRL fragments were measured byimmunoblotting.

The risk for any adverse maternal outcome and for having a small-for- gestational-age infant was higher among women with sFlt-1/PlGF ratios, sEng, and urinary PRL level values in the highest quartile (odds ratios

≥2.7)compared with the lowest quartile. Both serum PRL levels and the presence of antiangiogenic PRL fragments were more closely associated with the risk of specific adverse maternal outcomes (abruption placenta ,

61 hepatic hematoma or rupture, acute renal failure, HELLP ,pulmonary edema, maternal death, and need for endotracheal intubation, positive inotropic drug support, and hemodialysis; odds ratios ≥5.7 and ≥4.7, respectively) than either sFlt-1/PlGF ratio or s Eng alone. Hence they concluded that serum PRL concentrations and its antiangiogenic fragments appear to be better predictors of an adverse maternal outcome and may be useful for risk stratification in preeclampsia

Aim of the study

AIMS & OBJECTIVES

1. To find if prolactin has a role in pathogenisis of pre eclampsia.

2. To estimate serum prolactin during 14-20 weeks of pregnancy.

3. To correlate serum prolactin levels during 14 -20 weeks of

pregnancy as a predictor for pre eclampsia

Materials & Methods

MATERIALS & METHODS

TYPE OF STUDY

 Prospective observational study

PERIOD OF STUDY

 6 months

PLACE OF STUDY

Antenatal outpatient department & Antenatal Ward

Labour ward

Dept of Obstetrics & Gynaecology

Govt Kilpauk Medical College & Hospital, Chennai 10.

INCLUSION CRITERIA

Patients with known gestational age between (14-20) week will be selected irrespective of parity. Those who develop pre eclampsia will be the cases and others will be control.

EXCLUSION CRITERIA

 Chronic hypertension

 Type 1&2 Diabetes mellitus

 Multiple pregnancy

 Any chronic illness

 Thyroid disorders

 Patients with H/O galactorrhea

 Patients with H/O drug intake which affect serum prolactin

such as neuroleptics ,prokinectics, PPIs,H2 blockers.

SAMPLE SIZE

With the prevalence (p) of pre eclampsia of 8%, with absolute

precision (d) of 4% ,at 95% confidence limits

N=Z2*8*(1-P)/d2

N=(1.96)2*8*92/4*4=176.64

ACCONTING FOR TEN PERCENT NON RESPONSE

Sample size is 195

STATISTICAL ANALYSIS

The mean and standard deviation of the serum prolactin will be calculated and student 't’ test is used to compare mean.

MATERIAL AND METHODS

Careful history will be taken as per profoma.

Complete clinical examination will be done

Under aseptic precaution sampling will be done by venipuncture

6ml of blood is drawn out of which 4ml of blood will be used for routine investigation and TSH .2ml of blood for serum prolactin which is done by

ELIZA clear method. The patients were followed up until delivery.

BENEFITS OF THE STUDY

 To find if prolactin has a role in pathogeneis of pre eclampsia.

 To correlate serum prolactin as a predictor of pre eclampsia in early

second trimester

PROFORMA

NAME :

AGE :

IP NO :

PHONE NUMBER :

ADDRESS :

HUSBANDS NAME :

OCCUPATION :

QUALIFICATION :

SOCIOECONOMIC STATUS :

OBSTETRICS HISTORY

PARITY

LMP EDD

GESTATIONAL AGE BY LMP

GESTATIONAL AGE BY USG

COMPLAINTS IF ANY :

H/O DEFECTIVE VISSION /HEADACHE /GALACTORRHEA

MENSTRUAL HISTORY : Regular /Irregular

MARITAL HISTORY : Married since

PAST HISTORY

1. Diabetes

2. Hypertension

3. Heart disease

4. Tuberculosis

5. Epilepsy

6. Liver/renal disease.

7. Bronchial asthma

8. Drug intake

9. Thyroid disorders

GENERAL EXAMINATION

HEIGHT

PALLOR

WEIGHT

PEDAL EDEMA

TEMP :

PULSE :

BP :

CVS :

CNS :

RS :

PER ABDOMEN :

THYROID :

BLOOD INVESTIGATIONS

RFT

LFT

TSH

URINE ALBUMIN

SERUM PROLACTIN :

SIGNATURE OF THE INVESTIGATOR

SIGNATURE OF GUIDE :

DATE

Statistical Analysis

STATISTICAL ANALYSIS

Prolactin were considered as the primary outcome variables.

Presence or absence of Preeclampsia was considered as primary exposure variable. Age, gender are considered as other explanatory variables.

Descriptive analysis of all the variables was done using mean ,median and standard deviation for quantitative variables, frequency and percentage for categorical variables. The association between Preeclampsia and primary outcome variables was assessed by Independent Sample T-Test. Mean differences; their confidence intervals and p-value were calculated and presented. P value 0.001 was considered as statistically significant.

TABLE 1.Distribution of age in the study group

Frequency Percent

<= 20 YEARS 5 4.8

21 - 25 YEARS 36 34.3

26 - 30 YEARS 44 41.9

31 - 35 YEARS 12 11.4

>= 36 YEARS 8 7.6

Total 105 100.0

AGE GROUPS

8 5 12 <= 20 YEARS 36 21 - 25 YEARS 44 26 - 30 YEARS 31 - 35 YEARS >= 36 YEARS

In study group 4.8% were in the age group less than 20 years and

34.3% were in the age group 21 to 25 years 41.9 in the age group between

26 to 30 years 11.4% were in the age group between 31to 35 years 7.6% were above 36years.

TABLE 2.Distribution of parity in study group

Frequency Percent

Primi 63 60.0

2nd Gravida 27 25.7

3rd Gravida 9 8.6

4th Gravida 4 3.8

5th Gravida 2 1.9

Total 105 100.0

In this study 60% were primi 25.7%were second gravida 8.6% third gravida

PARITY

63 70

40 27 30

20 9

10 4 2

0 Primi 2nd Gravida 3rd Gravida 4th Gravida 5th Gravida

PRE ECLAMPSIA

TABLE 3.

Frequency Percent

YES 35 33.3

NO 70 66.7

Total 105 100.0

Among the study group 33.3% developed pre eclampsia remaining

66.7% remain normotensive.

PRE ECLAMPSIA

33.3%

YES 66.7% NO

TABLE 4.MILD & SEVERE PRE ECLAMPSIA

Frequency Percent

NO 70 66.7

MILD 23 21.9

SEVERE 12 11.4

Total 105 100.0

Among the study group 66.7% remain normotensive 21.9% developed mild pre eclampsia and 11.4% developed severe pre eclampsia.

80 NO, 70 70

30 MILD, 23 20 SEVERE, 12 10

0 NO MILD SEVERE

SEVERE PRE ECLAMPSIA

SEVERE PRE ECLAMPSIA Frequency Percent

HEAD ACHE, BLURRING OF 1 1.0 VISSION, VOMITING

OLIGURIA, VISUAL 1 1.0 DISTURBANCES

THROMBOCYTOPENIA 1 1.0

Total 105 100.0

Among the patient who developed pre eclampsia 1.0% developed head ache, blurring of vision & vomiting , 1%developed oliguria and visual disturbances and 1% developed thrombocytopenia.

URINE ALBUMIN

Frequency Percent + 11 10.5 2+ 9 8.6 3+ 11 10.5 4+ 4 3.8 NIL 66 62.9 TRACE 4 3.8 Total 105 100.0

10.5% of the pregnant women were with dipstick urine albumin 1+ and 8.6% of the study group with urine albumin 2+ and 10.5%with urine albumin 3 , 3.8% of the pregnant women with 4+ and 3.8%were with trace urine albumin.

URINE ALBUMIN

66 70 60 50 40 30 20 11 9 11 10 4 4 0 + 2+ 3+ 4+ NIL TRACE

SERUM PROLACTIN LEVELS

p VALUE MEAN STD. PRE_ECLAMPSIA N BY „t‟ ng/ml DEVIATION TEST

YES 27 286.93 91.46 <0.0001 NO 78 163.41 67.31

The statistical significant difference between the mean serum

prolactin levels of the pre eclamptic patients and normal patients denotes a

significant association of serum prolactin level with pre eclampsia.

S.PROLACTIN(ng/ml) 100

80 Sensitivity: 77.8 Specificity: 89.7 60 Criterion : >210

40 Sensitivity

0 0 20 40 60 80 100 100-Specificity

Area Under the Curve Asymptotic 95% Confidence Interval Area Std. Error p value Lower Bound Upper Bound

0.83333 0.0481 <.0001 0.748063 0.89895

Criterion values and coordinates of the ROC curve

Criterion Sensitivity 95% CI Specificity 95% CI +LR -LR ≥76 100.00 87.2 - 100.0 0.00 0.0 - 4.6 1.00

>76 100.00 87.2 - 100.0 1.28 0.03 - 6.9 1.01 0.00 >78 100.00 87.2 - 100.0 2.56 0.3 - 9.0 1.03 0.00 >93 100.00 87.2 - 100.0 3.85 0.8 - 10.8 1.04 0.00 >94 100.00 87.2 - 100.0 5.13 1.4 - 12.6 1.05 0.00 >97 100.00 87.2 - 100.0 6.41 2.1 - 14.3 1.07 0.00 >98 100.00 87.2 - 100.0 7.69 2.9 - 16.0 1.08 0.00 >99 100.00 87.2 - 100.0 8.97 3.7 - 17.6 1.10 0.00 >102 100.00 87.2 - 100.0 10.26 4.5 - 19.2 1.11 0.00 >104 100.00 87.2 - 100.0 11.54 5.4 - 20.8 1.13 0.00 >112 100.00 87.2 - 100.0 14.10 7.3 - 23.8 1.16 0.00 >113 100.00 87.2 - 100.0 15.38 8.2 - 25.3 1.18 0.00 >114 100.00 87.2 - 100.0 16.67 9.2 - 26.8 1.20 0.00 >116 100.00 87.2 - 100.0 17.95 10.2 - 28.3 1.22 0.00 >117 100.00 87.2 - 100.0 20.51 12.2 - 31.2 1.26 0.00 >119 100.00 87.2 - 100.0 21.79 13.2 - 32.6 1.28 0.00 >120 100.00 87.2 - 100.0 23.08 14.3 - 34.0 1.30 0.00 >123 96.30 81.0 - 99.9 26.92 17.5 - 38.2 1.32 0.14 >127 96.30 81.0 - 99.9 28.21 18.6 - 39.5 1.34 0.13 >132 96.30 81.0 - 99.9 30.77 20.8 - 42.2 1.39 0.12 >135 96.30 81.0 - 99.9 32.05 21.9 - 43.6 1.42 0.12 >136 92.59 75.7 - 99.1 35.90 25.3 - 47.6 1.44 0.21 >138 92.59 75.7 - 99.1 39.74 28.8 - 51.5 1.54 0.19 >139 92.59 75.7 - 99.1 41.03 30.0 - 52.7 1.57 0.18 >142 88.89 70.8 - 97.6 44.87 33.6 - 56.6 1.61 0.25 >143 85.19 66.3 - 95.8 46.15 34.8 - 57.8 1.58 0.32 >144 85.19 66.3 - 95.8 47.44 36.0 - 59.1 1.62 0.31 >146 85.19 66.3 - 95.8 51.28 39.7 - 62.8 1.75 0.29 >148 85.19 66.3 - 95.8 52.56 40.9 - 64.0 1.80 0.28 >153 85.19 66.3 - 95.8 53.85 42.2 - 65.2 1.85 0.28 >154 85.19 66.3 - 95.8 55.13 43.4 - 66.4 1.90 0.27 >156 77.78 57.7 - 91.4 58.97 47.3 - 70.0 1.90 0.38 >163 77.78 57.7 - 91.4 66.67 55.1 - 76.9 2.33 0.33 >164 77.78 57.7 - 91.4 70.51 59.1 - 80.3 2.64 0.32

Criterion Sensitivity 95% CI Specificity 95% CI +LR -LR >166 77.78 57.7 - 91.4 74.36 63.2 - 83.6 3.03 0.30 >169 77.78 57.7 - 91.4 75.64 64.6 - 84.7 3.19 0.29 >172 77.78 57.7 - 91.4 76.92 66.0 - 85.7 3.37 0.29 >174 77.78 57.7 - 91.4 78.21 67.4 - 86.8 3.57 0.28 >177 77.78 57.7 - 91.4 79.49 68.8 - 87.8 3.79 0.28 >186 77.78 57.7 - 91.4 80.77 70.3 - 88.8 4.04 0.28 >196 77.78 57.7 - 91.4 82.05 71.7 - 89.8 4.33 0.27 >199 77.78 57.7 - 91.4 83.33 73.2 - 90.8 4.67 0.27 >200 77.78 57.7 - 91.4 85.90 76.2 - 92.7 5.52 0.26 >210 77.78 57.7 - 91.4 89.74 80.8 - 95.5 7.58 0.25 >256 70.37 49.8 - 86.2 89.74 80.8 - 95.5 6.86 0.33 >263 70.37 49.8 - 86.2 91.03 82.4 - 96.3 7.84 0.33 >265 66.67 46.0 - 83.5 91.03 82.4 - 96.3 7.43 0.37 >268 66.67 46.0 - 83.5 92.31 84.0 - 97.1 8.67 0.36 >274 62.96 42.4 - 80.6 92.31 84.0 - 97.1 8.19 0.40 >279 59.26 38.8 - 77.6 92.31 84.0 - 97.1 7.70 0.44 >286 55.56 35.3 - 74.5 93.59 85.7 - 97.9 8.67 0.47 >294 51.85 31.9 - 71.3 93.59 85.7 - 97.9 8.09 0.51 >296 44.44 25.5 - 64.7 93.59 85.7 - 97.9 6.93 0.59 >324 40.74 22.4 - 61.2 93.59 85.7 - 97.9 6.36 0.63 >326 37.04 19.4 - 57.6 93.59 85.7 - 97.9 5.78 0.67 >333 37.04 19.4 - 57.6 94.87 87.4 - 98.6 7.22 0.66 >334 33.33 16.5 - 54.0 94.87 87.4 - 98.6 6.50 0.70 >336 29.63 13.8 - 50.2 94.87 87.4 - 98.6 5.78 0.74 >348 29.63 13.8 - 50.2 96.15 89.2 - 99.2 7.70 0.73 >354 25.93 11.1 - 46.3 96.15 89.2 - 99.2 6.74 0.77 >356 22.22 8.6 - 42.3 97.44 91.0 - 99.7 8.67 0.80 >362 18.52 6.3 - 38.1 97.44 91.0 - 99.7 7.22 0.84 >372 14.81 4.2 - 33.7 97.44 91.0 - 99.7 5.78 0.87 >383 11.11 2.4 - 29.2 97.44 91.0 - 99.7 4.33 0.91 >384 11.11 2.4 - 29.2 98.72 93.1 - 100.0 8.67 0.90 >386 7.41 0.9 - 24.3 98.72 93.1 - 100.0 5.78 0.94 >412 3.70 0.09 - 19.0 98.72 93.1 - 100.0 2.89 0.98 >426 3.70 0.09 - 19.0 100.00 95.4 - 100.0 0.96

>444 0.00 0.0 - 12.8 100.00 95.4 - 100.0 1.00

The cut of value for predicting pre eclampsia is more than 210ng/ml and sensitivity is 77.8% and the specificity is 89.7%

Validity of serum prolactin level as a marker for predicting preeclampsia

DISEASE Serum prolactin TOTAL + -

> 210ng/ml 21 8 29

<210ng/ml 6 70 76

TOTAL 35 70 105

TRUE POSITIVES 21 SENSITIVITY 77.8

FALSE POSITIVES 6 SPECIFICITY 89.7

TRUE NEGATIVES 70 PPV 72.41

FALSE NEGATIVES 8 NPV 92.11

κ coefficient of AGREEMENT .6520003

When serum prolactin is more than 210ng/ml, 21 developed pre eclampsia and rest of them remain normotensive and when serum prolactin is less than 210ng/ml, 6 of them developed pre eclampsia.

When serum prolactin is more than 210 ng/ml, true positives is 21

(that is who developed pre eclampsia) sensitivity is77.8 %and false positive is 6 and the specificity is 89.7 and the true negatives 70 and the positive predictive value is 72.41 and false negative is 8 and the negative predictive value is 92.11. Hence coefficient of agreement is .6520003 which is good.

Discussion

DISCUSSION

This prospective was carried out at kilpauk medical college and hospital .After getting informed consent from the patients serum prolactin was taken from 195 women between 14 to 20 weeks and was asked to come for follow up, only 105 came for follow up till delivery .Detailed history taken, proper clinical examination was done,blood pressure and urine albumin was checked in each ante natal visit .

Alfredo leanas mirenda et al study showed the following values of prolactin

Heathy Mild SPE Median pregnant Gestational PE 190.5 serum 139.0 hypertension P 162.6 0.027 ng/ml PRL ng/ml 148.6 ng/ml value0.032 ng/ml (75.5– (range) (44.2– (47–449.3) (64.8– 522.9) 472.9) 697.1)

Wendy cannan et al studied Prolactin levels in the plasma and amniotic fluid of 121 normal pregnant women, 78 women with preeclampsia and 30 women with essential hypertension complicating pregnancy were determined by radioimmunoassay. Mean prolactin levels in plasma, but not in amniotic fluid, were significantly lower than controls in the group with pre-eclampsia (P<0.01) and in the group with essential

82 hypertension (P<0.05). These findings suggest altered production and/or clearance of prolactin from the maternal compartment in these patients and may explain their increased response to pressor agents.

C.W.J.REDMAN AND J, BONAR et al conducted a study with 68 women with hypertension at 32 weeks and found serum prolactin were raised in pre eclamptic pregnancy with more uric acid in the urine and found prolactin level un altered with drug administration.

S.TIMALSINA AND P.GYAVAL et al. study showed that the median concentration* of prolactin was significantly higher in preeclampsia than in normal pregnancies (156.6 vs. 129.8 ng/mL,

P=0.012). Though the median concentration of prolactin was higher in severe preeclampsia in comparison to mild one, the difference did not reach the significant level (228.3 vs.152.9 ng/mL, P=0.061). No significant correlation of prolactin was found with mean arterial pressure and 24h

UTP. Due to poor correlation with established markers of severity, serum prolactin is not a reliable

In my study mean prolactin level is 286.93ng/ ml in women with pre eclampsia and 163.41 ng/ml in healthy pregnant. This study shows statistically significant increase in prolactin level in pre eclamptic women compared to healthy pregnant women.

Summary

SUMMARY

Pre eclampsia is a syndrome charecterised by hypertension and protein uria since from ancient times the etiology of pre eclampsia is unknown. This is due to incomplete invasion of trophoblast in muscular endothelial spiral arteries leading to decreased utreo placental blood flow and increased vaso pressor response. Since etiology is unknown many cross section study and case control study showed prolactin has a role in the patho physiology of pre eclampsia .prolactin naturally elevated in pregnancy found to be raised more in pre eclampsia. Normal non pregnant women prolactin level is less than 35ng/ml and in each trimester it is found to be elevated.

In this study majority of the women were in the age group between

26 to 30 years , 60% were primi gravida ,33.3% developed pre eclampsia,

22% developed mild pre eclampsia and 11% developed severe pre eclampsia, median duration of serum prolactin measurement is 17 weeks

3 days and median duration for pre eclampsia development is 33weeks and

6 days.

11% has one plus urine albumin and 11% has three plus urine albumin. Mean serum prolactin who developed pre eclampsia is

286.93ng/ml and the stand deviation is 91.467and the mean serum prolactin who has not developed pre eclampsia is 163.41 and the standard deviation is 67.312and the p value is<.0001 which is significant. When the serum prolactin is >210ng /ml sensitivity is 77.8 % and specificity 89.7% is > 210ng /ml is cut off value for predicting pre eclampsia. Based upon the statistical analysis sensitivity of the test is 77.8 %and specificity is

88.97% and positive predictive value is 72.41 and negative predictive value is 92.11 k coefficient of the agreement is .6520003, which is an good agreement.

Conclusion

CONCLUSION

In my study serum prolactin level is raised in women with pre eclampsia compared to healty pregnant women but some patients develop pre eclampsia even when the prolactin level is less than 210ng/ml and when even serum prolactin is more than 210ng/ml some dint develop pre eclampsia .Yet large number of study is needed to prove serum prolactin as a predictor of pre eclampsia.

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Annexures

ABBREVIATIONS

PRL - Prolactin

UPRL - Urinary Prolactin

SPE - Severe Pre Eclampsia

MPE - Mild Pre Eclampsia

VEGF - Vascular Endothelial Growth Factor

PLGF - Placental Like Growth Factor

CO - Cardiac Output

PVR - Pulmonary Vascular Resistance

GA - Gestational Age

INFORMATION SHEET

 We are conducting “A PROSPECTIVE STUDY FOR THE PREDICTION OF PRE ECLAMPSIA WITH SERUM PROLACTIN LEVEL”

 The privacy of the patient in the research will be maintained throughtout the study. In the event of any publication or presentation resulting from the research, no personally identifiable information will be shared.

 Taking part in the study is voluntary. You are free to decide whether to participate in this study or to withdraw at any time. Your decision will not result in any loss of benefits to which you are otherwise entitled.

 The results of the special study may be intimated to you at the end of the study period or during the study if anything is found abnormal which may aid in the management or treatment.

Signature of investigator Signature of patient / guardian

Date :

A PROSPECTIVE STUDY FOR THE PREDICTION OF PRE ECLAMPSIA WITH SERUM PROLACTIN LEVEL.

: :

. .

. , .

Master Chart GA AT WHICH GA AT WHICH S.PROLACTI DEVELOPED PRE DELIVERY S. NO NAME AGE PARITY DEVELOPED PRE MILD SEVERE URINE ALBUMIN B/UB SEC SEVERE PRE ECLAMPSIA IUGR HELLP PROLACTIN TAKEN N (ng/ml) ECLAMPSIA OR NOT OUTCOME ECLAMPSIA 1 REVATHY 24 primi 16+4 98 NO + B IV

2 GNANAMANI 26 G2P1L1 18+3 263 yes 34+0 130/90 2+ B IV

3 THANGAMANI 34 G3P1LIAI 15+6 120 NO NIL B IV

4 HARITHRA 33 G2P1LI 14+3 156 YES 34+0 130/90 B IV HEAD ACHE ,BLURRING OF 5 SHANMUGA PRIYA 29 G4P2L2A1 15+2 356 yes 36+0 160/110 3+ B IV IUGR PRETERM VISSION,VOMITING 6 SUNITHA 26 primi 15+6 127 NO NIL B IV

7 VASUMATHI 24 primi 18+4 94 NO NIL B IV

8 KANNAGI 28 G2P1L1 13+2 117 NO NIL B IV

9 SUDHA 21 primi 15+4 274 yes 29+ 136/94 + B IV

10 ANGAMMALAL 19 G2P1L1 16+3 138 NO NIL B IV

11 SATHYA 20 primi 19+0 146 NO NIL B IV

12 SINDUMATHI 26 primi 17+3 123 NO NIL B IV

13 YASMIN 23 primi 15+0 333 yes 29+4 160/112 3+ B IV

14 REKA 24 primi 19+3 136 NO NIL B IV

15 BHAVADHARINI 36 G5P1L1A3 20+0 132 NO 140/90 2+ B IV

16 ISHWARYA 32 primi 17+4 112 NO NIL B IV

17 KALPANA 43 G2P1L1 15+3 384 yes 33+3 160/110 4+ B IV THROMBOCYTOPENIA.,

18 DILLEMA 38 G2P1L1 19+5 78 NO TRACE B IV PRETERM

19 RAJALAKSHMI 26 G2P1L1 13+4 156 NO NIL B IV

20 PRIYA 24 primi 16+2 123 YES 33+2 130/94 2+ B IV

21 PUNITHA 26 primi 18+ 286 yes 29+4 150/100 3+ B IV

22 POORNIMA 29 primi 18+ 169 NO NIL B III

23 HAEMAVATHY 31 G3P2L2 14+3 268 yes 34+0 150/92 NIL B IV

24 POORNAM 32 primi 17+6 196 NO NIL UB IV

25 THANNIGAI SRI 36 primi 16+2 136 NO NIL B IV

26 SUBATHRA 26 primi 18+4 296 yes 33+2 120/96 + B IV

27 LAKSHMI 28 primi 16+2 163 NO NIL B IV

28 RADHA 27 primi 17+5 156 yes 140/90 NO B IV OLIGURIA ,VISUAL 29 MARIYA 22 primi 16+6 412 yes 35+4 180/120 3+ B III YES PRE TERRM DISTURBANCES 30 DHIVYA 24 primi 18+6 123 NO NIL B IV 31 RUBY 26 primi 16+4 136 YES 28+3 2+ B IV

32 DEEPA 21 primi 18+5 294 yes 36+6 140/92 + B IV

33 LAKSMI 26 primi 17+6 116 NO NIL B IV

34 RUTHRA 28 primi 14+3 76 NO NIL B IV

35 USHA 24 primi 17+6 153 NO NIL B III

36 JEYANTHI 22 primi 18+5 162 NO NIL B IV

37 VIDHYA 23 primi 16+4 168 NO NIL B IV

38 REENA 24 G4P2L2A1 16+4 386 yes 34+3 160/112 3+ B IV

39 JEYAPRIYA 26 G2P1L1 19+4 142 NO NIL B IV

40 PAVITHRA 28 G2P1L1 17+6 135 NO TRACE B V

41 JENNIFER 22 G2P1L1 15+3 143 NO TRACE B IV

42 SANGEETHA 23 G2P1L1 15+4 362 yes 35+6 154/98 3+ B IV YES

43 RUPA 22 G2P1L1 15+6 143 YES 32+0 130/92 2+ B III

44 REKA SRI 28 primi 17+6 163 NO NIL B IV

45 VAISHNAVI 21 primi 15+1 99 NO NIL UB IV

46 SRIDEVI 29 primi 19+0 146 NO NIL B IV

47 PUSHPA 21 G2P1L1 19+0 334 yes 24+2 160/102 2+ B IV

48 VINODHINI 26 primi 17+5 169 NO NIL B IV

49 SEETHA 38 primi 18+4 326 yes 31+0 150/100 NIL B IV

50 DHARINI 26 primi 19+5 163 NO NIL B IV

51 JANAKI 26 primi 15+3 144 NO NIL B IV

52 THAVAMANI 24 primi 15+3 138 NO NIL B IV

53 SUMITHRA 25 G3P1L1 17+2 286 yes 34+3 140/90 + B IV YES

54 ALAMELU 29 primi 18+3 136 NO NIL B IV

55 VISHNUPRIYA 24 G2P1L1 19+0 142 YES 36+0 130/92 B IV

56 SANGAMITHRA 26 G2P1L1 18+6 146 NO NIL B IV

57 DHIVYA 28 primi 18+5 119 NO NIL B IV

58 SARANYA 32 primi 17+1 117 NO NIL B IV

59 SOWNDHARYA 24 primi 16+2 324 yes 36+2 150/104 2+ B IV YES

60 PRIYADHARSHINI 25 primi 17+5 336 yes 34+2 160/116 3+ B IV

61 KARMEGAM 29 G3A2 19+2 142 NO NIL B IV

62 POONGULALI 33 G2P1L1 17+5 146 NO NIL B IV 63 RATHIMEENA 35 G3P1L1 16+5 148 NO NIL UB IV

64 GEETHA 36 G2P1L1 17+3 154 NO NIL B IV

65 NITHYA 24 primi 18+2 265 yes 33+6 130/94 NIL B IV

66 NARMADHA 28 G3A2 19+0 164 NO NIL B IV

67 ALPHONZE 29 primi 16+1 166 NO NIL B IV

68 SHARMITHA 26 primi 15+6 256 yes 29+0 140/100 2+ B IV

69 PRIYADHARSHINI 19 primi 16+4 177 NO NIL B III

70 RAJALAKSHMI 19 primi 19+3 123 NO NIL UB IV

71 KRISHNAVENI 24 primi 18+2 142 NO NIL B IV

72 RAMYA 29 primi 20+0 97 NO NIL B IV

73 PRIYA 28 primi 20+0 93 NO NIL B IV

74 LATHA 217 primi 19+0 186 NO NIL B IV

75 ANITHA 23 G2P1L1 18+3 104 NO NIL B IV

76 KOWSALYA 26 G2P1L1 17+3 296 yes 31+0 170/110 3+ B IV

77 KOKILA 34 G2P1L1 16+2 163 NO NIL UB IV

78 KANIMOZHI 36 G4P2L2A1 17+0 166 NO NIL B IV

79 RAJAJHOTHII 38 primi 16+6 132 NO NIL B IV

80 ARUNA 31 G5P1L1A3 15+4 279 yes 33+4 160/104 3+ UB IV YES

81 USHA 26 primi 19+5 156 NO NIL B IV

82 PADMA 25 primi 20+0 139 NO NIL B IV

83 NABEESHA 24 G2P1L1 19+1 383 yes 32+4 170/110 4+ B IV

84 MATHINIRAISELVI 26 G2P1L1 17+2 163 NO NIL UB IV

85 KARKUZHALI 23 primi 16+5 174 NO NIL B IV

86 SELVAPRIYA 24 primi 17+5 166 NO NIL B IV

87 SANGAVI 25 G4P1L1A2 18+5 354 yes 33+4 160/114 3+ B IV

88 KARTHIKEYANI 28 primi 19+0 164 NO NIL B IV

89 MOHANA 26 primi 16+5 138 NO NIL UB IV'

90 VIMALA 28 G3P1L1A1 17+5 372 yes 36+6 170/110 4+ B III

91 SHYAMALA 23 primi 19+0 156 NO NIL B IV YES PRETERM IUD

92 PREETHI 29 primi 17+6 138 NO NIL B IV

93 SOORYA 24 G2P1L1 16+5 356 yes 38+2 158/92 NIL B IV YES

94 SHANTHI 26 G2P1L1 19+3 112 NO NIL B IV 95 AKILA 29 G3P1L1 20+0 114 NO NIL BB IV

96 MANIMOZHI 28 primi 19+3 256 yes 34+3 150/94 NIL B IV

97 MOHANA 27 primi 17+5 102 NO NIL B IV

98 RAJALAKSHMI 24 primi 16+5 113 NO NIL B IV

99 KANIMOZHI 29 primi 17+2 348 yes 34+2 164/120 3+ B IV

100 GOMATHI 20 G2P1L 19+0 163 NO NIL B IV

101 CHELLAMAL 21 G3P1LA1 17+2 164 NO NIL B IV

102 SUBHA 34 G2P1L1 16+6 444 yes 33+3 180/120 4+ B IV YES YES PRETERM

103 RADHA 31 G2P1L1 17+3 172 NO NIL B IV

104 ARCHANA 26 primi 19+5 426 yes 37+2 170/106 4+ B IV

105 STELLA 24 primi 18+5 136 NO NIL B IV