study of mifepristone for pre- induction cervical …

i

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE

“STUDY OF MIFEPRISTONE FOR PRE-

INDUCTION CERVICAL RIPENING AND TERM

INDUCTION OF LABOUR”

Dissertation submitted to the

Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore.

In Partial fulfillment

of the requirement for the degree of

MASTER OF SURGERY

IN

OBSTETRICS AND GYNECOLOGY

BY

Dr. PRIYANKA M.B.B.S.,

UNDER THE GUIDANCE OF

Dr. SHUKLA S SHETTY M.D., D.G.O.,

PROFESSOR

DEPARTMENT OF OBSTETRICS AND GYNECOLOGY

J.J.M.MEDICAL COLLEGE DAVANGERE – 577 004.

KARNATAKA, INDIA

2019

ii

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA

DECLARATION BY THE CANDIDATE

I hereby declare that this dissertation entitled “STUDY OF

MIFEPRISTONE FOR PRE-INDUCTION CERVICAL RIPENING

AND TERM INDUCTION OF LABOUR” is a bonafide and genuine

research work carried out by me under the guidance of Dr. SHUKLA S SHETTY

M.D., D.G.O., Professor, Department of OBSTETRICS AND GYNECOLOGY, J.J.M.

Medical College, Davangere.

Place: Davangere

Date: / / 2018 (Dr. PRIYANKA )

iii

CERTIFICATE BY THE GUIDE

This is to certify that this dissertation entitled “STUDY OF



research work carried out by Dr. PRIYANKA in partial fulfillment of the

requirement for the degree of M.D. (OBSTETRICS AND GYNECOLOGY).

Place: Davangere

Date: / / 2018

DR. SHUKLA S SHETTY M.D., D.G.O.,

Professor,

Department of Obstetrics and Gynecology ,

J.J.M. Medical College

Davangere – 577004

iv

ENDORSEMENT BY THE HOD, PRINCIPAL / HEAD OF THE

INSTITUTION

This is to certify that this dissertation entitled “STUDY OF



research work carried out by Dr. PRIYANKA under the guidance of Dr. SHUKLA

S SHETTY M.D.,D.G.O., Professor, Department of Obstetrics and Gynecology,

J.J.M.Medical College, Davangere.

Seal and Signature of HOD Seal and Signature of Principal

Dr. H.V. RAVIGOWDA M.D.,D.G.O.

Professor and Head,

Department Obstetrics and Gynecology,

J.J.M. Medical College,

Davangere–577004.

Date: / / 2018 Date: : / / 2018

Place: Davangere Place: Davangere

Dr. MURUGESH S.B. MD., DVD., FAMS.,(Vienna)

Principal,

J.J.M. Medical College,

Davangere–577004.

v

COPYRIGHT

DECLARATION BY THE CANDIDATE

I hereby declare that the Rajiv Gandhi University of Health Sciences, Karnataka

shall have the rights to preserve, use and disseminate this dissertation / thesis in print

or electronic format for academic / research purpose.

DATE: / / 2018

PLACE: DAVANGERE (Dr. PRIYANKA )

© Rajiv Gandhi University of Health Sciences, Karnataka

vi

ACKNOWLEDGEMENT

I take this opportunity to extend my gratitude and sincere thanks to all those

who have helped me to complete this dissertation.

I am extremely indebted and remain grateful forever to my guide

Dr. SHUKLA S SHETTY M.D.,D.G.O. Professor, Department of Obstetrics and

Gynaecology, J.J.M. Medical College, Davangere, who with her knowledge and

experience has provided able guidance and constant encouragement throughout

the course of my postgraduate studies and residency and in preparation of this

dissertation.

It gives me immense pleasure to thank Dr.H.V.RAVIGOWDA M.D.,D.G.O.,

Professor and HOD , Department of Obstetrics and gynaecology, J.J.M. Medical

College, for his valuable guidance during this study and throughout my PG

course and residency in Davangere.

I express my sincere thanks to my Professors Dr. V.S.RAJU., M.D. D.G.O.,

Dr. H.N.MALLIKARJUNAPPA M.D., D.G.O., Dr. SHIVAMURTHY M.D.,

Dr. VANITHA V.G. M.D., Dr. G.Y. AGASIMANI M.D., Dr. A.C. RAMESH M.D.,

Dr. MANJUNATH G.H. M.D.,D.G.O., Dr. SHOBHA DHANANJAYA M.D.,

Dr. SARVAMANGALA M.D., Dr. VEENA G.R. M.D. , Dr. ANITHA G.S.M.D.,

Dr. S.N. ANURADHA M.D., Dr. LAKSHMI DEVI K.M.D. for their valuable help

and encouragement during my postgraduate course.

I also express my thanks to Associate Professor Dr. ASHWINI M.D.,

Dr. LATHA M.D., and Assistant Professors Dr. SAROJA C. KAMATKAR M.D.,

Dr. MADHU K.N. M.D., Dr. CHARITHA. M.D., Dr.SUHASINI V.M.D. Dr. VARADA

N.K.M.D., Dr. KUMAR GURUPRSAD G.A.M.S., Dr. VARSHITA VARUN ALUR.

vii

M.S., Dr. RASHMI S .M.S., and Senior resident Dr. NIVEDITHA M.D.G.O., and

Dr. DIVAKAR N.R. M.S.

I am extremely thankful to Dr. S.B.MURUGESH M.D.,D.V.D.,FAMS,

Principal, J.J.M. Medical College, and Dr. H. GURUPADAPPA M.D. Director of

Post graduate Studies and research, J.J.M. Medical College, Davanagere.

My sincere thanks to Superintendent and Staff of Chigateri General Hospital ,

Bapuji hospital and Women and Children hospital for permitting me to carry out this

study in their hospital.

I am indebted to my loving PARENTS Sri. RAJSHEKHAR NANDI

and Smt. RENUKA, sister AMBIKA and my brother ABHISHEK NANDI and

my family for their constant support and encouragement

I extend my sincere thanks to my post-graduate colleagues and all my

Friends, who had helped me in preparing this dissertation.

I also thank Mr .P.S. MAHESH, Chief Librarian and other staff of the

central library for their help during my research.

I thank Mr. PRAKASH., For help in statistical analysis of this dissertation.

My heartful thanks to all patients,who formed this study group and co-

operated wholeheartedly.

I thank Mr THOMAS, Thomas Computers, Davangere for preparing my

dissertation with a meticulous computerised alignment, Laser/Colour Prints, Binding

of my dissertation in a neat and coherent manner.

I thank the Almighty.

PLACE : Davangere

DATE : / /2018 (Dr.PRIYANKA)

viii

LIST OF ABBREVIATIONS USED

µ : Micro

ACTH : Adrenocorticotropic hormone

ARM : Artificial rupture of membranes

COX-1 : Cyclooxygenase

CS : Cesarean section

DHEA-S : Dehydroepiandrosterone sulphate

DNA : Deoxy ribonucleic acid

FFN : Fetal fibro nectin

FHR : Fetal heart rate

GR : Glucocorticoid receptor

IDI : Induction delivery interval

IL : Interleukins

IOL : Induction Of Labour

IUGR : Intrauterine growth restriction

LMP : Last menstrual period

LSCS : Lower segment cesarean section

mg : Milligrams

MMP : Membrane metalloproteinase

NICU : Neonatal intensive care unit

PR : Progesterone receptor

Tab : Tablet

TOLAC : Trial of labour after cesarean

TVUS : Transvaginal ultrasound

VBAC : Vaginal birth after cesarean

xii

LIST OF TABLES

SL.

NO TABLES

PAGE

NO

1 Sonological criteria for fetal maturity 10

2 The composition of cervix 15

3 Bishop score (1964) 17

4 Burnett’s modification 17

5 Calder modification (1974) of Bishop Score 18

6 Distribution of parity 44

7 Gestational age distribution 45

8 Maternal outcome 46

9 Mode of delivery 47

10 Other methods of induction 48

11 Indication for LSCS 49

12 IDI 49

13 Perinatal outcome 50

xiii

LIST OF GRAPHS

SL.

NO GRAPHS

PAGE

NO

1 Distribution of parity 44

2 Gestational age distribution 45

3 Pre and post induction Bishop score 46

4 Mode of delivery 47

5 Other methods of induction 48

6 Induction delivery interval 49

7 Perinatal outcome. 50

xiv

LIST OF FIGURES

SL

NO

FIGURES PAGE

NO

1 Fibrillar collagen synthesis and organization 14

2 Cascade of Events during cervical ripening 16

3 Mechanism of Initiation of Labour 24

4 Formula and X ray crystallographic structure of

mifepristone (RU-486). 28

5

Functional domains in steroid hormone receptors. TAF,

Transcriptional activation function, NL, nuclear

localization signal.

30

ix

ABSTRACT

Background and objectives

The ability to induce labour has been of interest to many societies from the

primitive to the ancient to the modern. For the majority of women, labour starts

spontaneously and results in vaginal delivery at or near term. One of the most

common indication for labor induction is prolonged pregnancy, which is associated

with many of the fetal complications. The objective of my study is to evaluate the

efficacy of Mifepristone in preinduction cervical ripening and induction of labour at

term.

Methods

This was a prospective study involving 110 women with gestational age 41

weeks admitted to Chigateri, Bapuji and Women and Children hospitals attached to

JJM Medical College satisfying inclusion and exclusion criteria. Tab Mifepristone

200mg single dose was given to study subjects after written informed consent after

assessing the bishop score at admission. Bishop's score was reassessed at the end of

24 hours , if the score was <6, other methods of induction like tab misoprostol 25µg

4th

hourly or cerviprime gel was given. If the bishop score was >6 ARM followed by

if needed oxytocin was used to augment labor. Maternal and fetal monitoring was

done throughout.

x

Results

Out of 110 patients 99(90%) patients delivered vaginally, 11(10%) patients

underwent caesarean section. There was significant change in mean bishop score

from 3.25 to 8.35 . Induction delivery interval was 47.7 hours. In our study 73.6%

women delivered without the need of any other methods of induction other than

Mifepristone. Incidence of meconium stained liquor was 2.7%, and NICU admission

rate was 0.9%. No significant side effects were noted.

Conclusion

Mifepristone is an safe ,efficient and suitable effective inducing agent for

cervical ripening which can be used in prolonged pregnancy.

Key words : Mifepristone, Induction of labour, prolonged pregnancy.

Introduction

1

INTRODUCTION

The ability to induce labour has been of interest to many societies from the

primitive to the ancient to the modern. For the majority of women, labour starts

spontaneously and results in vaginal delivery at or near term.1

Cervix plays essentially a passive role as an innocent obstruction and is acted

upon by all the forces of labour. A ripe or favorable cervix is a prerequisite for

successful vaginal birth.2 The cervical dilatation during labour is strongly influenced

by the cervical ripening which is done prior to induction of labour .

One of the most common indications for labour induction is prolonged

pregnancy as it is associated with increased risk to the fetus including:

Fetal distress

Low APGAR score at 5 minute

Meconium aspiration syndrome

Non-reassuring fetal heart rate

Increased risk of death within the first year of life

Placental dysfunction

Oligohydramnios

Recently, the most fascinating synthetic mifepristone (RU-486) has been the

focus of attention in the arena of various labour inducing agents.

Mifepristone is a steroidal compound that has antiglucocorticoid and

antiprogesterone properties. It increases uterine activity and causes cervical

effacement and dilatation for pregnancy termination.

Introduction

2

Mifepristone has an established role in termination of pregnancy during the

early first, and the second trimester.3

Animal studies have suggested that mifepristone

also has a role in inducing labour in late pregnancy.

There is insufficient information available from the clinical trials to support

the use of mifepristone to induce labour .

Keeping this in mind, the present study is undertaken to find out the safety and

efficacy of mifepristone for preinduction cervical ripening and labour induction in

women with prolonged pregnancy.

Objectives

3

OBJECTIVES

To study the effect of Mifepristone in pre-induction cervical ripening and

Induction of labour at term.

Review of Literature

4

REVIEW OF LITERATURE

Historical background

Labour inductions are among the most common obstetrical interventions

today. Labour inductions are considered to be any method used to artificially start

woman’s labour.4 The act of inducing labour has been around for thousands of years,

however, the method, frequency and reason for initiating labour has changed over

time. Medically indicated inductions are provided under circumstances where the

benefit of inducing is believed to outweigh the health risks to both the mother and

baby.5 Overall, the use of labour inductions (both medically indicated and elective)

have increased.6

Induction of labour in patients with unfavourable cervices may be medically

indicated or elective. The indicative induction is defined as initiation of labour due to

maternal or fetal indications that outweigh the benefits of continuing the pregnancy.

These indications may include pregnancy-induced hypertension, postdated pregnancy,

diabetes mellitus, IUGR and fetal death. Elective induction on the other hand is

defined as the initiation of labour for the convenience of an individual with a term

pregnancy and who is free of medical indications.7

The method for labour inductions has also changed over time. Both

mechanical and chemical methods are used to ripen a women's cervix to help initiate

labour.8

In 1949, the first modern inducing agent, oxytocin, was developed by du

Vigneaud who isolated pure oxytocin from the neurohypophysis. By 1953, synthetic


5

oxytocin was synthesized and was shown to be similar to natural oxytocin. Du

Vigneaud received noble prize for chemistry in 1955 for his remarkable contributions.

Soon after oxytocin introduction, Theobald, Graham, Campbell, Gange and

Driskoll introduced intravenous administration of oxytocin.

In 1930, Raphael Kurzoak and Charles C.Lieb, observed that fresh semen

applied to strips of myometrium from hysterectomy specimens made the muscle

contract or sometimes relax, Goldblatt in England and Von Euler in Sweden

independently demonstrated that extracts from seminal vesicles and prostate glands

caused effective contraction or relaxations in smooth muscles of various organs. In

1969 Elias J. Corey and his colleagues at Harvard and chemist from Upjohn

pharmaceuticals were able to synthesise prostaglandins and start the era of use of

prostaglandins.

Recently, the most fascinating synthetic mifepristone (RU-486) has been the

focus of attention in the arena of various labour inducing agents.

Mifepristone is a steroidal compound that has antiglucocorticoid and

antiprogesterone properties.

The search for the safest and the most efficacious method of labour induction

continues.9


6

INDUCTION OF LABOUR

DEFINITION

Ian Donald:

An induced labour is one in which pregnancy is terminated artificially any

time after 28 weeks of gestation by a method that aims to secure delivery per via

naturalis, whether or not the intention is fulfilled does not alter the definition.10

Williams:

Induction of labour implies stimulation of uterine contractions before

spontaneous onset of labour with or without rupture of membranes.11

Arulkumaran:

Induction of labour is the nonspontancous initiation of uterine contractions

that results in progressive effacement and dilatation with descent of the presenting

part to achieve vaginal delivery when continuation of pregnancy presents a threat to

the life and well being of the mother or her unborn child.12

ACOG 2009:13

According to ACOG 2009 Goal of IOL (Induction of labour) is to achieve

vaginal delivery by stimulating uterine contractions before the spontaneous onset of

labour.13

Incidence varies in different institutions but generally showing a rising trend

with a wide range of variation in the opinion14

on the indication, results and prognosis

of induction of labour . Induction of labour is indicated in medical, obstetric and fetal


7

conditions when prolongation of pregnancy would affect the maternal and fetal well

being provided there are no contraindications for the use of prostaglandins and

oxytocin.15

ACOG guidelines Indications for induction of labour as per ACOG guidelines

200913

are:

Abruptio placentae

Chorioamnionitis

Fetal demise

Gestational hypertension

Preeclampsia, eclampsia

Premature rupture of membranes

Post term pregnancy

Maternal medical conditions (eg, diabetes mellitus, renal disease, chronic

pulmonary disease, chronic hypertension, antiphospholipid syndrome) .

Fetal compromise (eg. severe fetal growth restriction, isoimmunization.

oligohydramnios) .

Logistic reasons

Risk of rapid labour

History of rapid labour

Distance from the hospital

Psychosocial indication

Contraindications for induction of labour as per ACOG guidelines 200913

are:

Placenta or vasa previa

Abnormal foetal lie


8

Cord presentation

Prior classical uterine incision

Prior myomectomy or uterine unification surgery entering the endometrial cavity.

Active genital herpes infection

Invasive cervical carcinoma

RISKS OF INDUCTION OF LABOUR

Fetal risks :

Iatrogenic prematurity

Hypoxia – due to hyperstimulation,disordered uterine action, prolonged labour,

and operative interference.

Maternal risks :

Psychological upset : More in failed induction and in prolonged labours.

Need for emergency caesarean delivery.

Failed induction.

Uterine rupture – in case of previous LSCS , injudicious use of oxytocin, it is

most commonly seen with grand multiparous women.

Placental abruption in case of hydramnios.

Precipitate delivery resulting in cervical or vaginal lacerations.

Water intoxication – associated with high dose of oxytocin.

Infection – the chance of infection mounts steadily with passage of time after

membranes have been ruptured.

Amniotic fluid embolism – occurs very rarely at the time of ARM/ few hours

later when uterine contractions are strong.


9

Monitoring of Induction: 16,17

Unlike spontaneous labour, induction carries possibility of uterine

hyperstimulation; therefore, during induction of labour, it is essential that uterine

activity be monitored closely. Fetal heart rate monitoring similar to that recommended

for high risk patients in active labour should be used. Properly trained nurses can

monitor the induction of labour, but a physician who has privileges to perform

caesarean deliveries should be readily available (ACOG technical bulletin,

217.Dec.95) .

FACTORS TO BE CONSIDERED WHEN ELECTING TO INDUCE ARE: 6, 16,17

Patient’s informed consent : method of induction should be explained to the

patient , possible need for caesarean

Gestational age

Pelvic adequacy

Readiness of cervix

Stability of maternal condition

Uterine integrity

Assessment of fetal maturity


10

Table-1: Sonological criteria for fetal maturity

Criteria Normal value Increase in

parameter/week

BPD 9-9.8 1mm

Femur length 7.1-7.9 1.5-2mm

Abdominal circumference 33-37cm3 1-2cm

3

Head circumference 30-34cm3 0.75-1.5cm

3

Maturity of placenta Grade 3

Appearance of ossification centre

at the upper end of tibia 34 weeks

Lower end of femur 36 wks (always)

32-36 wks (often)

Assessment of gestational age and consideration of any potential risks to the

mother or fetus are of paramount importance for appropriate evaluation and

counselling before initiating cervical ripening or labour induction. The patient should

be counselled regarding the indications for induction, the agents and methods of

labour stimulation, and the possible need for repeat induction or caesarean delivery.13

Although prospective studies are limited in evaluating the benefits of elective

induction of labour, nulliparous women undergoing induction of labour with

unfavorable cervices should be counselled about two fold increased risk of caesarean

delivery. In addition, labour progression differs significantly for women with an

elective induction of labour compared with women who have spontaneous onset of

labour . Allowing at least 12-18 hours of latent labour before diagnosing a failed

induction may reduce the risk of caesarean delivery.


11

At least one of the gestational age criteria in the box should be met, or fetal

Lung maturity should be established. A mature fetal lung test result before 39 weeks

of gestation, in the absence of appropriate clinical circumstances, is not an indication

for delivery.13

Confirmation of Term gestation:13

Ultrasound measurement at less than 20 weeks of gestation supports

gestational age of 39 weeks or greater.

Fetal heart tones have been documented as present for 30 weeks by Doppler

ultrasonography.

It has been 36 weeks since a positive serum or urine human chorionic

gonadotropin pregnancy test result. Additional requirements for cervical

ripening and induction of labour include assessment of the cervix, pelvis, fetal

size, and presentation. Monitoring FHR and uterine contractions is

recommended as for any high risk patient in active labour.13

In order to be successful, induction of labour must fulfill three aims:

It should result in labour namely, adequate uterine contractions and progressive

dilatation of cervix.

This labour should result in vaginal delivery, as there is little purpose in

bringing about labour as a mere preparation for caesarean section.

In variable pregnancies, these aims must be achieved with minimum of

discomfort and risk to both mother and fetus.


12

A ripe' soft yielding cervix requires a lower quantum of uterine work than an

unripe hard and rigid one would (Arulkumaran 1985) . An unripe cervix fails to dilate

well in response to myometrial contractions.12

Methods commonly employed in the recent times for induction of labour are:

Medical methods

Oxytocin

Prostaglandins

RU486

Corticosteroids

estrogen

Surgical methods

Sweeping/stripping of membranes

Amniotomy

Combined method

Mechanical : Extra amniotic saline infusion.

Predictors of successful induction:18

Because of the risk of failed induction of labour, a variety of maternal and

fetal factors as well as screening tests have been suggested to predictor labour

induction success.

Maternal factors:

Parity

Body mass index

Cervical status

Bishop score


13

Transvaginal ultrasound

Fetal factors:

Birth weight

Gestational age

Biochemical:

Fetal fibronectin (FFN)

Insulin like growth factor

Parous, young women who are taller and lower weight have a higher rate of

induction success (IS) .

Fetuses with a lower birth weight or increased gestational age are also

associated with increased success rate.

The condition of the cervix at the start of induction is an important predictor,

with the modified Bishop score being a widely used scoring system. The most

important element of the bishop score is dilatation.

Other predictors including TVUS and biochemical markers (including FFN)

have been suggested, but to date they have not been shown to be superior to Bishop

score. Further research is needed to evaluate these potential predictors and IGFBP-1

another potential biochemical marker.

Anatomy and physiology of cervical ripening

The uterine cervix has a pivotal role in the physiology of gestation and

parturition; it has to be firm enough to retain the conceptus throughout pregnancy and,

on the other hand, have the ability to soften before and during labour to enable the

birth of the infant. Some softening of the cervix (Goodell's sign) and especially of the


14

isthmus (Hegar's sign) can be palpated about six weeks after the LMP.19

At term,

however, the cervix changes from a firm, tough tissue to one that is soft and able to

dilate to about 10 cm, to allow delivery of the baby. The transformation process

thinning, softening, relaxing and opening of the cervix is termed cervical ripening and

has been observed for centuries.20

Priming and maturation of the cervix are also

commonly used term for this physiological change.

Anatomy of the cervix

The human cervix is a specialized portion of the uterus that lies below the

isthmus and projects into the vagina. Based on its attachment to the vagina, the cervix

is divided into a vaginal and supravaginal portion which is on the posterior surface

covered by the peritoneum of the recto-uterine space. The upper boundary of the

cervix is the internal so, the uterine portions of the cervix. The lower is the external

os, the vaginal portion of the cervix (the portio vaginalis) , which projects into the

vagina and is bound by the fornices.21,22

The portio vaginalis is approximately 3 cm long and 2.5 cm wide, although the

size and shape varies with hormonal status, age and parity.

Fig.1 : Fibrillar collagen synthesis and organization83


15

The cervical mucosa is a series of vertical and lateral folds with the lateral

folds emanating from the vertical folds. Mucous can become encrusted forming small

cysts frequently found on the portio vaginalis and are called ovules of Naboth or

cervix.

Table 2: The composition of cervix

Cells Extracellular matrix

Surface epithelium : Squamous

Endocervical cells: Columnar

Smooth muscle cells (5-10%)

Fibroblasts (80%)

White cells :

Macrophage

Eosinophils

Collagen

Type 1 : 70%

Type 2 : 30%

Type 4 : small amount

Elastin

Water

Glycosaminoglycans:

Hyaluronan

Decorin

Enzymes :

MMP – 1,8,13

Cytokines :

IL-1, IL-6, IL-8, TNF-alpha

There seems to be a fine balance between the MMPs and their inhibitors,

which are called tissue inhibitor of matrix protease (TIMP) . It is thought that TIMPS

can either prevent or stop the collagenase activity of MMPs. Progesterone has an

inhibitory effect on MMPs, and prevents activation of the enzyme.23,24

This makes sense in that progesterone has been the hormone, responsible for

maintaining a quiescent uterus and the pregnancy.


16

Summary

Collagen, elastin, smooth muscle cells, decorin, and hyaluronan are produced

by the fibroblasts in the cervix. The primary component of the cervix is collagen,

which unlike the smooth muscle of the corpus of the uterus, is firm connective tissue

with very little contractile function. Thus, the cervix functions to provide a strong

opening to the corpus of the uterus until a complex series of event occur in pregnancy

to ripen the cervix and initiate the process to open the cervix.

Increase in the ratio of decorin to collagen

Disorganisation of collagen fibrils

Dispersal of collagen fibres

Increase in water concentration

Decrease in collagen concentration

Softening of cervix

Fig. 2 - Cascade of Events during cervical ripening

The most effective method of preinduction cervical assessment is modified

Bishop score. The most important element of BS is dilatation followed by effacement,

station and position, with the least useful element being cervical consistency.


17

Bishop score: 25

Bishop score is the most prevalent scoring system for preinduction cervical

assessment. This system and its many modifications take into account the cervical

dilatation, effacement, consistency and position and the station of the presenting part.

Cervical dilatation is the factor with the strongest association with successful

induction.

Table: 3 Bishop score25

(1964)

Factor Score

0 1 2 3

Dilatation (cm) 0 1-2 3-4 5-6

Effacement (%) 0-40 40-60 60-80 >80

Station -3 -2 -1/0 +1/+2

Consistency Firm Medium Soft -

Position Posterior Mid Anterior -

Maximum score -13. Score 9 or above – induction was safe and uniformly successful.

Effacement was expressed in %- subjective

Station was expressed in thirds of pelvis.

Table: 4 Burnett’s modification26

Score 0 1 2

Dilatation (cm) <1.5 1.5-3 >3

Consistency Firm Intermediate Soft

Cervical length >1.5 1.5-1 0

Station -2 -1 0/+1

Position Posterior Mid Anterior

Maximum score - 10


18

Each Bishop category has maximum score of - 2

Effacement expressed in terms of cm

Interpretation:

9-10 -all patients delivered within 4 hrs mostly within 2 hours

6-8 - 90% delivered within 6 hrs

<6 - unpredictable

Table 5: Calder modification27 (1974) of Bishop Score is as follows.

Factor Score

0 1 2 3

Dilatation (cm) <1 1-2 2-4 <4

Length of

cervix(cm)

>4 2-4 1-2 <1

Station -3 -2 -1/0 +1/+2

Consistency Firm Average Soft -

Position Posterior Mid /anterior - -

Maximum score is 12

A score of >6 is a favourable score with a predictable outcome.

Hormones Involved in Cervical Ripening:

Hormones have historically been used to induce cervical ripening and

labour.27

Only recently has the role of hormones been considered in inhibiting

cervical ripening in pregnancy.28


19

1. Progesterone:

Progesterone receptors are found in the cervix and their concentrations

decrease with cervical ripening.29

Progesterone is important for the maintenance of

human pregnancy. Antiprogestins, such as RU-486, are capable of enhancing

myometrial responsiveness to prostaglandins at any age of pregnancy and induce

cervical ripening (Chwalisz & Garfield, 1994). Cervices treated with

antiprogesterones exhibit increased amounts of hyaluronan and decorin.30

2. Estrogen:

The effect of estrogen in target tissues is mediated by binding to estrogen

receptors. In humans, estrogen receptors in the cervix are lower in term pregnant and

postpartum women than in non pregnant women.31

Estrogen was found to modulate

the infiltration of eosinophils into the cervix and cervical collagen remodeling in the

rat cervix.32

Although estrogen may not have a direct effect on the collagen, leukocyte

invasion of the cervix is an important feature of cervical ripening. It has been

suggested that leukocyte infiltration of the cervix along with the increased

permeability of the tissue may be a mechanism to allow rapid passage of hormones

and enzymes that are responsible for collagen remodeling and cervical softening.

Eosinophils have traditionally had roles in allergy and parasitic infections.

However, there is evidence from other parts of the body that activated eosinophils can

cause intense acute inflammation with vascular permeability and tissue edema.

Eosinophils are seen in the cervix during cervical ripening and in cases of cervical

carcinoma, which suggests a similar role in producing intense inflammation.


20

3.Prostaglandins :

Prostaglandins have been extensively used to artificially induce cervical

ripening in the first trimester of pregnancy and at term. However, the role of

prostaglandins in ripening the cervix has increasingly come into question.

Prostaglandins as the final mediator of cervical ripening is evident when

indomethacin or the enzyme cyclooxygenase (COX-1) inhibitors were used. These

inhibitors were able to suppress the formation of prostaglandins but not the cervical

ripening effects of anti-progestins on the cervix, 33

suggesting a role for progesterone

in preventing cervical ripening. The cyclooxygenase enzyme is responsible for

converting arachidonic acid to prostaglandins, prostacyclin, and thromboxane A2.34

There was hope that the use of prostaglandins to induce cervical ripening before

labour would reduce the caesarean section rate due to cervical factors.

However this has not occurred. There is still a higher rate of caesarean section

with induction of labour, even when the cervix is considered "ripe" by the Bishop

Score.35

Also, the effect of prostaglandin often promotes tetanic uterine contractions,

which can cause adverse effects on the fetus and potentiate the risk of uterine rupture

in women with a previous caesarean section.36

4. Relaxin:

Relaxin is a peptide hormone produced in the corpus luteum during

pregnancy. Relaxin has also been identified in the placenta, decidua, and chorion in

the human and the rabbit.37,38


21

Serum relaxin concentrations increase until 10 weeks of gestation, then

decrease between 12-24 weeks, and then remain constant throughout the rest of

pregnancy.39

It is thought that relaxin is responsible for softening the connective

tissues and ligaments of the reproductive tract during pregnancy in many species.40

Elevated serum relaxin levels have been used as a marker for preterm labour.

In women with preterm labour symptoms, the odds ratio of preterm delivery and an

elevated serum relaxin was 4.8. It was hypothesized that an elevated serum relaxin

may signal or cause preterm delivery in symptomatic women. Women with the

highest serum relaxin levels had fewer tears and less bleeding during delivery than

women with lower levels of serum relaxin, suggesting a role for preparing the genital

tract for birth.39

5. Oxytocin :

Oxytocin most likely does not have a great role in cervical ripening, as

oxytocin stimulates smooth muscle cells to contract. The corpus of the uterus is

composed of smooth muscle, which has a function to contract in labour.

Approximately 90% of the human cervix is composed of connective tissue, which has

very little contractile function in labour (Danforth, 1947) .

Maternal serum levels of oxytocin are very low during pregnancy. Around the

time of labour, there are more frequent pulses of oxytocin at night, which coincide

with uterine contractions.41

Oxytocin mRNA has been found in the human amnion,

chorion, and deciduas, and along with maternal pituitary and fetal contribution.42

Oxytocin may be important for stimulating prostaglandin synthesis, which is

important in cervical ripening .


22

There are oxytocin receptors in myometrial smooth muscle cells and in the

cervix. Myometrial cells exposed to oxytocin for 20 hours resulted in an almost 10

fold reduction in oxytocin binding capacity, suggesting down regulation of the

oxytocin receptors.

Maternal serum oxytocin levels rise with stimulation of the cervix during an

examination, instrumentation of the cervix, or stretching of the cervix, an effect called

Ferguson's reflex.42

6. Prolactin :

Prolactin is a hormone mainly secreted by the anterior pituitary gland.

There have been reports of a possible role of prolactin in labour. Cervical

dilation, cervical examination, or instrumentation resulted in increased maternal

serum prolactin levels. Maternal prolactin levels were static or decreased during the

first stage of labour and increased markedly during the second stage of labour,

suggesting a neural signal from the ocrvix. Exactly why prolactin increases is not

clear. The role for prolactin in cervical ripening is not clear, but it is interesting that

there are neural signals in the cervix for prolactin secretion.43

Summary

Hormones have historically been used to induce labour and only recently has

their role been considered in inhibiting labour and possibly cervical ripening. Cervices

treated with antiprogesterones exhibited increased amounts of hyaluronan and

decorin, 44,45

thus suggesting a role for anti-progesterone in stimulating the process of

cervical ripening. Estrogen was found to be associated with leukocyte infiltration of


23

the cervix, which is important for increased tissue permeability to allow rapid passage

of cytokines and hormones to act on the collagen.32

Prostaglandins are the most common hormones, which are used clinically for

cervical ripening.

CAUSATION OF ONSET OF LABOUR

The factor or factors that lead to onset of labour in women are not defined,

however , at present our understanding of the biomolecular events involved in

initiation of parturition in humans is incomplete. Nevertheless several hypothesis can

be formulated to explain the nature of the underlying events that lead to the onset of

labour.

Hippocrates (370 BC) and later William Harvey and Naegale postulated that

onset of labour is determined by nutritional needs of the fetus, i.e.,when the placenta

is no longer able to satisfy the fetus, the latter seeks another favourable environment.

Fabricus in the 16th, Mauricean in 17th and Baudeloqu in 18th century

attributed the onset of labour to a muscle reaction in increasing distention of the

uterus. Various nervous, mechanical and chemical theories were put forward in the

19th century. Probably a single factor cannot explain the onset of labour. As

Reynold’s conducted (1949) a study where parturition begins as a result of gradual

accelerating nervous, nutritional and circulatory systems which are so closely

associated that they lead to the process of parturition.

1.Neurogenic theory:

Pressure of the presenting part on the cervix and lower uterine segment

stretches the same in turn stimulates the para cervical ganglion which sends impulses


24

to the hypothalamus. Hypothalamus, in turn stimulates the pituitary to produce

oxytocin. Uterus has autonomic nerve supply. Sympathetic nervous system does seem

to have an influence on the onset of labour. Probably, the chemical state of the uterus

or the hormonal state of the pregnant women determines, whether the stimulus should

be excitatory or inhibitory. But it is proved that uterus has its own rhythmic

contractility independent of autonomic nervous system. Complete transaction of

spinal cord at very high level has been found not to interfere with progress of labour,

though pain sensation is abolished. Although labour may start in denervated uterus,

labour may also be initiated through nerve pathways. Both alpha and beta adrenergic

receptors are present in the myometrium. Oestrogen causes the alpha receptors and

progesterone causes the beta receptors to function predominantly. The contractile

response is initiated through the alpha receptors of the post ganglionic nerve fibres in

and around the cervix and the lower part of the uterus. This is based on observation of

the onset of labour following stripping of membranes and low rupture of membranes.

Fig.3 : Mechanism of Initiation of Labour82


25

2.Uterine Distension

Stretching effect on the myometrium by the growing size of the fetus and

liquor amnii can explain the onset of labour as in case of twins or polyhydramnios.

It has been postulated that due to unknown factors, fetal anterior pituitary is

stimulated prior to onset of labour. This leads to increased release of ACTH which in

turn stimulates fetal adrenals to secrete Cortisol. This increased cortisol secretion

accelerates the production of oestrogen and prostaglandins from the placenta. The

probable modes of action of oestrogen are:

Increase the release of oxytocin from maternal pituitary.

Promotes the synthesis of receptors for oxytocin in the myometrium and

decidua.

Accelerates lysosomal disintegration inside the decidual cells resulting in

increased prostaglandin synthesis.

Stimulates the synthesis of myometrial contractile proteins actin and myosin

through activation of adenosine triphosphatase.

Increases the excitability of the myometrial cell membranes.

Hormone Theory:

Pregnancy is supported to be maintained by quantitative and qualitative

balance between different hormones. A shift in the balance might explain the

gradually increasing activity of the myometrium as term approaches.

a) Adrenaline and Noradrenaline:

Carrett (1954, 1955) and Caldyro (1959) showed that adrenaline inhibits the

contraction in pregnancy and labour, where as noradrenaline stimulates them. So


26

probably by producing noradrenaline or adrenaline, an emotional upset may

occasionally initiate or temporarily arrest labour.

b) Oxytocin:

It is probable that myometrial contraction is more dependent on its own

readiness to respond to oxytocin. There is no conclusive proof that oxytocin level is

increased prior to labour. There is however, increase in oxytocin receptors especially

in the decidua vera which in turn stimulates prostaglandin synthesis. Vaginal

examination and amniotomy causes rise in maternal plasma oxytocin level (Ferguson

reflex) . Oxytocin level reaches the maximum at the moment of birth. Fetal plasma

oxytocin level is found increased during spontaneous labour compared to that of

mother.

c) Oestrogen and Progestrone:

Increased fetal production of dehydroepiandrosterone sulphate (DHEA-S) and

cortisol may inhibit the conversion of fetal pregnenolone to progesterone, there by

altering the oestrogen; progesterone ratio. It is probably the alteration of oestrogen:

progesterone ratio rather than fall in the absolute concentration of progesterone which

is linked with prostaglandin synthesis.


27

“BIOSYNTHESIS PHARMACODYNAMICS AND PHARAMCOKINETICS

OF MIFEPRISTONE”

RU486 (mifepristone) has proved to be a remarkably active antiprogesterone

and antiglucocorticoid agent in human beings. The mechanism of action involves the

intracellular receptors of the antagonized hormones (progesterone and

glucocorticoids) . At the molecular level, the most important features are high binding

affinity to the receptor, interaction of the phenylaminodimethyl group in the 11beta

position with a specific region of the receptor binding pocket and RU486-induced

transformation differences in the ligand–binding domain. These particularities have

consequences at different steps of the receptor function as compared with agonists.

However, the reasoning cannot be limited to the RU-486 receptor interaction, and for

instance, there is the possibility of a switch from antagonistic property to agonist

activity, depending on the intervention of other signaling pathways. It would be

desirable to have derivatives with one of the two antagonistic properties

(antiprogestin, antiglucocorticoid) in spite of similarities between steroid structures,

receptors involved, and responsive machineries in target cells.

Clinically, the RU-486 plus prostaglandin method is ready to be used on a

large scale and is close to being as a convenient and safe as any medical method of

abortion may be.


28

Fig. 4 – Formula and X ray crystallographic structure of mifepristone (RU-486)

:17beta-hydroxyl-11beta-(4-dimethyl-aminophenyl-1) -17alpha-(prop-1-ynyl) -

estra-4, 9-diene-3-one and the antiestrogen tamoxifen 9179; JP Mornon,

unpublished data) .

MOLECULAR AND CELLULAR ASPECTS OF THE STEROID

ANTAGONISTIC ACTIVITY OF RU-486

Basically, events that mediate antagonism of a steroid analogue are dependent

on the steroid structure and bioavailability, and on the appropriate receptor’s ability to

bind to the steroid analogue and to undergo a ligand-induced transconformation

leading to the inactivation of one or several steps of the receptor’s mechanism of

action.

Steroid structure and metabolism

The main structural characteristic of Ru-486 (code name and number ,

Roussel-Uclaf 38486; generic name ,mifepristone) is the phenyl-aminodimethyl group

perpendicularly graffed onto the 11-beta position of the steroidal skeleton (Figure-3) :

All currently known antiprogestins and antiglucocorticoids produced by Rossel-Uclaf,

ScheringBerlin ,Organon, and other groups have the same basic structure, which upon


29

binding ,reversibly maintains the receptor in an inappropriate conformation. RU486

binds with high affinity (K of dissociaton £ 10-9 M) to both the progesterone receptor

(PR) and the glucocorticosteroid receptor (GR) . There exists no pure antiprogestin

compound. The antiglucocorticosteroid effect of RU486 is not useful for pregnancy

termination, but conversely, this is not medically inconvenient at the usual single dose

of 600 mg.46

Nevertheless, it does limit long-term use, so efforts have been made to

find new derivatives with dissociated antagonist activities.47,48

Besides the binding of RU486 to steroid receptors and formation of a complex

that directly modifies the response of the cellular machinery to the endogenous

hormone, the distribution and metabolism of the steroid analog influences its

efficiency. RU486 is readily absorbed by the oral route and the peak serum

concentration occurs within 1 h of administration. Receptors have lower affinity for

demethylated and hydroxylated (in the 17a-side chain) metabolites, which are less

active than RU486, but their abundance allows them to participate in the global action

of the compound. In humans and some other primates, RU486 binds to plasma or so

mucoid, a particularity responsible for a long half-life, strengthening the antisteroid

effect. This effect is not observed with RU40555 and onapristone. The analogue

RU43044 is heavily metabolized and is not active after administration to whole

animals, but locally it retains its antiglucocorticosteroid efficacy.

Steroid Receptor Structure and Ligand-Induced

Transconformation

The steroid hormone receptors are intracellular proteins that mediate the

genomic responses to the hormones. They belong to the superfamily of nuclear

receptors and are hormone-dependent transcription factors positively or negatively


30

regulating a large set of genes. Steroid receptor molecules consist of different

domains (Figure 4) : 49,50,51

The N-terminal domain carries a transactivation function called TAF1 or t1

and is followed by the DNA binding domain (DBD) , which mediates the interaction

of receptors with specific DNA sequences called hormone regulatory elements (HRE)

, usually present in the promoter upstream of the 5¢ coding region of hormone-

regulated target genes. Separated from the DBD by a hinge region, the ligand binding

domain (LBD) contains a second transactivation function (TAF2) , the activity of

which is dependent on hormone binding. The LBD is also involved in the formation

of amultiprotein complex principally made up of molecular chaperons such as hsp90

and immunophilin, in which the receptor is maintained in a biologically inactive form

in the absence of hormone. Nuclear localization signals and homodimerization

regions of the receptor protein are also shown in Figure 4.

Fig.5 : Functional domains in steroid hormone receptors. TAF, Transcriptional

activation function, NL, nuclear localization signal.


31

Upon binding, progestin and antiprogest in do not contact the same

aminoacids in the binding cavity of the PR. Agonist binding requires amino acids to

be located at the C-terminal end of the PR, which is not required for antagonist

binding: It has been proposed that this partly involves a so-called 11-b pocket,

implicating amino acids in the N-terminal region of the LBD. Truncation of the 42 C-

terminal amino acids of human PR (hPR) or punctual mutations in the GR C terminus

give receptor mutants that no longer bind progesterone or glucocorticosteroid

agonists, respectively, but that allows the antagonist to bind and function as an

agonist.52,53

Subtle modifications in the amino acid sequence such as those observed

between receptor species and between PR isoforms or due to mutations, inherited or

experimentally introduced, in the receptor molecules induce variations in antagonist

binding and/or activity. RU486 and several parent compounds do not bind to the chick

PR54, because of an exchange of a Gly residue (575 in the human and most

mammalian PR) for a Cys in chick PR.51 Chick PR chimeras, obtained by

exchanging LBD segments with corresponding hPR segments, recognize the hPR

antagonists RU486 and RU39115 (without the N-dimethyl group) as partial and

complete agonists, respectively.55

Following steroid binding, receptors undergo a conformational change that is

probably crucial for receptor interaction with cellular targets. Antagonist binding

seems to trigger a transconformation of the hormone binding domain that differs from

that observed with agonist binding. A number of physicochemical techniques such as

those for determining the susceptibility to proteolytic enzymes, identifying differential

antibody binding, and measuring changes of electrophoretic mobility56,57,58

have been


32

used along with mutagenetic approaches55,56

to demonstrate differences located at the

extreme C terminus of the protein between complexes of receptor with agonist and

antagonist.

Thus, both chemical differences in the steroid and modifications of the

receptor by genetic or biochemical processes can change the final response. This may

be of importance for explaining different activities of a given compound, including

RU486, according to the physiological status (interference by other signaling

pathways) or pathological states (cancers with receptor mutations) .

CLINICAL APPLICATIONS OF MIFEPRISTONE (RU486)

Up to now, the clinical uses of RU486 have mainly been based on its

antiprogesterone activity. During the luteal phase of the nonfertile cycle and during

early stages of pregnancy, progesterone activity is dominant, and its interruption

rapidly provokes alteration of the endometrium/decidua alteration, which is easy to

detect. The first trial, performed in Geneva in 1982,59

indicated the actual

antiprogesterone activity of RU486 in human beings, and it was followed by many

clinical studies mostly in the gynecologic and obstetrical fields.

OBSTETRICAL USES

For early pregnancy termination.

Second trimester pregnancy termination.

Labour induction at term. Preliminary trials for cases of postdate pregnancies

or other medical indications for labour induction, show that RU486 is able to

induce labour and is well-tolerated by both newborn and mother.


33

GYNECOLOGICAL USES

Uterine fibroids (25 to 50mg/day)

Endometriosis(50mg/day)

In breast cancers

CONTRACEPTIVE AND CONTRAGESTIVE USES OF RU-486

Emergency postcoital contraception.

Late luteal phase administration.

MIFEPRISTONE IN INDUCTION OF LABOUR

Mifepristone (RU 486) is a 19-norsteroid which has specific high affinity

binding to the progesterone receptor and thus to compete with progesterone at the

level of their respective binding site.60

Also this compound exerts some

antiglucocorticoid property.

Mifepristone is absorbed rapidly after oral administration, reaching maximum

serum levels within 2 hours and has a half-life of about 25 h.61

As a result of the

withdrawal of the inhibitory effect of progesterone there is an increase in the synthesis

of prostaglandins and inhibition of prostaglandin dehydrogenase action.62,63

Sensitivity of the myometrium to the contraction inducing activity of prostaglandins

markedly increased after mifepristone administration64

and labour often starts without

addition inductors.

Mifepristone exposure at 41 weeks of gestation associated with significant

increase of estradiol, estriol, progesterone and cortisol in saliva and plasma without

alterations of corticotropin-releasing hormone and adrenocorticotropic hormone

levels. 65,66


34

Prevention of progestogenic effect by mifepristone promotes cervical ripening

owing to the action of estrogens, such as increase in cervical collagenase and

prostaglandin synthetize activity; enhance expression of the extracellular matrix

degrading protease stromelysin-1 (MMP-3) .67,68

These properties of mifepristone determined its use for the cervical ripening

and preparation for the pregnancy termination. Mifepristone is recognized as a

component of safe abortion and is included to the WHO Model Lists of Essential

Medicines.69

Efficacy and safety of medical abortion has been confirmed based on use of

mifepristone for over two decades.

The most commonly used approved indications for mifepristone in obstetrics

include: termination of early pregnancy, cervical dilatation prior to surgical abortion,

labour induction in case of fetal death in utero. Fewer studies have been conducted on

the effect of mifepristone on cervical ripening and induction of labour in term

pregnancy with a live fetus.

CLINICAL EVIDENCE

Yelikar Kanan, Deshapande Sonali 201470

conducted a study on 100

subjects with late term pregnancy beyond 40 weeks and bishop score <6. Concluded

that MIFEPRISTONE is an effective inducing agent for cervical ripening and

initiation of labour when given 24 hours prior to induction in late term pregnancy with

reduced need for prostaglandins and can be administered safely with no increase in

adverse events on the fetus or mother.


35

Ruthuja Athawale, Neema Acharya, S.Samel 201371

conducted study

including 100 patients with late term pregnancy after their informed consent.

Patients were categorized by Bishop Score at the beginning of induction for

comparison of BS, mode of delivery, induction delivery interval (IDI) . Women

undergoing induction with RU486 (200mg PO) were grouped in one and those with

placebo control group into another. Statistical analysis of categorical variables was

done.

Results: Rate of successful IOL or vaginal delivery was 76% in study group and only

36% in control group. After induction with mifepristone for cervical ripening in study

group 76% patient who had cervical score <3 on admission had cervical score

improved to>8 within 24 hours, whereas in control group 2% female’s cervical score

was>8. Among the babies, 44% in the control group required baby unit admission as

compared to 36% in the study group.

To conclude in the present study, the 76% who had cervical score < 3 on

admission had cervical score improved to >8 within 24 hours and concluded that

women who were induced with mifepristone 200mg orally showed drastic

improvement in cervical score within 24-48 hours and decreased the caesarean rate in

study group and decreased amount of dose required for augmentation of labour with

misoprostol or oxytocin.

Hapangama D Neilson Jp. (2009) 72

in their study “On Mifepristone for

Induction of Labour” more women had favourable cervix after 48 hours, with less

number of caesarean sections as a result of failure to induce labour and they were less

likely to need the augmentation with oxytocin.


36

Shanitha Fathima, Nayak, SR, Rao Bharathi (2013) 73

Conducted a study

using mifepristone for labour induction at term with gestational age between 37-42

weeks in Lady Goschen Hospital and Kasturba Medical College ,Mangalore. The

study demonstrated significant efficacy of mifepristone for cervical ripening and

induction of sponataneous labour after drug administration as more women had

favourable Bishop’s score at the end of 24 hours.

Frydman R, Lelaidier C, Baton-Saint-Mleux, Fernandez H. (1992) 74

conducted a study to assess the safety and efficacy of mifepristone as an induction

agent for initiation of Labour or as an cervical ripening agent in women at term and

concluded Mifepristone to be safe, efficient and suitable induction agent.

Chanderdeepsharma, Anjali Soni PawanK. Soni Suresh Verma, Ashok

Verma, Amit gupta75

conducted a study on "Role of Mifepristone for induction of

labour in women with previous caesarean section” . It was retrospective study all

women with prior section received mifepristone for induction of labour were

compared with women who had spontaneous onset of labour pains and concluded that

mifepristone may be considered as an alternative agent for induction of labour .

Acharya R, Choudhari P, Choudhari A, Sharma A, Jains S76

conducted a

study on Mifepristone as a cervical ripening agent for labour induction with previous

one caesarean section” .Total 50 women with previous 1 LSCS included in studies

were given tab. mifegest 200mg single oral dose and bishop score was reassessed

after 48 hours. Labour was augmented with oxytocin or ARM if needed, and

concluded, Mifepristone (RU-486) is a safe, efficient and suitable agent for cervical

ripening and for initiation of labour when given 48 hr before labour induction. In

previously scarred uterus, when other methods of induction of labour are


37

contraindicated, mifepristone is a wonder drug to be used for labour induction. Even

though mifepristone is expensive, as it can be administered on outpatient basis and

significantly less need for hospital admission, it may be speculated that, there might

be overall savings in this group. Induction of labour is facilitated in term women with

prior caesarean section by the use of mifepristone. This induction agent appears safe

and useful with no adverse events on the fetus or mother.

Oleg R.Baev, Valentina P. Rumyantseva, Oleg V. Tysyachnyu, Olga A.

Kozlova, Gennady T. Sukhikh77

,conducted randomized controlled trial of 149

women were randomized, 74 for cervical ripening and induction with mifepristone

(200 mg orally at the moment of enrollment and, if applicable, second dose after 24

h), 75 – expectant management. Primary outcomes: gain in Bishop Score within 24

and 48-h of mifepristone; number of women going into spontaneous labour within 24,

48 and 72 hours of mifepristone; rate of failed induction or expectant management.

Secondary outcomes: enrollment-induction to delivery interval; mode of delivery;

requirement of oxytocin augmentation, neonatal outcomes. Results: After 48 h from

enrollment mean gain in Bishop score was 2.58 -1.33 in the induction group and 1.15-

0.97 in the expectant group (<0.001) .

To conclude Mifepristone was efficient on inducing cervical ripening and

labour in full-term pregnancy. There were no significant difference in main maternal

and neonatal outcomes between mifepristone use and expectant management. There

were no serious adverse side effects of mifepristone, but there were some features of

the course of labour , like more painful uterine contractions and trend of higher rate of

cephalopelvic disproportion, that might be directly related to the mifepristone action.

Methodology

38

METHODOLOGY

Cases for the present study were taken from Chigateri General Hospital ,

Bapuji Hospital and Women and Children Hospital, Davangere from the period

November 2016 –October 2018.

110 cases with gestational age between 41-42 weeks including cases with

previous LSCS willing for normal vaginal delivery were approached for the study.

After detailed history, examination, confirmation of diagnosis, investigations

and after written informed consent, the participant was given tab.mifepristone 200mg

single dose orally.

Inclusion Criteria

Maternal age >18 years

Gestational age 41-42 weeks

Singleton pregnancy

Cephalic presentation

Reactive FHR pattern in live fetus

Intact membranes

Bishop’s score <6

Vaginal birth after caesarean (VBAC)

Exclusion Criteria

Estimated fetal weight >4.5kg or <2kg(IUGR)

Antepartam hemorrhage

Hypertensive disorders of pregnancy

Chorioamnionitis

Methodology

39

Parity<4

Severe oiligohydramnios

Any medical complications of mother

Contraindications to vaginal birth

Indications For Induction In Our Study

Post dated pregnancy

PROCEDURE:

After obtaining informed consent, patients with full term pregnancy who

would fulfill the above inclusion criteria were selected for study.

History was noted down

general physical examination

Systemic examination

Per abdomen examination

Per vaginal examination – gentle pelvic examination was done to assess the

status of cervix by modified bishops score.

Tab mifepristone 200mg single dose was given after examination was

complete. Bishop score was assessed on admission.

Repeat bishop score was assessed at the end of 24 hours. If it was <6, labour

was induced using other inducing agents like tablet misoprostol 25micrograms 4th

hourly, cerviprime gel instillation till the bishop score became >6 or the women

entered active labour, no other method of induction was used.

Methodology

40

If the bishop score was >6 at the end of 24 hours , ARM was done and if

required oxytocin was started for augmentation of labour.

After induction patients were monitored for signs of labour, when labour

ensued, they were closely monitored for maternal vital signs, progress of labour, and

fetal heart rate which was monitored by intermittent auscultation.

If fetal heart rate remained normal with satisfactory progress of labour , those

women were kept for vaginal delivery.

If the progress was unsatisfactory or variable fetal heart rate pattern, those

women were taken for caesarean section.

The effectiveness of Mifepristone was assessed on the basis of improvement

in bishop score, and duration of induction to active phase of labour .

Safety of Mifepristone was assessed in terms of effect of the drug on maternal

and prenatal outcome.

Successful induction was considered when women entered into active labour

within 24 to 48 hours after administration of mifepristone.

Failed induction was considered when women failed to enter into active labour

at the end of 48 hours of administration of tab Mifepristone.

For hyperstimulation syndrome terbutaline 250µgms subcutaneous injection

was given.

Episodes of uterine tachysystole defined as >5 contractions in 10 minutes or a

single contraction lasting more than 2 minutes and FHR abnormalities (variable

Methodology

41

decelerations and bradycardia) were sought. The frequency was assessed by counting

the number of contractions occurring was measured in seconds.

Hypertonus is defined as a single sustained uterine contraction lasting for >2

minutes.

Hyperstimulation syndrome is defined as presence of tachysystole or

hypertonus accompanied by fetal heart rate abnormality. (Deceleration or tachycardia)

.

Sample Size Estimation

42

SAMPLE SIZE ESTIMATION

Sample size is calculated using the formula : n= {Z1-α/2}2 × S

2

d2

Z1-α/2 = 1.96

S = Standard deviation of Bishop's score based on previous literature70

d = 7% of mean Bishop's score = 7.1 (2.02) = 0.1414

Sample size = (1.96)2 × (0.749)

2

( 0.1414)2

= 108 110

Results

43

RESULTS

The present study was conducted over period of 24 months from September

2016 to August 2018 on 110 cases who fulfilled the mentioned criteria with prolonged

pregnancies, admitted in hospitals attached to JJM Medical College, Davangere.

(Bapuji Hospital, Chigateri Hospital, and Women and Children Hospital)

These 110 patients with prolonged pregnancy were given 200mg of single

tablet Mifepristone after assessing the modified Bishop’s score.

Results

44

Table 6: Distribution of parity.

PARITY NO. OF

PATIENTS Percent

PRIMI 65 59.1

MULTI 28 25.5

G2P1L1 PREVIOUS 1 LSCS 17 15.5

Total 110 100.0

In our study 65 women (59.1%) were primigravidae, 28 women (25.5%)

multigravidae, and 17 women (15.5%) were with previous 1 LSCS.

Graph-1 : Distribution of parity

Results

45

Table -7 : Gestational age distribution.

GA NO. OF PATIENTS Percent

≤40 15 13.6

>40 95 86.4

Total 110 100.0

95 (86.4%) women involved in the study were with gestational age 41 weeks

and beyond and 15 women (13.6%) of women were with gestational age less than 40

weeks.

Graph-2 : Gestational age distribution

Results

46

Table 8. Maternal outcome

Pre and Post Induction Bishop's Score

BISHOP SCORE Mean Std.

Deviation t value p value

PRE 3.236 0.918 -33.890 0.000

POST 8.355 1.810

Minimum Maximum Mean Std.

Deviation

PREBISHOPSCORE 2 5 3.24 .918

POSTBISHOPSCORE 4 12 8.35 1.810

IDI 24 72 43.59 11.890

In our study there was mean change in the bishop’s score from 3.24 to 8.35 at

the end of 24 hours after the administration of tab Mifepristone.

Graph -3 : Pre and post induction Bishop score.

Statistically significant change in the bishop’s score was observed at the end

of 24 hours.

Results

47

Table 9. Mode of delivery

MODE OF DELIVERY NO. OF PATIENTS Percent

FTVD 99 90.0

LSCS 11 10.0

Total 110 100.0

The above table explains the maternal outcome. Out of 110 patients induced,

99 delivered vaginally, 11 patients underwent caesarean section.

Graph - 4 : Mode of delivery.

Results

48

Table -10 : Other methods of induction

Other Methods of Induction No. of patients Percent

1 CP GEL 11 10.0

1 MISO 10 9.1

2 CP GEL 8 7.3

NO 81 73.6

Total 110 100.0

After 24 hours of administration of tab Mifepristone , if the bishop score

remains <6, patients were induced with other methods of induction. The above table

shows 11 patients among 110 were induced with 1 dose of cerviprime gel , 10 patients

were induced with tab misoprostol 25 micrograms and 81 (73.6%) patients required

no other methods of induction where in the bishop score at the end of 24-36 hours was

>8.

Graph – 5 : Other methods of induction

In our study 73.6% women delivered without the need of any other methods of

induction other than mifepristone.

Results

49

Table : 11 Indication for LSCS

Indication No. Of patients Percent

Failed Induction 8 7.27

Other causes 3 2.73

Above table shows failed induction rate in our study which was 7.27%. i.e. 8

patients were taken up for caesarean section in view of failed induction.

Table 12 : IDI

Parity Mean Std. Deviation p value

PRIMI 47.77 12.320 0.000

MULTI 37.56 8.151

The above table shows mean induction delivery interval in primigravidae was

47.77 hours and in multigravidae was 37.56 hours.

Graph -6 . Induction delivery interval

Results

50

Table – 13: Perinatal outcome

Neonatal outcome No. Of patients Percent

MECONIUM 3 2.7

NICU ADMISSION 1 0.9

HEALTHY 106 96.4

Total 110 100.0

The above table explains the incidence of meconium stained liquor was 2.7%,

and NICU admission rate was 0.9%.

Graph – 7 : Perinatal outcome.

Results

51

RESULTS

Table 4 and 5 showed distribution of women according to gestational age and

parity.

Table 6 shows maternal outcome. At the end of 24 hours there was significant

change in Bishop’s score from 3.24 to 8.35. Mean induction to delivery interval was

47.77 hours in primigravidae.

73.6% of women delivered without the need of any other methods of induction

within 48 hours of admission. 9.1% of women delivered with 1 dose of 25g oral

misoprostol and 10% women were induced with 1 dose cerviprime gel. 10% women

underwent caesarean section.

Table 11, Perinatal outcome was assessed and comparison was made between

healthy baby and Babies with adverse outcome (perinatal death / NICU admission) .

Only one baby was admitted to NICU in view of low APGAR score. No perinatal

deaths and no significant perinatal morbidity and mortality.3 babies were admitted to

NICU in view of meconium and discharged successfully.

Discussion

52

DISCUSSION

In our study we intended to assess the efficacy of tab Mifepristone for pre-

induction cervical ripening and induction of labour at term. This study was restricted

to the patients who were admitted to the Chigateri hospital, Women and Children

hospital, and Bapuji hospital, Davangere , who fulfilled inclusion and exclusion

criteria. Ours is a prospective study involving 110 patients.

Research continues to invent and modify doses of different drugs for induction

of labour . The female sex hormone, progesterone stops the uterus contracting during

pregnancy. Drugs such as mifepristone have been used to stop the action of this

hormone, either to induce labour or to allow the pregnancy to be terminated. In the

present study tab Mifepristone 200mg single dose was given after assessing Bishop’s

score on admission..

In the present study 90% patients were delivered vaginally, 10% underwent

emergency LSCS. There was significant change in the Bishop score at the end of 24

hours after the mifepristone administration.73.6% patients delivered vaginally without

any other method of induction followed by mifepristone. 10% patients were induced

with single dose of cerviprime gel at the end of 24 hours where the Bishop's score was

<6. The average induction delivery interval was 47.57 hours in primigravidae. Similar

results were reported by Wing et al. More spontaneous vaginal deliveries and less

incidence of LSCS and less instrumental deliveries were noted by Fathima et al.73

Byrne78

demonstrated that Mifepristone exposure and induced labour were

associated with increase in cortisol levels, which was observed within 18 hours.

Discussion

53

Hapangama D, Neilson JP (May 2009) 72

, in their study of “Mifepristone for

induction of labour” compared to placebo (108 women) , mifepristone treated women

were more likely to have a favourable cervix at 48 hours [risk ratio (RR) 2.41, 95%

confidence intervals (CI) 1.70 to 3.42]. Less likely to undergo caesarean section or

failure of induction .

Li L, Gao W79

, Chen S did a study at Beijing Tian Tan Hospital, Capital

University of Medicine on Labour induction in women at term with mifepristone and

misoprostol. Results of their study, women who were given mifepristone: the cervical

length was 1-3 cm shorter and Bishop score was 4-5 higher than those before

treatment.

In our study statistically significant improvement was observed in mean

Bishop’s score at the end of 24 hours. This improvement in score indirectly indicates

withdrawl of progesterone.

Wing et al.80

demonstrated favorable Bishop score after 24 hours of

mifepristone.

Atwale et al.71

and Fathima et al.73

also noted the significant change in Bishop

score with the use of oral Mifepristone.

Our results were consistent with the literature that showed decreased

prostaglandin requirements for term induction.

Hapangama and Neilson72

reported that mifepristone -treated women were less

likely to undergo caesarean section as a result of failure to induce labour (RR 1.43,

95 % CI 0.20–0, 80) and they were less likely to need the augmentation with oxytocin

(RR 0.80, 95 % CI 0.66–0.97) . The rate of successful induction in our study was

Discussion

54

comparable with Wing et al. Hapangama and Neilson reported abnormal fetal heart

rate pattern, common after mifepristone treatment (RR 1.85,95 % CI 1.17–2.93) ,but

there was no difference in other neonatal outcome.

Similar study done by Lelaidier C81

, in 1994, also reported its safety and

efficacy as a labour induction method in women at term in previous caesarean

section. In one such study of over 12,000 women with singleton gestations ≥ 39

weeks and one low transverse caesarean delivery, women undergoing induction of

labour at 39(0/7 to 3/7) weeks without an acute obstetric medical indication were

more likely to deliver vaginally than those managed expectantly.

Study conducted by Khanan yelikar 70

, A single blind randomized control trial,

68% women delivered vaginally within 24-48 hours after single dose mifepristone

administration , 12% caesarean section rate and there was reduced need of

prostaglandin or oxytocin augmentation following use of mifepristone.

In our study total – cases with previous 1 LSCS willing for trial of labour were

given a single dose of tab mifepristone at 39 weeks . Total 17 patients were involved

in the study, and all delivered vaginaly with proper maternal and fetal monitoring

throughout. Hence it is found to be safe as an inductive agent as a cervical ripening

agent in a patient with previous 1 LSCS willing for normal vaginal delivery.

MATERNAL COMPLICATIONS

In the present study no patients were reported to have tachysystole,

hyperstimulation of the uterus or post partum hemorrhage. No significant maternal

mortality and morbidity.

Discussion

55

NEONATAL COMPLICATIONS

In this study 96.7% neonates were healthy , with 0.9% rate of NICU admission

with no perinatal deaths . No significant perinatal mortality and morbidity.

Conclusion

56

CONCLUSION

Mifepristone is a safe, efficient,suitable and effective inducting agent for

cervical ripening which can be used in prolonged pregnancy.

It is a progesterone antagonist, is known to cause softening and dilation of the

human pregnant cervix and an increase in uterine activity.

Mifepristone is associated with an increase in the chance of vaginal delivery

within 24-48 hours with decreasing incidence of LSCS. Hence mifepristone combined

with or without augmentation is a safe, economical and convenient induction agent

for initiation of labour in women at term.

It is an attractive agent as it has no major maternal side effects nor the fetal

side effects.

As a inducing agent it has very less effects like uterine tachysystole, fetal heart

rate variations, meconium stained liquor, NICU admissions and risk of scar rupture in

case of previous CS.

In a previous scarred uterus when other drugs can not be used to induce

labour, Mifepristone is a wonder drug for induction of labour in a case of previous

LSCS willing for trial of labour.

However more studies are required on larger population to prove it to be an

ideal agent for cervical ripening. Therefore, this may justify future trials comparing

mifepristone with the routine cervical ripening agents currently in use.

Summary

57

SUMMARY

The present study to evaluate the efficacy of Mifepristone in preinduction

cervical ripening and induction of labour at term was carried out on 110 women with

prolonged pregnancy in department of obstetrics and gynaecology, J.J.M. Medical

college, Davangere, from 2016 to 2018.

It was a prospective study where post datism was the major indication who

participated in study following informed consent.

There was significant change in the mean Bishop’s score at the end of 24, 48

hours after the administration of tab Mifepristone single dose.

Mifepristone as a cervical inducing agent was well tolerated without any

adverse effects on the mother or fetus.

Mifepristone is an effective inducing agent for pre-induction cervical ripening.

There were no major adverse effects like uterine hyperstimulation , or

abnormal fetal heart rate pattern.

There was increase in the rate of vaginal deliveries.

It can be used as an inductive agent at term.

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Annexures

74

CONSENT

Annexures

81

Annexures

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ANNEXURE - I

Annexures

70

Annexures

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Annexures

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Annexures

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Annexures

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KEY TO MASTER CHART

CP Cerviprime

FTVD Full term vaginal delivery

IDI Induction delivery interval

Meso Misoprostol

Multi Multigravida

Primi Primigravida

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Annexures

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study of mifepristone for pre- induction cervical …

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