RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA

SYNOPSIS OF

DISSERTATION

“COMPARITIVE STUDY OF EARLY 24 HOURS VERSUS LATE 48 HOURS MISOPROSTOL

ADMINISTRATION AFTER MIFEPRISTONE FOR TERMINATION OF EARLY PREGNANCY”

Submitted by

Dr. N. PRIYA M.B.B.S.

POST GRADUATE STUDENT IN OBSTETRICS AND GYNAECOLOGY (M.S)

DEPARTMENT OF OBSTETRICS AND GYNAECOLOGY ADICHUNCHANAGIRI INSTITUTE OF MEDICAL SCIENCES,

B.G.NAGARA-571448

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1 NAME OF THE CANDIDATEAND ADDRESS(in block letters)

Dr. N. PRIYAP.G IN OBSTETRICS & GYNAECOLOGY,ADICHUNCHUNAGIRI INSTITUTE OF MEDICAL SCIENCES.B.G NAGARA,MANDYA DISTRICT -571448

2. NAME OF THE INSTITUTION ADICHUNCHANAGIRI INSTITUTE OFMEDICAL SCIENCES, B.G.NAGARA.

3. COURSE OF STUDY AND SUBJECT M.S. IN OBSTETRICS & GYNAECOLOGY

4. DATE OF ADMISSION TO COURSE 1ST AUGUST 2013

5. TITLE OF THE TOPIC“COMPARITIVE STUDY OF EARLY 24

HOURS VERSUS LATE 48 HOURS MISOPROSTOL ADMINISTRATION

AFTER MIFEPRISTONE FOR TERMINATION OF EARLY

PREGNANCY”6. BRIEF RESUME OF INTENDED WORK

6.1 NEED FOR THE STUDY

6.2 REVIEW OF LITERATURE

6.3 OBJECTIVES OF THE STUDY

APPENDIX-I

APPENDIX-IA

APPENDIX-IB

APPENDIX-IC

7 MATERIALS AND METHODS

7.1 SOURCE OF DATA

7.2 METHOD OF COLLECTION OF DATA : (INCLUDING SAMPLING PROCEDURE IF ANY)

7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER ANIMALS, IF SO PLEASE DESCRIBE BRIEFLY.

7.4 HAS ETHICAL CLEARENCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF 7.3

APPENDIX-II

APPENDIX-IIA

APPENDIX-IIB

YESAPPENDIX-IIC

YESAPPENDIX-IID

8. LIST OF REFERENCES APPENDIX – III

9. SIGNATURE OF THE CANDIDATE

1

10. REMARKS OF THE GUIDEThe spectrum in management of MTP has evolved from surgical methods to medical methods, which is highly effective and well accepted in early 1st trimester (upto 9 weeks). It is important to ensure compliance and decrease the time interval between induction and expulsion of conceptus while on medical abortion. Thus it is worthwhile to compare the efficacy of early (24 hours) versus late 48 hours of misoprostol administration after mifepristone for termination of early pregnancy.

11 NAME AND DESIGNATION (in Block Letters)

11.1 GUIDE Dr. PRASHANT. S. JOSHI M.D, D.N.B.

Associate Professor,Department of Obstetrics and Gynecology,AIMS, B.G. Nagara-571448

11.2 SIGNATURE OF THE GUIDE

11.3 CO-GUIDE (IF ANY) -

11.4 SIGNATURE -

11.5 HEAD OF DEPARTMENT Dr. S. VIJAYALAKSHMI, M.D, D.G.O

Professor and HeadDepartment of Obstetrics and GynecologyAIMS, B.G. Nagara-571448

11.6 SIGNATURE

12 12.1 REMARKS OF THE CHAIRMAN AND PRINCIPAL

Dr. SHIVARAMU. M.G., M.B.B.S., M.D.

PRINCIPAL,AIMS, B.G. NAGARA.

12.2 SIGNATURE

2

APPENDIX-I

6.BRIEF RESUME OF THE INTENDED WORK:

APPENDIX –I A

6.1 NEED FOR THE STUDY:

This study is designed to compare the efficacy of early administration of misoprostol

(24 hrs after mifepristone) with standard protocol of mifepristone-misoprostol combination at

48 hrs interval for termination of pregnancy less than 9 weeks.

An estimated 40 million pregnancies are terminated worldwide each year.1,2 Safety of

procedure is therefore of global public health importance. The annual number of legal

terminations in India is 0.6 million per year, which contribute hardly 10% of total abortions

done in the country.3 In other words, illegal terminations are still rife and 9% of maternal

deaths in India are because of illegal terminations per year.3 Termination of pregnancy can be

performed by medical and surgical methods. Medical abortion, also called “chemical abortion”

is the induction of early abortion by means of medications. A medical abortion is said to be

successful when the medication used, achieves complete expulsion of the products of

conception, without the need of any surgical intervention.4 Medical terminations are safe and

effective alternative to surgical vacuum aspiration of uterus with high level of patient

satisfaction.5

Mifepristone (RU486) is a potent antiprogestin but when it is administered alone for

early pregnancy termination, it results in incomplete expulsion in approximately 20% of

women.6 This relative lack of efficacy may be due to an insufficient increase in prostaglandin

concentration in uterus to allow completion of termination.4 Administration of misoprostol

after mifepristone, in different dosage schedules, has been found to be effective, feasible, and

3

acceptable method of medical termination in early pregnancy.5 The current common protocol

for medical termination of pregnancy is oral administration of 200 mg mifepristone followed

by 800microgram of misoprostol vaginally after 36-48 hrs.4 It is anticipated that compliance

may increase if the above protocol can be successfully modified to reduce the time interval

between induction of abortion and expulsion of conceptus.

The aim of the present study is to compare the efficacy of mifepristone followed by

misoprostol after 24 hrs with the standard protocol (mifepristone followed by misoprostol after

48 h).

APPENDIX –I B

6.2 REVIEW OF LITERATURE

The word abortion was derived from the latin word aboriri-to miscarry. Abortion is the

termination of pregnancy either spontaneously or intentionally before the fetus develops

sufficiently to survive. WHO defines abortion as expulsion or extraction from its mother of an

embryo or fetus weighing 500 gm or less, when it is not capable of independent survival. This

500 gm of fetal development is attained in 22 weeks of gestation.7

In modern obstetrics, there are few indications for therapeutic abortion7 such as,

1. Cardiac disease (III and IV) and decompensation in a previous pregnancy. It is

necessary that optimum compensation be established prior termination.

2. Epilepsy and other forms of psychosis in the mother who had a number of children may

justify a therapeutic abortion.

3. Intractable hyperemesis gravidarum will necessitate termination of pregnancy.

4. If the mother contracts German measles in the early weeks of pregnancy, induction of

abortion is advocated by some on the plea of a malformed fetus being born.

5. Chronic glomerulonephritis, malignant hypertension, pregnancy following radical

mastectomy for carcinoma of breast are other indications.

4

Methods of first trimester termination of pregnancy

Medical methods:7

1. Prostaglandin

2. Anti-progesterone-RU486 (Mifepristone)

3. Methotrexate-intramuscular and oral

Surgical methods:7

1. Vacuum aspiration (suction curettage)-manual or electric

2. Cervical dilatation and evacuation. (D+E)

3. Curettage

Features of medical and surgical methods7

Medical Methods Surgical Methods

1 Usually avoids invasive procedure Invasive procedure

2 Usually avoids anaesthesia Sedation used if desired

3 Regular two or more visits Usually requires one visit

4 Days to weeks to complete Complete in a predictable period

5 Available during early pregnancy Available during early pregnancy

6 High success rate (95%) High success rate (99%)

7 Regular follow up to ensure completion of abortion

Doesn’t require follow up in all cases

8 Requires patient participation throughout multi step process

Requires participation in a single step process

CONTRAINDICATIONS OF MEDICAL ABORTION7

Allergy

Intrauterine disease

Severe anaemia

Coagulopathy

5

Acute liver disease

Cardio vascular disease

Uncontrolled seizure disorder

Adrenal diseases

On glucocorticoid therapy.

Medical abortion has been a revolution in obstetrics practice, for ease and safety it

provides to the clinician and the patient. Over the past 5 years multiple studies have focused on

time interval between the two medications.8,9 Decreasing the time interval allows most women

to complete the process in lesser time. Additionally, because approximately 50% of women

started having vaginal bleeding during 48 h interval between mifepristone and misoprostol

administration with standard regimen, administering the drugs on the same day would decrease

undesirable adverse effects.

Various studies10,11 have shown that peak serum concentration of mifepristone is more

or less invariable for a dose that ranges between 100 mg and 800 mg. On the basis of this fact,

200 mg single dose of mifepristone is used in the study. Vaginal route of misoprostol is more

efficacious than oral route at equivalent doses. Various studies12,13 reported 95% success rate

with vaginal misoprostol compared to only 87% with oral misoprostol at 48 h interval.

This was because systemic bio-availability of misoprostol was 4 times higher through

vaginal route when compared with oral route and peak level was attained more slowly

sustained for longer period.14 The success rate of 48 h interval regimen ranged from 92% to

97%.15

Crenin et al. reported success rate of 24 h regimen to be 98.1% and 96.9% in their

studies carried out in 2004 and 2007. Manju V et al reported a success rate of 94% in their

study.1

6

Ashok et al. (2002)16 showed that women with lower gestational age were significantly

more likely to abort successfully even after mifepristone alone. The continuing pregnancy rates

were higher in the higher gestational band.

Spitz et al. (1998)17 observed that failure rate in women undergoing medical abortion

using 200 mg oral mifepristone and single dose of 400 μg oral misoprostol after 48 h was

significantly higher with increasing gestation. Efficacy of only 77% was observed at 57-63

days of gestation compared to 90% in 50-56 days of gestation and 94% in gestation of 49 days

or less.

Common side effects of mifepristone are abdominal pain, nausea, vomiting, and

diarrhea.8,18 Pelvic pain, fainting, and headache. Side effects of misoprostol are nausea,

vomiting, diarrhea, headache, and dizziness.8,18 Coyaji et al. (2007) showed a higher percentage

of women in 48 h interval group reported side effects such as nausea and vomiting after

mifepristone administration than women in the 24 h group.18 This may be related to fact that as

time interval is longer there is more chance to experience these symptoms. In the present also,

as 24 h interval is used to see if it is associated with lower rates of the symptoms and it is

reasonable to recommend it.

To assess the satisfaction status, Yiu Tai Li et al. (2006)3 analyzed as to how many

patients agreed with the therapy they had received. They observed that 72.2% cases strongly

agreed, 18.9% cases agreed, 6.7% were neutral, and only 2.2% disagreed. The overall

satisfaction rate was 91.1%.

The present study is being carried out to see if the interval between mifepristone and

misoprostol could be reduced to 24 h when compared with the present standard of 48 h and to

see if this regimen is equally efficacious and safe when compared with the standard regimen.

7

APPENDIX –IC

6.3 AIMS AND OBJECTIVES OF STUDY

1. The aim of the present study is to compare the efficacy of mifepristone followed after

24 hrs by misoprostol with the standard protocol (mifepristone followed by misoprostol

after 48 hrs).

2. To evaluate whether this 24 hr interval between Mifepristone and Misoprostol will be a

reasonable alternative to standard protocol (48 hrs interval).

8

APPENDIX-II

7.0 MATERIALS AND METHODS

APPENDIX-II A

7.1 SOURCE OF DATA

This prospective case-control study will be carried out in the Department of Obstetrics

and Gynaecology, Sri Adichunchanagiri Hospital and Research Centre, B.G.Nagara during the

period November 2013 to November 2015.

Study Design - A Prospective case control study.

Study Period - 24 months (November 2013-November 2015)

APPENDIX-II B

7.2 METHOD OF COLLECTION OF DATA

SAMPLE SIZE :

A sample size of minimum 30 women with gestational age of less than 9 weeks

undergoing medical termination of pregnancy will be taken under case group and control

group.

INCLUSION CRITERIA :

1. Women with gestational age of less than 9 wks as determined by ultrasonographic dating

and who decided to go for medical abortion will be considered in the present study.

2. Women who are willing for follow-up.

3. Age group between 18-34 years.

EXCLUSION CRITERIA

1. Women in whom ectopic gestation is suspected (even clinically).

2. Women who are not willing for follow-up protocols.

3. Breast feeding mothers.

9

4. Women with haemoglobin of < 10 gm%

5. Women with previous cervical surgery.

Scarred cervix.

6. Women with previous scar in the uterus.

7. Women with asthma/glaucoma/adrenal insufficiency/poorly controlled seizures /

cardiovascular disease/coagulopathy.

8. Women on systemic corticosteroid therapy/anticoagulant therapy

9. Pregnancy with IUCD.

PROCEDURE:

Informed written consent of the patient will be taken.

PREPARATION OF THE PATIENT

- Complete history will be taken and thorough general and systemic examination will be

carried out.

- Speculum and vaginal examination will be done in all the cases. Patients will be counselled

about the method and side effects of the drug.

Subjects in study arm will be given 200 mg oral mifepristone followed by 800 μg

vaginal misoprostol after 24 h, whereas those in control arm will be given 200 mg oral

mifepristone followed by 800 μg of vaginal misoprostol after 48 h.

Sequential allocation will be done in the ratio of 1:1. All the subjects will be informed

about the signs and symptoms of expulsion and need for follow-up. All women will be given a

24 hours contact telephone number for any post-treatment advice. They will be asked to come

for follow-up after 14 days when transvaginal ultrasound (TVS) will be performed to confirm if

expulsion process was complete.

10

STATISTICAL ANALYSIS :

It will be done by using Student t test where continuous variables will be involved and

Chisquare test where frequency variable will be involved. The P value will be calculated and if

P < 0.05, it will be considered as statistically significant.

APPENDIX-II C

7.3 Does the study require any investigation or intervention to be conducted on the

patients or animals, if so please describe briefly

YES

Investigation :

Haematological:

1. Haemoglobin percentage.

2. Blood grouping and Rh typing

3. Packed cell volume

4. Bleeding time and Clotting time

5. Platelet count.

URINE:

1. Albumin

2. Sugar

3. Microscopy

Blood sugar

HIV screening

HBSAg.

VDRL.

Transvaginal Ultrasound

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APPENDIX-IID

PROFORMA APPLICATION FOR ETHICS COMMITTEE APPROVAL

SECTION A

a Title of the study

“COMPARITIVE STUDY OF EARLY 24 HOURS VERSUS LATE 48 HOURS

MISOPROSTOL ADMINISTRATION AFTER MIFEPRISTONE FOR TERMINATION OF

EARLY PREGNANCY”

b Principle investigator(Name and Designation)

Dr. N. PRIYAP.G IN OBSTETRICS & GYNAECOLOGY,ADICHUNCHUNAGIRI INSTITUTE OF MEDICAL SCIENCES.B.G NAGARA,MANDYA DISTRICT -571448

c Co-investigator(Name and Designation)

Dr. PRASHANT. S. JOSHI M.D, D.N.B.

Associate Professor,Department of Obstetrics and Gynecology,AIMS, B.G. Nagara-571448

d Name of the CollaboratingDepartment/Institutions NO

eWhether permission has been obtained from the heads of the collaborating departments & Institution

NA

Section – B

Summary of the Project APPENDIX – I

Section – C

Objectives of the study APPENDIX – IB

Section – D

Methodology APPENDIX – II

A Where the proposed study will be undertakenDEPARTMENT OF O.B.G.,

S.A.H. & R.C., B.G.NAGARA

B Duration of the Project 24 MONTHS

C Nature of the subjects:

Does the study involve adult patients?

Does the study involve Children?

Does the study involve normal volunteers?

Does the study involve Psychiatric patients?

Does the study involve pregnant women?

YES

NO

NO

NO

YES

12

D If the study involves health volunteers

I. Will they be institute students?

II. Will they be institute employees?

III. Will they be Paid?

IV. If they are to be paid, how much per

session?

NO

NO

NO

NO

E Is the study a part of multi central trial? NO

F If yes, who is the coordinator?(Name and Designation)

Has the trail been approved by the ethics Committee of the other centers?

If the study involves the use of drugs please indicate whether. I. The drug is marketed in India for the indication in which it will be used in the study.

II. The drug is marketed in India but not for the indication in which it will be used in the study

III. The drug is only used for experimental use in humans.

IV. Clearance of the drugs controller of India has been obtained for:

Use of the drug in healthy volunteers Use of the drug in-patients for a new

indication. Phase one and two clinical trials Experimental use in-patients and healthy

volunteers.

NA

NA

-

YES

NO

NO

NA

NO

13

G How do you propose to obtain the drug to be

used in the study?

- Gift from a drug company

- Hospital supplies

- Patients will be asked to purchase

- Other sources (Explain)

Patient will be asked to purchase

H Funding (If any) for the project please state

- None

- Amount

- Source

- To whom payable

NO

IDoes any agency have a vested interest in the

out come of the Project? NO

JWill data relating to subjects /controls be stored

in a computer? NO

K

Will the data analysis be done by

- The researcher?

- The funding agent

YES

NO

L Will technical / nursing help be required form

the staff of hospital.

If yes, will it interfere with their duties?

Will you recruit other staff for the duration of

the study?

If Yes give details of

I. Designation

II. Qualification

III. Number

IV. Duration of Employment

NO

NO

NO

NA

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M Will informed consent be taken? If yes

Will it be written informed consent:

Will it be oral consent?

Will it be taken from the subject themselves?

Will it be from the legal guardian? If no, give

reason:

YES, INFORMED WRITTEN CONSENT

WILL BE TAKEN FROM THE PATIENT

NO

YES

YES

N Describe design, Methodology and techniques APPENDIX II

Ethical clearance has been accorded.

Chairman,P.G Training Cum-Research Institute,

A.I.M.S., B.G.Nagara.Date :

PS : NA – Not Applicable

15

APPENDIX-III

8. LIST OF REFERENCES

1. Verma ML, Singh U, Singh N, Shankhwar P, Srivastava D. Efficacy of misoprostol

administration 24 hours after mifepristone for termination of early pregnancy. Indian J Med

Sci. 2011; 65: 511-7.

2. Sedgh G, Henshaw S, Singh S, Ahman E, Shah IH. Induced abortion: Estimated rates and

trends worldwide. Lancet. 2007; 370: 1338-45.

3. Ministry of Health and Family Welfare GOI. Department of Family Welfare. Year Book.

1992-1994.

4. ACOG. ACOG practice bulletin. Clinical management guidelines of obstetrician

gynecologists. Obstetrician gynecologists. Medical management of abortion. Obstet

Gynecol. Number 67, 2005; 106: 871-82.

5. Winikoff B, Sivin I, Coyaji KJ, Cabezas E, Xiao B, Gu S, et al. Safety, efficacy, and

acceptability of medical abortion in China, Cuba, and India: A comparative trial of

mifepristone-misoprostol versus surgical abortion. Am J Obstet Gynecol. 1997; 176: 431-7.

6. Kulier R, Gülmezoglu AM, Hofmeyr GJ, Cheng LN, Campana A. Medical methods for

first trimester abortion. Cochrane Database Syst Rev. 2004; 2: CD002855.

7. Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY. Abortion. In:

Williams Obstetrics, 23rd edition. New York, McGraw-Hill. 2010: 215-237.

8. Creinin MD, Schreiber CA, Bednarek P, Lintu H, Wagner MS, Meyn LA, et al.

Mifepristone and misoprostol administered simultaneously versus 24 hours apart for

abortion: A randomized controlled trial. Obstet Gynecol. 2007; 109: 885-94.

9. Creinin MD, Fox MC, Teal S, Chen A, Schaff EA, Meyn LA, et al. A randomized

comparison of misoprostol 6 to 8 hours versus 24 hours after mifepristone for abortion.

Obstet Gynecol 2004; 103: 851-9.

16

10. Shi YE, Ye ZH, He CH, Zhang GQ, Xu JQ, Van Look PF, et al. Pharmacokinetic study of

RU 486 and its metabolites after oral administration of single doses to pregnant and non-

pregnant women. Contraception. 1993; 48: 133-49.

11. Swahn ML, Wang G, Aedo AR, Cekan SZ, Bygdeman M. Plasma levels of antiprogestin

RU 486 following oral administration to non-pregnant and early pregnant women.

Contraception 1986; 34: 469-81.

12. El-Refaey H, Rajasekar D, Abdalla M, Calder L, Templeton A. Induction of abortion with

mifepristone (RU 486) and oral or vaginal misoprostol. N Engl J Med. 1995; 332: 983-7.

13. Guest J, Chien PF, Thomson MA, Kosseim ML. Randomised controlled trial comparing the

efficacy of same-day administration of mifepristone and misoprostol for termination of

pregnancy with the standard 36 to 48 hour protocol. BJOG. 2007; 114: 207-15.

14. Tang OS, Gemzell-Danielsson K, Ho PC. Misoprostol: Pharmacokinetic profiles, effects on

the uterus and side-effects. Int J Gynaecol Obstet. 2007; 99: S160-7.

15. Schaff EA, Fielding SL, Westhoff C, Ellertson C, Eisinger SH, Stadalius LS, et al. Vaginal

misoprostol administered 1, 2, or 3 days after mifepristone for early medical abortion: A

randomized trial. JAMA. 2000; 284: 1948-53.

16. Ashok PW, Kidd A, Flett GM, Fitzmaurice A, Graham W, Templeton A. A randomized

comparison of medical abortion and surgical vacuum aspiration at 10-13 weeks gestation.

Hum Reprod. 2002; 17: 92-8.

17. Spitz IM, Bardin CW, Benton L, Robbins A. Early pregnancy termination with

mifepristone and misoprostol in the United States. N Engl J Med. 1998; 338: 1241-7.

18. Coyaji K, Krishna U, Ambardekar S, Bracken H, Raote V, Mandlekar A, et al. Are two

doses of misoprostol after mifepristone for early abortion better than one? BJOG 2007;

114: 271-8.

17

PROFORMA

“COMPARITIVE STUDY OF EARLY 24 HOURS VERSUS LATE 48 HOURS MISOPROSTOL ADMINISTRATION AFTER MIFEPRISTONE FOR

TERMINATION OF EARLY PREGNANCY”

By : Dr. N. Priya

Guide : Dr. Prashant S Joshi

Name : Education :

Age : Occupation :

MR NO : Per capita income :

Address :

Socioeconomic status :

Married life :

Consanguinity :

Obstetric score :

H/O previous deliveries :

Period of pregnancy :

Whether any medical disease associated with pregnancy :

Menstrual History :

Previous menstrual cycles -

Last menstrual period -

Past Medical History :

Drug History :

Family History :

Personal History :

General Physical Examination

Built :

Nourishment :

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Pallor :

Height :

Weight :

Pulse rate :

Blood pressure :

Respiratory rate :

Per abdomen :

Per speculum :

Per vaginal :

Ultrasonogram findings :

Coagulation profile :

Hb & HCT before induction with misoprostol :

Hb & HCT 48 hrs after expulsion :

Date of application of Misoprostol :

Time of first vaginal application of misoprostol :

Intial dosage :

Number of doses applied :

Date of expulsion :

Time of expulsion :

Induction expulsion interval :

USG after expulsion : Complete incomplete

Whether underwent curettage later :

Side effects if any :

Follow up after 1month :

19