for the use only of .a registered medical
practitioner or a hospital or a laboratory.
ROLE OF LEPTADEN AS A TOCOLYTIC AGENT FOR THE PREVENTION OF UNTIMELY TERMINATION OF PREGNANCY
by
Dr. S. C. Saxena M.S. Reader
in Obst. & Gynec. Medical College, Jabalpur, M.P.
The Medicine & Surgery VOL. XIX No. 3 March, 1979
Paper before: XXI All India Obst: & Gynec., Conf. Cuttack 27-29 Dec. 1977.
INTRODUCTION
In a developed country like U S A.,
between 5 to 10 million of conceptions occur every year, and of these 2-3 million
are early spontaneous abortions. Out of 3.2 million pregnancies that reach 20
weeks of gestational age each year, approximately 40,000 foetuses die before
delivery. Almost the same number succumb in the first month of life, and an
equal number are born with congenital malformations. l0% of all pregnancies
end in premature labour and account for two-third of infant deaths in U.S.A.
The old saying that "prevention is better than
cure" is particularly apt in relation to prematurity, both from the medical
and economic points of view. Most of the causes of prematurity may be grouped
under two main headings of 1. Cervical Incompetence and 2. Foetal Stress.
Cervical incompetence probably predominates as
the
main cause in the earlier part of pregnancy, from 25th week of gestation
onwards, when survival is possible following delivery. However, as pregnancy
progresses and term is approached, foetal stress would appear to play a more
important role in prematurity.
The present study aims at studying the
tocolytic role of Leptaden for the prevention of untimely termination of
pregnancy.
MATERIALS & METHODS
The present study consists of 47 cases of high risk
pregnancies where previous history suggested that the present pregnancy is precious
and in some cases factors relating to intra-uterine foetal jeopardy were
present.
Leptaden was given in a dosage of 2 tablets three
times a day, throughout pregnancy. Where necessary additional measures were
also adopted. They consisted of hormones, sedatives, uterine relaxants and
surgical closure of incompetent internal os of the cervix.
The present study was conducted at the Dept. of Obst. & Gynec., Medical College, Jabalpur, from 1st June 1976 to 31st August, 1977. Among the 47 cases taken for study, 29 cases were studied throughout their pregnancies till termination, the pregnancies in 12 patients were still progressing satisfactorily at the time of presenting this report, and 6 cases were lost to follow-up.
AGE INCIDENCE
The youngest patient was aged 18 years
and the oldest patient was aged 35 years (Table No. I).
TABLE 1
Age incidence
|
Age Group |
No. of cases |
% |
|
18-20 Yrs. |
8 |
17.0 |
|
21-25 Yrs. |
15 |
31.9 |
|
26-30 Yrs. |
20 |
42.6 |
|
31-35 Yrs. |
4 |
8.5 |
|
Total |
47 |
100.0% |
DURATION OF MARRIED LIFE
Table II shows the duration of married life
of these patients. The shortest duration was 1.5 years and the longest duration
was 16 years.
TABLE II:_
of Married Life
|
Duration |
No.
of cases % |
|
1-2 Yrs. |
8 17.0 |
|
2-3 Yrs. |
3 6.4 |
|
3-4 Yrs. |
10 21.3 |
|
More than 4 yrs ._~s ..._. .... |
26 53.3 |
|
Total' . |
47 100.0% |
OCCUPATION
Table
III shows the occupation of these patients. 40 patients were housewives (Table
III)
TABLE III:
Occupation
|
Occupation |
No. of cases |
% |
|
Housewife |
40 |
85.1 |
|
Teacher |
3 |
6.4 |
|
Doctor |
2 |
4.3 |
|
Clerk |
1 |
2.1 |
|
Telephone Operator |
1 |
2.1 |
|
Total |
47 |
100.0% |
PARITY
TABLE IV: Parity
|
Parity. |
No.
of cases |
% |
|
Primigravida |
4 |
8.5 |
|
11
Para |
16 |
34.0 |
|
III
Para |
5 |
10.6 |
|
IV
Para |
10 |
21.3 |
|
V
Para |
10 |
21.3 |
|
More
than V |
2 |
4.3 |
|
Total |
47 . |
100.0% |
PREVIOUS OBSTETRIC HISTORY
These 47 patients gave a
history of previous pregnancies totaling 107 for all the patients of these 107
pregnancies. 73 ended in abortions, 17 in premature deliveries, 16 had full
term deliveries (out of these 16 full term deliveries, 4 were still births)
and one ectopic pregnancy.
Out of 73 previous abortions, 9 patients had one abortion, 9 patients had two
abortions, 7 patients had three abortions, 5 patients had four abortions and 1
patient had five abortions.
Out of 17 previous
Premature Deliveries, 5 patients had one Premature Birth, 4 patients had Two
Premature Births, and 1 patient had 4 Premature Births previously.
Out-of 16 Full Term
Deliveries, 12 patients had one Full Term delivery; out of them 2 patients had
Still Birth; 4 patients had Two Full term deliveries; one of them had 2 Still
Births previously. (Table V A, V B, V C & D.)
Table V: Previous
Obstetric History of (A) Abortions, (B) Premature Deliveries. (C) Full Term
(including Still Births) and (D) Ectopic Pregnancy. (N = 47)
|
No. of Previous Abortions |
No. of cases |
Total Abortions |
|
ONE |
9 |
9 |
|
TWO |
9 |
18 |
|
THREE |
7 |
21 |
|
FOUR |
5 |
20 |
|
FIVE |
1 |
5 |
|
Total |
31 |
73 |
(B): Previous
Premature Deliveries
|
Premature Delivery |
No. of cases |
Total Deliveries |
|
ONE |
5 |
5 |
|
TWO |
4 |
8 |
|
THREE |
- |
- |
|
FOUR |
1 |
4 |
|
TOTAL |
10 |
17 |
(C): Previous Full Term
Deliveries
|
No. of full term deliveries |
No. of cases |
Full term Live Births |
Still Births |
|
ONE |
12 |
10 |
2 |
|
TWO |
4 |
2 |
2 |
|
Total |
16 |
12 |
4 |
(D) Ectopic Pregnancy = 1
DURATION
OF PREGNANCY AT THE TIME OF FIRST VISIT
Table VI shows the
duration of pregnancy at the time of the first visit of the patient. Out of
them 6 patients showed signs of intra-uterine foetal growth retardation. (Table
VI)
CONDITION OF CERVIX AT THE TIME OF THE FIRST VISIT.
Table VI shows the
condition of the cervix. In 25 cases the cervical os was closed. In 20 patients
the internal os was patulous, and two patients had uterus didelphys. (One of
them had vertical septum throughout the length of vagina and haemomatocolpos
and haemotometra on one side. Both had the surgical correction done earlier).
Both of them were treated for sterility and were given Leptaden in the pre
conceptional period.
TABLE VI Duration of Pregnancy At The
Time of First Visit
|
Duration of Pregnancy |
No. of cases |
% |
|
4
weeks |
7 |
14.9% |
|
6
weeks |
10 |
21.3% |
|
8
weeks |
9 |
19.1% |
|
12 weeks |
6 |
12.8% |
|
16 weeks |
2 |
4.3% |
|
20 weeks |
5 |
10.6% |
|
24 weeks |
4 |
8.5% |
|
28 weeks |
4 |
8.5% |
|
Total |
47 |
100.0% |
TABLE VII: Condition of cervix at the
time of the first visit
|
Condition of the cervix |
No. of cases |
% |
|
Os closed Patulous |
25 |
53.2 |
|
internal os |
20 |
42.5 |
|
Double uterus with double |
2 |
4.3 |
|
Total |
47 |
100.0% |
LABORATORY INVESTIGATIONS
Routine blood, urine and stool examinations were carried out in all the cases and were found normal. Blood urea, blood sugar-fasting and post-meal, serum cholesterol, Blood for K. T. & VDRL of both husband and wife, and ABO and Rh of both husband and wife, were carried out in all the cases. Except in one case, these finding were normal. One patient had Rh isoimmunisation and had previous foetal losses due to this. In addition she had incompetence of internal os.
TREATMENT
Patients were kept on hormones, sedatives,
isoxsuprine and Leptaden. In 38 Patients, lnj. 17-hydroxy progesterone caproate
was given in doses of 250 mg. i.m. weekly upto 32 weeks. 5 cases received lnj.
Oestradiol valerinate 10 mg.
i.m. fortnightly. They showed signs of
intrauterine foetal growth retardation. This was given upto 32 weeks of
pregnancy. In 32 patients isoxsuprine was given in doses of 10 mg., three
times a day. Diazapam was given in doses of two tablets three times a day upto
32 weeks, while Leptaden was given in doses of two tablets three times a day up
to the termination of pregnancy. (Table VIII)
TABLE
VIII Treatment
|
Treatment |
No. of cases |
|
Oestrogen progesterone isoxsuprine, diazepam, Leptaden |
6 |
|
Progesterone,
isoxsuprine, diazepam,
Leptaden : |
3 |
|
Progesterone,
isoxsuprine, Leptaden: |
15 |
|
Diazepam,
Leptaden : |
9 |
|
Progesterone, Isoxsuprine, Diazepam, Leptaden, Shirodkar's Cerclage operation : |
14 |
|
Total |
47 |
14
patients had Shirodkar's Operation for cervical Incompetence. (Table IX).
TABLE IX Time of performing Shirodkar
Operation
|
Duration of Pregnancy |
No. of cases |
|
16
weeks |
3 |
|
20
weeks |
6 |
|
24
weeks |
4 |
|
26
weeks |
1 |
|
Total |
14 |
RESULTS
Out of 47 cases, 29 cases (Group I), were followed
till the termination. 12 cases (Group II) were still pregnant at the time of
this report and 6 cases were lost to follow-up. (Group lll).
GROUP 1
There were 29 cases in
this group and these were followed till termination. In 4 cases, the pregnancy
terminated in abortion, 5 cases terminated in premature labour, 19 cases had
mature births and one had post-mature birth.
Out of four cases,
abortion took place at 12 weeks in three cases and in one case abortion took
place at 16 weeks of pregnancy. Among these 4 cases, previous history was as follows: One patient had history of five previous abortions;
2 patients had history of one previous abortion; one patient was a primigravida
who was treated for sterility. (Table X)
TABLE X
Previous history of those cases who had
abortion in the present series
|
History |
No. of cases |
|
One
abortion |
2 |
|
Five
abortion |
1 |
|
Primigravida |
1 |
|
Total |
4 |
Five cases had premature
labour in this series. One case had premature labour at 28 weeks, one had at 32
weeks and 3 cases had at 34 weeks of pregnancy. The previous history in these
case was as follows: 2 cases had history of four abortions; one case had three
previous abortions; one case had two previous abortions; one case had two
abortions plus one premature labour. (Table XI).
TABLE XI Previous obstetric history of patients of premature Labour
History No. of
cases
|
Two abortions |
1 |
|
Two abortions + one
premature labour |
1 |
|
Three abortions |
1 |
|
Four abortions |
2 |
|
Total |
5 |
These five cases of
premature labour in the present series gave birth to three females and two
males. Three children weighed 21h kg each, and two children weighed
11/2 kg each. However,
among these five children, three children died of diarrhoea and dehydration;
one child died on the second day, one child on the 4th day, and one child on
the 10th day.
Nineteen patients delivered at term and 1 patient went post term. 12 children
were males and 8 were females. The weights of these children were; One child
weighed 2750 gms; 8 children weighed 3000 gms. each; 10 weighed 3500 gms each;
one child weighed 4000 gms. (Table XII).
TABLE XII
Weight of Full Term babies
|
Weight |
No. of cases |
|
2750 gms. |
1 |
|
3000 gms. |
8 |
|
3500 gms. |
10 |
|
4000 gms. |
1 |
|
Total |
20 |
Out of 20 deliveries, 17
delivered vaginally while 3 patients were delivered by lower segment Caesarian
section. Indications for Caesarian section were: one child, Precious; one case
was post-maturity; one case was of cervical dystocia. (Table XIII).
Type of delivery
TABLE XIII
Type of delivery No. of cases
Normal : 17
Lower segment
Caesarian section :
(a)
Precious Child : 1
(b)
Post-maturity with
toxemia : 1
(c)
Cervical dystocia : 1
Total 20
Table XIV gives the nature of previous history in
those 17 cases who delivered vaginally in this series.
TABLE XIV
Previous obstetric history of patients (17) who
delivered at term vaginally
|
Previous Obst. History |
No of cases |
|
One abortion |
5 |
|
Two abortions |
2 |
|
Three abortions |
1 |
|
Two abortions + One
premature labour |
1 |
|
Three abortions + 1
premature labour |
1 |
|
One premature labour |
1 |
|
Two premature labours |
1 |
|
Four premature labours |
1 |
|
One full term delivery |
1 |
|
One full term Still
Birth |
1 |
|
Ectopic pregnancy |
1 |
|
Primigravida |
1 |
|
Total |
17 |
SUCCESS RATE
Of these 29 cases of I Group, 4
pregnancies ended in abortion and 25 children were delivered. Out of these 25
children, four children died (3 of them were premature). The success rate of
this series is 86.2%.
Two
patients were given Leptaden in pre conceptional period also. One of them went
to
full term, but the other
had missed abortion at 12 weeks.
II GROUP: THOSE STILL UNDER FOLLOWUP AT THE TIME
OF THIS REPORT:
There were 12 patients in this Group. One patient
came at 4th week of pregnancy; 3 patients came at 6th week; 2 patients came to
8th week; One patient came 12th week,2 patients came at 16th week: one came at
20th week and two patients came at 24th week of pregnancy. Among these, 3
patients had cervical incompetence and 2 patients had uterus didelphys. Out of
the three patients of Cervical incompetence, two patients had Shirodkar's
Operation at 16th week of pregnancy, and the third patient was treated
conservatively. The first two patients have gone to 24th week, and the third
has gone to 28th week of pregnancy.
Both the patients with uterus diselphys were
treated for vaginal septum surgically before pregnancy and now (at the time of
this report) are in the 24th week of pregnancy.
The
previous obsteric histories of II Group (12 cases) are shown Table XV:
TABLE XV
History No of cases
|
One abortion |
1 |
|
Two abortions |
1 |
|
Two abortions + one Premature labour |
1 |
|
Two abortions + one Still birth |
2 |
|
Three Abortions |
2 |
|
Two Premature labours |
1 |
|
Full Term |
2 |
|
Primipara |
2 |
|
Total |
12 |
At the time of writing this report, among 12 cases
of II Group, 3 patient had gone to 12 weeks of pregnancy, 2 patients to 16
weeks, one patient to 20 weeks, 3 patients to 24 weeks, one patients to 28
weeks and 2 patients to 32 weeks of pregnancy. (Table XVI).
TABLE XVI
Progress of Pregnancy of Patients still
under study at the time of report
|
Duration of pregnancy |
No. of case's |
|
12 weeks |
3 |
|
16 weeks |
2 |
|
20 weeks |
1 |
|
24 weeks |
3 |
|
28 weeks |
1 |
|
32 weeks |
2 |
|
Total |
12 |
III GROUP: PATIENTS LOST TO FOLLOWUP
There were 14 cases who were lost to followup. At
the time of dropping from follow up, 2 cases were carrying 4th week, 3 were 8th
week and one was in 24th week of pregnancy.
LEPTADEN AS TOCOLYTIC ADJUVANT DRUG
AFTER SHIRODKAR'S OPERATION FOR CERVICAL INCOMPETENCE
There were 14 cases who underwent Shirodkar's
Operation of cerclage of cervix. Three patients were operated at 16th week of
pregnancy, fi patients at 20th week, 4 patients at 24th week and one patient at
26th week of pregnancy. Leptaden was given in post-operative period along with
hormones and sedatives and isoxsuprine. Hormones were discontinued at 32nd
week, while Leptaden was continued till the termination of pregnancy.
Out of these 14 patients 3 patients had premature
deliveries, (one at 28 weeks, one at 32 weeks and one at 34 weeks) 2 children
were under weight, one was 1.'/2 Kg.
which died after 2 days, and one was 2 Kg.
Eight patients had full term deliveries (6 children
3 Kg; 1 child - 2'/2 Kg, one
child - 4 Kg.) One patient gave birth to post-mature infant weighing 3'/2 Kg.
She was delivered by Lower Segment Caesarian section. 2 patients were still
pregnant at the time of this report with 24 weeks of pregnancy.
TABLE XVII
LABOUR NHIBITING DRUGS
Psychotropic drugs Central
Peripheral Psycho sedative Valium Librium
Spasmolytic relaxing
smooth
musculature
Anaesthetics Peripheral Membrane effect Halothane, Ether
Alcohol Inhibitin of oxytocin release Ethyl alcohol
in hypophysis
Steroid hormones Peripheral Smooth musculature
cellular
membrane
respiration
Progesterone
Spasmolyfic Peripheral Smooth musculature Papaverine,lsoptine
Calcium antagonism D-600
Opium alkaloids Central On hypophysis Dilantin
(adirretin, Oxytocin)
B-adrenergical B-stimulatives Aludrin,
Alupene
Sympathicomimetics Dilatol,
Rito drine,
Partusisten.
Additional therapy Prostaglandin antagonism Colfarit,Aspirin
acetyl salicylic acid
LEPTADEN
SIDE EFFECTS OF LEPTADEN
Four patients complained
of bad taste and 4 had occasional vomiting after taking Leptaden. The bad taste
disappeared when Leptaden was taken with milk, while vomiting disappeared after
reducing the dose temporarily.
COMMENTS
In most cases the causes
of dysregulation of the uterus are unknown and drug induced inhibition of
labour must, therefore, be considered symptomatic treatment.
Although the effective mechanism of tocolytic substance has not yet been
completely cleared up, unwanted uterine activity can be inhibited. The
substances shown in Table XVI! have been used for labour inhibiting effects in
recent years.
In 1964 Schwalm & Mosler pointed to the fact that progesterone exogenously
employed, has no tocolytic effect. Even with normal doses a synergistic effect
on extocin with increased uterine activity can be demonstrated.
Leptaden is an Ayurvedic drug consisting of two Indian herbal drugs:-
Leptadenia reticulata (Jeevanti) and Breynia patens (Kamboji). The former is
mentioned as `stimulant' and `Tonic' and latter as astringent. Its tocolytic
action was first observed by Patel (1947). Naik (1957) and Mangeshikar (1957)
made observations on this drug in cases of threatened and habitual abortions.
Mahendra Patel (1965), Achari & Sinha (1966) and Achari (1975) used this
drug in cases of habitual abortions. Its mode of action is unknown.
Sharma (1976) conducted an experimental study on
guinea pigs at Trinity College, Dublin, to study the mode of action of this
drug.
By using a sensitive
radio-immunoassay he came to conclusion that the drug has an inhibitory effect
on the ability of guinea pig uterine tissue to biosynthesise PGF 2 alpha.
Recently, much evidence
has accumulated to suggest that PGF 2 alpha plays an important role in abortion
and uterine activity. (Von Drop, 1966, Karim 1966, Csapo 1969, Karim &
Hiller 1970, Horton 1972, Poyser 1972, Sharma 1972, Sharma, et. a1.1973, Csapo
et. a1.1974).
It has been observed that
the ultimate response to oxytocin is partially dependent upon the release of
Prostagladin, which is identified as the intrinsic myometria! stimulant.
Synthesis of Prostaglandin is prompted by the increase in the uterine volume
and by oestradiol. The pregnancy is maintained by the regulatory balance of
opposing forces (Csapo 1974), and when the intrinsic mechanism of prostaglandin
is amplified; abortion or labour occurs. Suppression or inhibition of
Prostaglandin is a rational method to control abortion, and this is the possible
mechanism of action of LEPTADEN for prevention of abortion and premature
labour.
Leptaden
is safe, simple to use, cheap and without serious side effects. It can be
safely used as a tocolytic drug alone or in combination with other labour
inhibiting drugs.
SUMMARY
1. A study of 47 cases of high risk pregnancy,
where Leptaden was used to prevent untimely termination of pregnancy is presented.
2. Its
mode of action and usefulness is discussed.
ACKNOWLEDGEMENT
I am thankful to Dr. K. Gupta, Prof of
Obst. & Gynaecology, and Dr. M. C. Mittal, Dean, Medical College,
Jabalpur, for their kind permission to publish this series, I am thankful to
Mr. Yuvraj Singh and Ms. Alarsin Pharmaceuticals Bombay for liberal supply of
Leptaden tabs.
REFERENCES
1. Achari K. & Sinha R. : The Patna J. of Medicine
30;1,1966.
2. Achari K. : Paper read at 2nd International Seminar
on maternal & perinata( mortality, Pregnancy termination & . Sterilization,
Bombay 3-5 March, 1975.
3. Csapo, A. I. : Progesterone
- Its regulatory effect on the myometrium, Ciba foundation Study Group Churchill,
London, 1969.
4. Csapo A. I. : B.M.J.1;137,1974.
5. Horton E. W. : Monograph on Endocrinology `Prostaglandins'
Springer Vorly Berlin (Quoted by Sharma,1976).
6. Karim S. M. M. : Obst. Gynec. Brit. C'wlth 73;903,1966.
7. Karim S. M. M. & Hiller, K. : J Obst. Gynec.
Brit. Cwlth 77; 837,1970.
8. Mangeshiker. S. N. :
The Antiseptic, Vol. 55.1958.
9. Naik, M. G. : The Indian
Practitioner, Vol. 10, NO p 41, 1957.
10. Patel, M. C. : Current Med. Practice, 9, 764,
1965.
11. Patel, N. V. : The Antiseptic, June, 1947.
12. Poyser, N. L. : J. Emdocerinol 54 ; 147. 1972.
13. Schwalm & Mosler Quoted by G. : Seidenschnur
in Perinatal Medicine p. 206, ed. Stembera Polack & Sabata, George Thieme
Pub. Stuttgart, 1964.
14. Sharma, S. C. : J.
Physiol. (Lond) 226 ; 741972
15. Sharma, S. C. Hibbard,
B. M. Hamelett. J. D. & Fitzpatrick, R. J. : B. M. J. I; 709,1973.
16. Sharma, S. C. : Ind. J. Med. Res. 64 ; 4, 1976.
17. Von Dorp, D. A.: Mem.
Soc. Endocrinol 14 ; 391966.
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