The induction of therapeutic abortion using intravenous prostaglandin F2α

THE INDUCTION OF THERAPEUTIC ABORTlON USING INTRAVENOUS PaSTAGLANDlN F2a

Gerald G. Anderson, M.D. John C. Hobbins, M.D. Leon Speroff, M.D. Burton V. Caldwell, Ph.D. Department of Obstetrics and Gynecology Yale University School of Medicine New Haven, Connecticut 06510

ABSTRACT Intravenous prostaglandin F2,was given to 42 patients to induce abortion. The overall success rate was &out 50% using 3 separate protocols in which the dosage varied between 25 and 200 p4/ min and in which the duration of infusion varied from 6 to 24 hours. A high and unacceptable rate of side effects was associated with all dosage levels, but especially with the highest rate of infusion. There was no association of eventual abortion with duration of pregnancy, but there was a marked association with parity; multiparas aborted 2.5 times more frequently than primigravidas. It is concluded that intravenous prostaglandins given in accordance with the described protocols is not a clinical approach of terminating human pregnancy which offen any advantage over existing methods.

Accepted

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for publication

February 29, 1972

1972 VOL. 5 NO. 4

303

CONTRACEPTION

INTRODUCTION The first reports of the successful use of prostaglandins for the termination of early pregnancy appeared in Lancet in January of 1970. Roth-Brandel et al.(l) reported on 11 patients in Stockholm and, Karim and Filshie (2) reportem patients in Uganda. The latter series was more successful and resulted in abortions in 14 patients. Both reports served mainly to indicate potential usage and resulted in stimulating other researchers to begin clinical studies. In the’two years since the original’ publications, several reports have been published (3-10). Reviewing the literature, one is struck with the variability in results and side effects in various series. For instance, Karim (11) has reported a 94% success rate in 290 patients between 5 and 21 weeks gestation receiving PGF2a or PGE2 at 50 and S pg’min, respectively. Although side effects were prevalent, these were felt to be minor and controllable with medication and it was concluded that this method of &ortion is both effective and safe. On the other hand, Bygdeman and Wiqvist (12) noted an 18% success in 34 patients between the 10th and 20th weeks of pregnancy using F at 50pg’min and were concerned about both the efficacy and incidence and severity o f”*srde effects. Some discrepancies can be accounted for by differences in reporting Some investigators report patients as “successes” if they partially abort, results. while others require complete abortion to be counted as complete sucesses. It is significant that as this first sizable U.S. series is published (42 patients), the I.V. route has all but been abandoned as a workable clinical approach. This, however, does not deter from the value of close scrutiny of I.V. studies in that of all the it offers the best model for studying the physiological role routes of administration, of prostaglandins in the termination of pregnancy. MATERIAL

AND

METHODS

Studies were done using 3 different protocols. Protocol 002 was used in 10 patients, Protocol 005 in 7, and Protocol 006 in 25. Protocol 002 was more a doseresponse tolerance study than on attempt at reaching maximal efficacy, while the other 2 protocols were directed towards accomplishing efficacy. Dosage schedules for the 3 protocols are seen in Tables I, II and Ill. Protocol 002 called for a 12-hour infusion with dosages increasing with time as tolerated by side effects, while both Protocol 005 and 006 called for lower constant dosage rates over 6 and 24 hours, respectively. Under Protocol 005, 5 patients reAll protocols al lowed for a decrease ceived a repeat bhour infusion on the next day. in dosage rates if unacceptable side effects were observed.

304

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I.

Table

Dosage Schedule

0.5 PGF2a

1.0 2.0 4.0

50

Table

II.

PGF2a (THAM

50

salt)

Drug

p-2, (THAM

III.

1972

30 min

50 100 200

4 hrs hrs

3.5

for Protocol

0.75 12.0 24.0 42.0

005

25

1 .O

50

3.00

hrs

9.00

100

2.50

hrs

15.00

Dosage Schedule

Cont.

Rate (cc/min)

;*“o

SQlt)

APRIL

002

0.5

(pg/cc)

50

25

Dosage Schedule

2.0

Table

for Protocol

VOL. 5 NO. 4

.

30 min

for Protocol

Dose (pg/min)

3;

0.75

006

Duration

Amount

of Infusion

(mg)

30 min 24 hrs

0.75 72.00

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CONTRACEPTION

Duration

of

8 to 16 weeks; Pregnancies chorionic

pregnancy

Protocol

were confirmed

gonadotropin.

40 years

of

age or

signs

of

abortion

of

recent

jaundice,

The were

of

was prepared

pressure,

Blood

pulse,

samples were

cortisol,

***

the meager

platelet

of

of conception

after

of anemia

or

0.9%

in water

NaCI.

for

Infusions

and EKG

were taken

and re-

partial

serum

activity,

white

and

blood

cell

serum bilirubin, electrolytes

SGOT,

(Na,

K,

Cl),

system either

obtained

and continuously

in six

recorded

of the 10 patients

transabdominally

did not warrant

of

on a Coro-

Protocol

002.

or transcervically;

continuing

this

An

however,

practice

in

view

of

infections. the total occurred

at the end of the infusion, If,

or

disease,

in evidence,

5% glucose

and total

BUN,

were monitored

was placed

If expulsion

other

or findings

hematocrit,

products

of

conception

total infusion time, the infusion was discontinued. ducts

inflammatory

at peak uterine

direct

estimation,

monitoring

information of

treatment,

of the study for:

serum creatinine,

contractions

catheter

the frequency

pelvic

were made:

and progesterone.

pressure

open-end

temperature,

taken before

phosphatase,

Uterine

in

for

incompetancy

sensitization

solution

test

and were

pump**.

respiration,

at termination

and differential,

serum alkaline

infusion

cervical

it was mixed with

-

90 to 190 pound

exclusions

history with

002

hourly.

abortion

glucose,

05 a 50 &ml

by an electronic

least

following

metric

or glacoma.

disease,

whtle in the other protocols,

delivered Blood

count

asthma

of

of active

incompatability

urinary

the study

to the

specific

or history

or findings

or hepatic

of rhesus

PGF2: 002,

corded at

renal

were restricted

9 months

history

for

Protocol

- 4 to 20 weeks.

and a positive

The following

history

006

were free volunteers

weights

less.

abortion,

known cardiac,

and a history

Protocol

Patients’

of 4 or

were cs follows:

and Protocol

examination

patients

in the preceding

of threatened

history

the 3 protocols

by pelvic

All

less.

range and to a parity history

under

005 - 4 to 16 weeks,

expulsion,

means before

or if the

the patient

putient

the case was termed

a partial

or if

gynecologic

indicated

a dilatation

the stipulated of the pro-

an “inevitable

by standard

it was deemed medically

before

expulsion

was considered

was treated

the end of the infusion

occurred

If partial

abortion” techniques.

to empty the uterus

and curettage

by

was required,

success. RESULTS

The

results

*Generously

are detailed

supplied

in Table

by E.M.

IV.

Southern,

M.D.,

of the Upjohn

Company,

Kalamazoo,

Michigan. **Model

900,

***Corometrics

306

Harvard

Apparatus

Medical

Systems,

Company, Inc.,

North

Millis, Haven,

Massachusetts. Connecticut.

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Table IV. Summary of Data in 42 Women Who Received Intravenous Prostaglandin F2a Accordingto Three Rotocols Gmvida/ km

Ritient

Gestation (weeks)

Tota'Dose pGF2a (mg)

Protocol 002 1 2 3 4 5 6 7 8 9 10

l/O 1/O l/O 2/l l/D 5/4 5/3 4/3 4pL 2/l

1: 16 10 14 14 10 11

79 79 20 46 64 80 65 58 67 35

PmiIxoloo5 11 12 13 14 15 16 17

2/l 3/2 6/4 2/l 2/l 3/2 4/3

11 14 16 14 10 13 14

19 19* 19 19* 19* 19* 19*

Rot0clJ1006 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42

2/l 2/l 3/2 l/O 5/3 l/O l/O 2/o 2/O l/D 4/3 5/3 l/O 4/3 6/4 l/O 5/4 l/D 5/2 4/2 5/3 l/O 3/2 l/O l/O

14 14 19 16 14 18 21 18 20 18 20 18 14 16 20 15 12 20 11 14 14 17 18 18 19

71 71 71 71 71 71 71 71 75 67 71 71 71 71 40 71 71 71 59 71 71 71 71 70 71

9.5 7

Side EffectIndex

Outcome

12 6 14 9 11 5 12 19 16 4

Failure Partial Failure Partial Pbrtial bmplete Failure &tial Failure Portia1

8 6 4 5 4 4 4

Gmplete Complete Failure Failure

3 4 4 2 14 6 8 3 7 5 8 6 4 6 8 2 2"

Partial t%xtial Failure Failure Failure PDrtial Partial Failure Failure Failure ~tiial PortiaI Failure Partial Complete Failure Phrtial Failure Complete Failure Failure Failure Complete Failure Failure

2 3 12 2 7 3 4

Partial

Failure Failure

*Infusiongivenon two succawive days.

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Table V.

Compilation of Results: 42 Patients Given Intravenous Prostaglandin F2, for Therapeutic Abortion Partial

Success Study

Group

Failure

Success 1 No. %

%

No.

%

1 No.

10

1

50

5

40

4

Protocol 005, 7 patients

28.6

2

14.3

1

57.1

4

Protocol 006, 25 patients

12

3

32

8

56

14

Overall,

14.3

6

33.3

52.4

22

Protocol 002,

10 patients

42 patients

14

The overall success rate was nearly 50% (Table V) in the 42 patients: 6 complete abortions, 14 partial abortions, and 22 failures. Of the ten patients under Protocol 002, there was 1 complete success, 5 partial successes and 4 failures. Under Protocol 005, there were 2 complete successes, 1 partial success, and 4 failures. Among the 25 patients under Protocol 006, there were 3 complete successes, 8 partial successes, and 14 failures. The percentage of complete clbortions under the 3 protocols were as follows: Protocol 002 - 10%; Protocol 005 - 28.6%; and Protocol 006 - 12%. Combining complete and partial successes, the results were: Protocol 002 - 60%; Protocol 005 - 42.9%; and Protocol 006 - 4.4%. Of the 42 patients, there were 16 primigrwidas and 26 multiparas. The primiparas had no complete and 4 partial abortions, while the multiparas had 6 complete and 10 partial abortions. The mean duration of pregnancy in patients who had complete or patial abortions was 14.7 weeks (*3.7), while in those who were failures, it was 15.2 weeks $3.2). All patients, except 2, developed cramping and/or bleeding within 4 hours of starting the infusion, most within 2 hours. The 2 patients who were exceptions never developed bleeding and were failures.

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1972 VOL. 5 NO. 4

CONTRACEPTION

The weight of the patients who aborted (127.3 different from those who did not (133 pounds).

pounds) was not significantly

Side effects were more prevalent and severe among the 10 patients under Protocol 002. Nausea, vomiting and diarrhea were prevalent and usually severe. In addition, 6 patients became febrile and 3 required antibiotics, 2 required blood transfusions, and 6 eventually needed a DBC. Two patients developed vasovagal symptoms, one associated with moderate shock which was present for over an hour. Occasional diastolic hypertension and tachycardia were also noted. The frequency and severity of side effects associated with lower dosages under Protocols 005 and 006 was much less. In order to quantitate these differences, a scoring index was devised to assign a single number to the type and severity of various side effects. The side effects were classified as mild (1 point), moderate (2 points), or severe (3 points). Thus a patient with severe nausea and vomiting and rrodemte dysmenorrheic pain would receive a “side effect index” of 5. The mean index of 10 patients under Protocol 002 was 9.6 (f3.5) while under Protocol 006, it was 4.7 (t2.5; p zeO.05). The following side effects were noted: nausea and vomiting (63%), diarrhea (70%), hypotension (2 patients), diastolic hypertension (4 patients), dysmenorrheic pain (95%), epigastric pain (2 patients), fever of looOF or greater (25%), headache (2 patients), infusion site pain (4 patientsj, and a positive bacterial culture from maternal blood and/or uterine culture representing endometritis (4 patients). Except for anemia associated with blood loss and an increased WBC in patients with infections, no significant changes were noted in liver function tests, electrolytes, cortisol, or progesterone levels. An amniotic fluid specimen was analysed in one patient after the uterine size was found to be increasing with duration of the infusion and yielded the following results: glucose - 24 mg%, creatinine -0.9 mg%, chloride -109 mEq/l, sodium - 136 mEq/l, and total protein - 0.5 mg%. DISCUSS10 N Protocol 002 was devised more as a dose-tolerance study than as an efficacy study. The results indicated that a 200 &min infusion of PGF2a was certainly an intolerable dose and that 100 ra/min was associated with undesirable side effects in an unacceptable number of patients. Therefore, Protocol 005 was devised in which patients received 50-100 pg/min of PGF pafor 6 hours on 2 successive days, if necessary. The success rate was not any better than that associated with Protocol 002 (1 complete abortion and 5 partials under 002 as compared to 2 complete and 1 partial abortion under 006); however, side effects were substantially reduced. In that the 50pg/min dosage was the level which seemed to produce adequate contractions without causing severe side effects in the previous 2 protocols, Protocol 006 called for this dosage for 24 hours. Although the overall oJccess rate of 48.9% was not significantly different from that noted under the previous protocols, the

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1972 VOL. 5 NO. 4

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CONTRACEPTION

side

effect

cations the

total

either

prostaglandin

dosage.

infusion

The results

in terms of efficacy The

(12)

rate was again noted to be reduced.

of

greater

do not

efficacy of

14.7

Complications as partial

compare favorably

rate in earlier weeks

Under

gestations

Patients while

were especially

abortions.

reporting

results,

The “side severity

it

effect

prevalent

Protocol

is important

002,

002 was 9.6 tically

while

clinical

impression

of greater under

severity

Protocol

forced

the

different that

than an infusion of greater

unattached

compli-

infusion

methods

than

of abortion

fetus

five

or partial 15.2

produced

as complete under

result This

by 200 pg/min

was statis-

abortion was felt

infusion

cervix,

and

Protocol the

in more side effects

high partial

dilated

or partial.

the number

The difference will

had

when

one to substantiate

a complication.

a partially

classified

the 4 failures

of patients

allows

had

abortions

Therefore,

one to compare

The

of 50pg/min.

partial

while

successes

of PGF2,

abortion

weeks.

who were

with

antibiotics.

006 was 4.7.

infusion

intensity

patients

antibiotics,

and thus

be considered through

by Bygdeman and Wiqvist

was

The index

Protocol

a 200pg/min

it

allows

protocols.

under

as noted

abortion

gross,

(p = < 0.05)

002 can also

to the contractions

rather

in various

the index

significantly

other

in those patients

the

to stipulate

although

of side effects

that

rate of

with

in the failures,

350 cc and only one required

index”

indicate

the

who had a complete

had a mean blood loss of 600 cc and 2 required a mean blood loss of

would

more with

or side effects.

was not seen in our study.

a mean gestation

This

are associated

rate (50%)

to be due rate

but retained

which the attached

placenta. An increase

in uterine

size

two examiners

in several

at termination

of the infusion

A similar tonic

phenomenon

saline.

Analysis

the

gestion,

or an increase

310

increase

investigation

(but

during

of

before

the amniotic

in size of this

finding

fundus

abortion)

was noted often

fluid of

felt

revealed amniotic

fluid

of hyper-

concentrations myometrium,

and its

by

larger

the infusion.

by installation

normal

contracting

independently

3 to 4 weeks

than it did before

who are aborted

is due to edema of

in the production

infusion

PGF2,

The uterine

is noted in patients

Whether Further

patients.

solutes

of solutes. venous

con-

is unknown.

is underway.

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CONTRACEPTION

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Roth-Brandel, glandins

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3.

S.M.M.

1:157,

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Kaufman,

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Embrey, J.

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7.

9.

10.

&

8

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Bygdeman,

M.

and Wiqvist,

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Sci.

Gillespie,

A.:

N.Y.

Jr.:

Prosta1970.

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F2,.

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by prostaglandins

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