Intrauterine extra-amniotic administration of prostaglandin F2α for therapeutic abortion

Intrauterine extra-amniotic administration 07 prostaglandin Fga for therapeutic abortion Early myometrial

JELLE

T.

BRAAKSMA,

WILLIAM JOHN

E. I.

LINDA Chapel

effects

M.D.

BRENNER,

M.D.

FISHBURNE,

JR.,

STAUROVSKY, Hill,

North

M.D.

C.N.M.

Carolina

A method of administering prostaglandin Fe= (PGFz=) solutions at various intrauterine extra-amniotic sites to induce abortion and to study the eflect of PGFSa on the myometrium is described. Three observations were noted during the study of 7 women between 8 and 20 weeks’ gestation: (1) Injection of PGFza in the fundus resulted in a greater myometrial response when compared to the response elicited by the same dose injected at lower uterine sites; [2) the sensitivity of the myometrium to PGFz= appeared to be greater in early pregnancies as compared to later pregnancies; (3) the myometrium responded to PGFza by increasing the basal tonus more in early pregnancy than it did in later pregnancies.

I N T R A U r r4 n r N E extra-amniotic administration of prostaglandin F*= (PGF*&) has been demonstrated to be an effective means of inducing abortion with few complications in a small group of patients by Bygdeman and Wiqvistl (9 patients) and Embrey and Hillier2 (2 patients). Both groups observed

extremely variable oxytocic responses to the same dosages of PGFza, not only in the same patient, but also between patients. Before this method becomes practical for clinical use, the reason for this variability must be explained so that a standard method of administration and dosage schedule might be devised. After we observed a significant oxytocic and abortifacient response to about one tenth the dose described by the above investigators, we studied the variability of the myometrial response to prostaglandin Fza administered at various levels of the uterus in the extraamniotic space.

From the Department of Obstetrics and Gynecology, University of North Carolina. This work was supported in part by grants from the National Institute of Child Health and Human Development (HD-04148-03), The General Research Centers Program of the Division of Research Sources, National Institutes of Health (RR-46), The Upjohn Co., and the International Fertility Research Program of the Carolina Population C’enter of the University of North Carolina (AID/csd 2979), Received

for publication

March

6, 1972.

Accepted

for publication

April

27, 1972.

Material

and

methods

Prostaglandin Fza was administered extraamniotically to 7 physically healthy women from 8 to 20 weeks’ gestation (Table I) to induce therapeutic abortion. Two patients (Nos. 6 and 7), whose uterine sizes varied widely, at 9 and 17 weeks, respectively, were studied for differences in myometrial response to PGFza administered at 3 different sites

Reprint requests: Dr. William E. Brenner, Dept. of Ob./Gyn., University of North Carolina, Chapel Hill, North Carolina 27514.

511

512

Table

Braaksma

et

October Am. J. Obstet.

al.

I. A summary

of preabortion

and abortion

data Patient

Patient

data*

Gestation (wk.) Gravida Parity Site of injection Injection (No.) Total PGF*= (mg.) AB time (hr.) Results

8 5/7 I 0 I 4 2.1 7 C

Comfdications Nausea Emesis Diarrhea

++ -!-

Maximum

2

I

temperature

974

*Abbreviations for site of injection: I = of the cervix. AB time = hours from first Complications, + = present; ++ = recurrent;

3

13 4/7 1 0 I 16 2.1 12 C

-

976

983

fundus; II = halfway theraoeutic instillation - = absent.

No.

*Becton, VXOZO. fAm.erican

Dickinson Catheter

& Company, Manufacturers,

Rutherford, Inc.,

New

Jersey,

7 Fr. ZCQISP.

No. 4

20 o/7 I 0 I 50 38.5 12 C

++ ++ -

in the extra-amniotic space. The differences in sensitivity of the myometrium to PGFZa administered in the fundus of the uterus were studied in all 7 patients. Prostaglandin FZa was injected through a calibrated polyethylene* “administration catheter” introduced into the extra-amniotic space. After visualization of the cervix with a vaginal speculum, a calibrated ureteral catheter,? with the tip removed, was introduced transcervically to the fundus via the extra-amniotic space. The length of the uterine cavity was measured from the fundus to the external OS of the cervix. The “administration catheter” was threaded through the ureteral catheter to the fundus before the ureteral catheter was withdrawn, leaving the catheter” in the tip of the “administration fundus. Catheters were placed in other extraamniotic sites with the use of a similar method. For comparison of different myometrial areas, 3 catheters were placed: “I,” in the extra-amniotic space at the fundus; YI,” in the extra-amniotic space halfway between the fundus and cervix; “III,” in the extra-amniotic space 2 cm. above the internal cervical OS (Fig. I ) . Intra-amniotic pressure and direct radial

15, 1972 Gynecol.

14 5/7 1 0 I 19 1.2 7 C

5 8 O/7 1 0 I 29 11.0 13

6 9 o/7 2 0 I, II, III 21 4.5 6

C

+ +

-

978

98O

C

7 17 o/7 1 0 I, II, III 54 27.4 -

F

i

986

99O

between fundus and cervix; III = 2 cm. above internal os until abortion. C = complete abortion; F = failure. Unda

arterial blood pressure were recorded by the open-ended catheter technique.3 A polyethylene catheter was introduced into the amniotic cavity either transabdominally or transvaginally through a No. 18 T thin-wall needle. A No. 18 Venocath* was introduced percutaneously into the radial artery for monitoring maternal blood pressure and heart rate. Oral temperature by mercury thermometer was obtained every hour. Each contraction greater than 6 mm. Hg was analyzed for intensity, frequency, and basal tone (the lowest pressure between contractions) and Montevideo units (M.U. ) were calculated.3 If abortion did not occur within 16 hours of the initial instillation, the trial was delared a failure. Sterile solutions of 5 pg per milliliter to 2 mg. per m?IliIiter of PGFZti were obtained by diluting a 5 mg. per milliliter diluent solution with isotonic saline. Following the injection of I CC. of PGFZa, the catheter was cleared with I C.C. of isotonic saline. Therefore, although the dose varied, the volume was constant. Results Efficacy. Six of the 7 patients aborted with an average abortion hours (Table I). *Dewret

brand

of indwelling

catheter,

completely time of 9.4

Volume Number

114 4

PGFza

for

therapeutic

abortion

513

: B

It: :> DOSAGE Fig. 1. Initial of PGF*= given uterus.

1 20

myometrial response. Comparison in 3 different sites of the intrauterine

Fig. 2. Later PGFXa given uterus.

responses of various dosages space of a g-week-pregnant

effects.

myometrial in 3 different

No

T,lMiE IN MINUTES

t fig pg. Fza 1

serious

response. Comparison sites of the intrauterine

side

effects

were

and pain were severe in Patients No. 2 and No. 3 after large initial doses of 1 mg. and 250 pg, respectively, were administered. Maternal blood pressure, heart rate, and temperature did not significantly change. All patients who aborted were discharged from the hospital within 24 hours of abortion and on examination at 2 weeks after discharge appeared to be without complications. The oxytocic effect of PGFza in diRerent extra-amniotic areas. The effects of PGFza injected at 3 different extra-amniotic areas (I, II, III), as indicated in Figs. I and 2, observed.

of the oxytocic extra-amniotic

, , 4050 DOSAGE

Side

pg. l&J

Vomiting

of the oxytocic extra-amniotic

responses space

of various dosages of a 17-week-pregnant

of

were studied in 2 patients. Beginning with 5 pg, the doses (5, 10, 20, 40, 100, and 200 pg) were administered at > 20 minute intervals in each of the 3 catheters. The rotation of I, II, III was used in Patient No. 6, and III, II, I in Patient No. 7. Therefore, in Patient No. 6, 5 pg of PGFza was initially injected and flushed with 1 ml. of isotonic saline through Catheter I. Twenty minutes later, the same dose was injected and flushed in Catheter II; 20 minutes later, the same dose was administered in Catheter III. The maximum basal tonus of Patient No. 6 at each dose is graphed, and the record of the initial uterine response to 100 pg at each

514

Braaksma

October 15, 1972 Am. J. Obstet. Gynecd.

et al.

20 wks 10

50

. # 2x?

IO0

INTRA-UTERINE

Fig. 3. Dose response. Comparison administered at the fundal site of of the first half of pregnancy.

DOSAGE

of the mean the intrauterine

(pq

pg Fzaz?

increase in basal extra-amniotic

tone space

in response to during various

PGFw weeks

9wk

8 wk l3wk I5 wk 2Owk I

I IO

I 20

I 30

1 40 %

I 50

ABORTION

1 60

I 10

I 80

t 90

7 100

TIME

Fig. 4. Myometrial response throughout abortion. Comparison of the increase of the basal tone measured from the intra-amniotic pressure throughout the abortion process induced by PGFu injected into the intrauterine extra-amniotic fundal site during various weeks of pregnancy.

uterine level is displayed in Fig. 1. No response tias observed until 100 pg was injected into, Catheter I. After the uterine contractions subsided, the same dose resulted in much less of a response in Catheters II and III. Patient No. 7 received the same dosages in the. iame areas of a larger ( 17 week size) uterus’ (Fig. 2). After 3 hours of significant uterihe activity, instillation of 200 pg of PGFza at Sites III and II resulted in significantly less increase in the basal tone and uterine activity, when compared to that resulting from

The various

instillation

at

the

fundal

site

(I).

oxytocic effect of administration at gestational ages. The response of the

myometrium as measured by the rise of basal tone in response to the various dosages of PGFza instilled in the fundal area of the extra-amniotic space was studied in various weeks of the first half of pregnancy. After a significant amount of uterine activity was induced (> 350 M.U.), increasing dosages (5, 10, 20, 50, 100, and 200 pg) were administered in the fundal area at 20 to 90 minute intervals, and the response by the myometrium

was

crease The the 99 strates

of the basal tone. mean response at each dosage level of instillations plotted in Fig. 3 demonthe greater rise of the basal tonus in

calculated

from

the

maximum

in-

Volume Number

114 5

early pregnancies, as compared to the response from the same dosages in more advanced pregnancies. After progressively increasing the dosage to 200 pg of PGFzC, all but the 20-week-pregnant uterus gave a significant response. No significant correlations were noted between the dosage and the duration of the basal tone elevations. Not only did the earlier pregnancies respond with a larger increase of the basal tone to the same dosages of PGFza, but throughout the whole course of abortion the basal tone calculated at every 10 per cent of the abortion time was significantly higher in the earlier pregnancies (Fig. 4). Comment The average abortion time (9.4 hours) and the abortion rate for 6 of 7 patients aborting within the 16 hours of the trial are not significantly different from the results obtained during our previous intravenous studies with the maximally efficient dose.4 Although Patient No. 7 is the first reported subject who failed to abort by this method, trials by other investigators ls z have continued for longer than 16 hours and only a few trials have been reported. The observation of the fundal site of the myometrium being more sensitive than other areas is in agreement with the in vitro findings of Embrey and Morrisor? and of Sandberg, Ingelman-Sundberg, and Ryden6 Although the observations that muscle obtained from the fundus is more sensitive to PGFzO in vitro when compared to muscle of the lower segment may explain why the uterus responds more to extra-amniotic PGFza in-

REFERENCES

1. 2. 3. 4.

Bygdeman, M., and Wiqvist, N.: Ann. N. Y. Acad Sci. 180: 473, 1971. Embrey, M. P., and Hillier, K.: Br. Med. J. 1: 588, 1971. Obstet. 91: 1, 1950. Alvarez, H.: Surg. Gynecol. Brenner, W. E.: AM. J. OBSTET. GYNECOL. 113: 1037, 1972.

PGF2@

for

therapeutic

abortion

515

jetted in the fundus, there may be local factors that are of more importance. The uterus of earlier gestational age responds with a higher tonus to the same dose of PGFza when compared to that of a uterus in later pregnancy. It appears from the absolute increase of the basal tone after intrauterine administration of PGFzm that the sensitivity of the myometrium during the first half of gestation decreases with the age of the pregnancy. However, the differences in uterine volume have to be taken into account7 according to the La Place equation R (T = - .T) . T = wall tension, R = radius, 2P and P = pressure. Since the radius of a 17 week pregnancy is twice as large as the radius of an 8 week pregnancy,* it can be easily understood that for the same intra-amniotic pressure in the 17 week uterus the wall tension has to be twice as high as the 8 week uterus. Therefore, the differences in sensitivity as measured by intra-amniotic pressure may be less than the sensitivity as measured by wall tension. Although the extra-amniotic administration technique has the disadvantage of requiring repeated, frequent injections, it has the advantage over the intra-amniotic technique in that it is applicable before 14 weeks’ gestation when amniotic puncture is often difficult. Further investigation of this route is indicated, and, as protocols are developed for clinical application, two variables must be considered : ( 1) the site of extra-amniotic injection, and (2) the stage of pregnancy being aborted.

5. 6.

7. 8.

Embrey, M. P., and Morrison, D. L.: J. Obstet. Gynaecol. Br. Commonw. 75: 829, 1968. Sandberg, F., Ingelman-Sundberg, A., and Ryden, G.: Acta Obstet. Gynecol. Stand. 44: 585, 1965. (Suppl. 4.) Mosler, K.: Zrz The Dynamics of Uterine Muscle, Base& 1968, S. Karger AG, p. 24. Braaksma, J. T.: Unpublished figures, 1971.