Clinical trial on termination of early pregnancy with RU486 in combination with prostaglandin

Contraception

CLIRICAL

TRIAL

46:203-210,

1992

TIa OF Elwp PLLEQlgllcyWITH RU486 OR T111 COHBIHATIO~ WITH PRO8TAGLMDI~

Wu Shangchunl Gao Jil Wu Yuming2 , Wu Muzhen', Fan Huimin3, Yao GuangzhenS, Zheng khuron 4 Wang Ping4, Du Min kun5, Huang Zirong5, Huang Juxiang %I , Zhu Ge6, Lei Zhenwu 7 Chen Xiaoqin7, Pen Dunren', Song Li'uan', Wu Xiruig, H&g Shag, Xia Jingzhong ?O , Zhang Jianguo ,a ABETRACT Termination of early pregnancy was performed in 1572 healthy women with RU486 (mifepristone, 600mg orally once), followed ester of 36-60 hours later by administration of methyl dl-15-methyl-PGF2a (PG05, lmg vaginal suppository). Complete abortion was accomplished in 91.2% (1433/1571), incomplete in 3.9% abortion in 4.8% (76/1571), and continued pregnancy (62/1571). The time elapsed between RU486 intake and complete expulsion was 2.4 + 1.3 days. Expulsion took place on the third day in 935 women (72%), and on the 4th day in 273 women (21.0%). Uterine bleeding occurred on the second or third day after RU486 intake in 1256 women(88.8%), and lasted 11.7k6.4 (SD) days, range 2-55 days. One subject had blood transfusion due to excessive bleeding. The main side effects were nausea/vomiting (22.3%), abdominal pain (10.2%), headache/dizziness (4.1%) and diarrhea(2.8%). Fatal side effects have not been reported in this study. About 73% of subjects with complete abortion assessed the treatment as good to excellent. Even in the failed cases, 25-42% of subjects considered the treatment as good. Further studies are needed to determine the optimal dose of the RU486 regimen. It should be emphasized that the treatment must be used under close medical supervision in order to monitor the uterine bleeding.

1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

National Research Institute for Family Planning Peking Union Medical College Hospital Beijing Gynecoloav and Obstetrics Hosoital Beijing MGdical University, 1st Affil'iated Hospital Shanghai Medical University, Obstetrics and Gynecoloay Hospital Shenyang Municipal Family Planning Research I&titut;_ Sichuan Research Institute For Family Planning Tianjin Family Planning Institute Tong Ji Medical University, Family Planning Research Institute Henan provincial Family Planning Research Institute

Submitted for publication February 28, 1992 Accepted for publicatjon June 2, 1992

Copyright01992

Buttetworth-Heinemann

Contraception

204

It is well known that anti-progestogens have an effect on termination of early pregnancy and induction of menstruation, but without supplemental prostaglandin, the effect is not ideal. A previous study in China showed that in 204 cases of early pregnancy (within 42 days), a single dose of 600 mg RU486 (mifepristone) administered alone, gave a success rate of 65.2% complete abortion. When prostaglandin suppository (methyl ester of dl-15-methyl- prostaglandin F2a) was given in combination with RU486, the success rate increased to 86.6% (l), even when the gestation age increased to 49 days of amenorrhea. In 1988-89, an expanded national multicentre study in 10 institutions in 7 provinces and municipalities was conducted in order to confirm the efficacy and side effects of RU486 in combination with prostaglandin for termination of early pregnancy.

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Am

METHODS

A total of 1572 cases was investigated. The women recruited in this study were aged 18-44, average 29.5+4.5(50), healthy and with no history of cardiovascular diseases or hypertension. Diagnosis of early pregnancy was confirmed by size of uterus, coincidental with period of amenorrhea, positive urine pregnancy test or serum D-hCG test, and ultrasonic examination in doubtful cases. The average pregnancy period was 41.5k4.1 (SD) days, with a range of 28-59 days. RU486 in a 200 mg tablet was provided by Roussel-Uclaf Co., France. PG05 (methyl ester of dl-15-methyl-prostaglandin F2a) in 1 mg suppository was supplied by the Institute of Materia Medica, Chinese Academy of Medical Sciences. After admission examination, the patient was given RU486 600 mg orally under fasting condition (Dl). A suppository of PG05 was inserted into the vaginal posterior fornix within 36-60 hours after RU486 medication at the outpatient clinic. The subject was allowed to return home after observation for 4 hours when there were no serious complications. On the 8th day after medication, the woman returned to the clinic for evaluation of the result. Ultrasonic examination was performed when necessary. When continuation of pregnancy was diagnosed, vacuum aspiration was carried out. If complete abortion could not be confirmed, further follow-up on the 14th day was required. Side effects were recorded according to the subjects* complaints without any suggestions.

205

Contraception Criteria for evaluation of results

1. Complete abortion: Complete fetal sac is expelled after medication without supplementary operation. If the fetal sac is seen at the cervical OS and removed with ovum forceps, it is also considered a complete abortion. When no fetal sac is seen, but serum l3-hCG level declined markedly, bleeding decreased and the uterus involuted to normal in follow-ups, abortion is considered complete. 2. Incomplete abortion: Conceptus is incompletely expelled, serum l3-hCGlevel slightly reduced, bleeding is still significant and vacuum aspiration is required. Histopathological examination of the aspirated sample shows chorionic tissue. 3. Continuation of pregnancy: Slight bleeding after medication, no expulsion of conceptus, size of uterus unchanged or even enlarged. Serum D-hCG level increased or reduced insignificantly. Criteria for evaluation of side effects Side effects such as pain are classified as classified according to as moderate, and over 7

nausea, vomiting, headache and abdominal mild, moderate or severe. Diarrhea is frequency: 1-3 times as mild, 4-6 times times as severe.

The chi-square test was used for comparisons of qualitative variables. RESULTS The age distribution of the 1572 cases is a'sshown in Table I; over 85% of the women were aged 20-34. Table I. Age Distribution Age

15 - 19 20 - 24 25 - 29 30 - 34 35 - 39 40 - 44 Total

Number 3 204 570 571 199 25 1572

% 0.2 13.0 36.3 36.3 12.7 1.6 100.0

206

Contraception

Efficacy

Among 1572 cases of early pregnancies, one was terminated with vacuum aspiration due to severe nausea and vomiting 26 hours after RU486 medication; this case is not included in the abortion and analysis. The results of complete, incomplete continuation of pregnancy are shown in Table II. Complete abortion was found in 91.2%. When broken down into different gestational III, no significant age, as shown in Table differences were found among them (P>O.O5).

Table II. Efficacy of RU486+PG05

in 1571 Women

Number Complete Incomplete Continued pregnancy Total

%

1433 76

91.2 4.8

62 1571

3.9 100.0

Table III. Efficacy of RU486+PG05 Treatment Related to Gestational Age Gestational Age (Days) 43 - 49 36 - 42

135 No. Complete Incomplete Continued pregnancy Total

%

No.

%

No.

%

250 No.

%

134 7

90.5 4.7

875 34

92.6 3.6

406 35

88.3 7.6

18 0

100.0 0.0

7 148

4.7

36 945

3.8

19 460

4.1

0 18

0.0

Time required

for complete abortion

Among 1433 cases of complete abortion, there were 1299 cases where time of expulsion of fetal sac was recorded. The average time of expulsion was 2.4k1.3 days; 93% of cases had expulsion on the 3rd or 4th day after medication (Table IV), among which only 43 cases of expulsion occurred before the administration of PG05 suppository.

207

Contraception

Table IV. Time of Expulsion of Fetal Sac after RU486 Intake in Complete Abortion Cases Time Dl* D2 D3 D4 D5-D8 D9-D14 >D14 Total

Number 0

% 0.0

1.4 72.0 21.0 4.2 1.2 0.2 100.0

18 935 273 55 15 3 1299

* Dl=the day of RU486 administration. Among 1256 cases of complete abortion, 81% of the cases had expulsion of fetal sac within 6 hours after PG05 administration. The distribution of hours to expulsion after PG05 insertion is shown in Table V. Table V. Time Between PG05 Administration Expulsion of Fetal Sac in Complete Abortion Time

(hours)

13 -6 -9 -12 -24 -48 -72 >72 Total

Number 595

422 73 14 25 82 16 29 1256

and Cases

% 47.4 33.6 5.8 1.1 2.0 6.5 1.3 2.4 100.0

Bleeding occurred on the 2nd or 3rd day of RU486 treatment in 88% of women with complete abortion (Table VI). The average bleeding days were 11.7+6.5(SD), with a range of 2-55 days. Bleeding lasted less than two weeks in 75.7% of women who had complete abortion (Table VII). According to subjective estimation by the woman herself, the amount of bleeding was classified as slight, moderate or heavy in comparison to her usual amount of menstrual blood loss; 56.3% (796/1414) of the women who had complete abortion had slight and/or moderate bleeding, 47.4% (67011414) of the subjects experienced heavy bleeding. One subject suffered excessive bleeding after expulsion of the fetal sac, which occurred 3 hours after PG administration. Bleeding was slightly more than her usual menstrual flow at that time. She was allowed to return home, having given her

Contraception

208

precautions. The subject came back to the clinic 4 hours later with heavy bleeding. The amount of bleeding was estimated to be 500 ml. Hemoglobin was 95 g/L. Curettage was performed and 300 ml of blood was transfused at that time. Another 200 ml of blood was given the next day. Table VI. Time to Onset of Bleeding after RU486 Intake Time

Number

Dl D2 D3 D4 2 D5 Total

45 521 735 80 33 1414*

% 3.2 36.8 52.0 5.7 2.3 100.0

* Subjects with complete bleeding records.

Table VII. Distribution of Duration of Bleeding in Complete Abortion Cases Duration

(days)

<7 7142128Total

Number 173 895 236 51 59 1414

% 12.2 63.3 16.7 3.6 4.2 100.0

Side Effects The main side effects were nausea and vomiting (22.3%), headache and dizziness (4.1%), abdominal pain (10.2%), diarrhea (2.8%), thirst (1.2%) and others, such as fatigue, sleepiness, frequent urination (3.7%). There were no complaints of serious side effects. Seventy-five point eight percent of subjects with nausea/vomiting and 79.7% with headache/dizziness felt the symptoms were related to RU486, and 79.3% subjects with abdominal pain and 86.3% with diarrhea felt the symptoms were due to prostaglandin. The above side effects were mild or moderate in 79.5-96.2% of the cases, and lasted 17 hours to 1% days on the average. Assessment

of the method

Assessment of the method by the subjects themselves showed that over 92% of the complete abortion group considered the method to be good or excellent. Even in the incomplete abortion group, 26.3%, and in the failed group, 41.9%, considered the method to be good.

209

Contraception

DIBCDSBIOI

The results of the expanded clinical trial in China showed that the efficacy of RU486 600 mg once orally in combination with

PG05 1 mg suppository for termination of early pregnancy was satisfactory. The complete abortion rate was 91.2%; It is slightly higher than that found in previous study (1). It seems that the treatment regimen when followed carefully plays an important role on the effectiveness of the method. Bleeding is one of the problems with this treatment. Prolonged bleeding/spotting lasting more than two weeks had been found in more than 20% of women who had complete abortion in this study (Table VII). As long as the complete abortion was confirmed, the patients with bleeding could be followed without medical treatment. The excessive bleeding should be considered as the major hazard even if it occurs rarely. Blood transfusion was reported in one case in this study, although the fetal sac had been expelled. Decidual tissues remaining in the uterine cavity may be the main reason for heavy bleeding. Curettage is an effective treatment to control the bleeding. It should be emphasized that RU486 in combination with PG be used only in clinics where emergency facilities are available. The incidence of the common side effects were not high in this study. Although serious complications related with use of RU486/PG, such as myocardial infarction, are very rare (2), careful screening for history of cardiovascular diseases and heavy cigarette smoking as a contraindication of RU486/PG treatment is worthy of mention. Most of the serious complications are believed to be linked with the use of the prostaglandin sulprostone (3), an intramuscularly injectable agent. Lack of fatal side effects in this study may mean that the vaginal approach for PG administration is safer than intramuscular injection. Long-term health effects of the RU486/PG regimen are unclear. The impact of RU486 on pregnancy carrying to term remains questionable. This is noteworthy since RU486 used alone results in a continuing pregnancy rate of 9.3% (4), and the study by Frydman has demonstrated that RU486 can cross the placenta (5). Other problems which may be associated with heavy and prolonged bleeding, such as infection and endometriosis, should be monitored. A WHO study (6) revealed that RU486 may be equally effective at doses significantly lower than 600 mg. Alternate PGs, including an orally administered formulation, are now being explored. The new regimen may provide more effective and acceptable alternative methods for early pregnancy termination.

for RU486/PG regimen of In conclusion, the current termination of early pregnancy has been proven to be effective and safe. The common side effects were mild to moderate. Tolerance to side effects could be increased by providing The safety of RU486/PG counselling before the treatment. treatment can be assured if it is used correctly and if it is provided through a clinic that can administer the drugs appropriately. Acknowledgements This national coordinated study was supported by Roussel-Uclaf Co. by provision of the RU486 and research funds. We thank Dr. Andre Ulmann for valuable advice and Mr. Wang Ming for coordinating between the centres of the study. We also thank the Institute of Material Medica, Chinese Academy of Medical Sciences, for the supply of PG05.

1. Gao Ji, Qiao Gen-mei, Wu Yu-ming et al. Pregnancy interruption with RU 486 in combination with dl-15-methyl-prostaglandin-F2cr methyl ester: The Chinese experience. Contraception 1988;38:675-683 2. RU486 in developing 1991;9:1-6

countries:

3. Editorial : A death associated one. The Lancet 1991;337:969-70

questions

remain.

Outlook

with mifepristone/sulprost-

4. Maria B, Stampt F, Goepp A et al. Termination of early pregnancy by a single dose of mifepristone (RU486), a progesterone antagonist. Eur J Obstet Gynaec Reprod Biol i988;28:249-255 5. Frydman R, Tayloret S, Ulmann A. Transplacental mifepristone. The Lancet 1985;2:1252

passage

of

6. World Health Organization. Pregnancy termination with mife pristone and gemeprost: a multicentre comparison between repeated doses and single dose of mifepristone. Fertil Steril 1991;56:32-40