Medical Management of Missed Abortion:

A Randomized Clinical Trial

S. L. Wood, MD, MSc, and P. H. Brain, BSc, MD
OBJECTIVE: To estimate the efficacy of vaginal misoprostol
for medical management of missed abortion.
METHODS: Fifty women with missed abortion were randomized to treatment with up to two 800-mg doses of
misoprostol vaginally or a placebo. Participants were reviewed daily for 2 days, then again at 1 week. A blood
sample for hemoglobin and serum -human chorionic
gonadotropin (hCG) was obtained on day 1 and the
hemoglobin level checked again on day 7. Complete abortion was defined as expulsion of the products of conception
without dilation and curettage (D&C) and a negative follow-up urine hCG test after 4 weeks, or as no products of
conception obtained at D&C in cases of suspected incomplete abortion.
RESULTS: The rate of complete abortion was 80% (20 of 25)
in the misoprostol group and 16% (four of 25) in the
placebo group, relative risk 0.20 (0.08, 0.50), P < .001. The
rate of D&C was 28% (seven of 25) in the misoprostol group
and 84% (21 of 25) in the placebo group, relative risk 0.33
(0.17, 0.64), P < .001. One participant in the misoprostol
group had an emergency D&C for heavy bleeding. No
participants required blood transfusion. The mean reduction in hemoglobin from day 1 to day 7 was 3.2 g/L in the
misoprostol group versus 4.3 g/L in the placebo group, P
.72. Patient satisfaction with misoprostol treatment was
high with 19 of 21 participants reporting they would try
medical management again if they experienced another
missed abortion.
CONCLUSION: Medical management of missed abortion is
effective, reduces the need for D&C, and is associated with
high levels of patient satisfaction. (Obstet Gynecol 2002;
99:563 6. 2002 by the American College of Obstetricians and Gynecologists.)

Missed abortion is a common complication of early

pregnancy occurring in up to 15% of all clinically recognized pregnancies.1 The majority of cases are currently
treated by dilation and curettage (D&C). The rationale
From the Department of Obstetrics and Gynecology, University of Calgary,
Calgary, Alberta, Canada.
This work was supported by a grant from the Office of the Associate Dean of
Research, Faculty of Medicine, University of Calgary.

that all spontaneous abortions should be treated with

D&C to prevent infection and hemorrhage has been
questioned,2 and several studies have reported success
with expectant management of incomplete abortion.3,4
Treatment of incomplete abortion with misoprostol has
also been reported with varying degrees of success.5 8
With the rising use of early ultrasound, an increasing
number of miscarriages present as missed abortions before the onset of cramping and bleeding. A small case
series reported seven of eight women with missed abortion had a complete abortion after treatment with vaginal
misoprostol compared with three of 12 treated by the
oral route.9 We decided to investigate this further in a
randomized trial in subjects with missed abortion to
determine what the rate of complete abortion and D&C
would be compared with expectant management.
MATERIALS AND METHODS
Subjects were approached for enrollment if they had an
ultrasound diagnosis of a nonviable pregnancy and were
not experiencing uterine cramping or bleeding. Standard
ultrasound criteria for missed abortion were used. One
of the following was necessary for a diagnosis of a
nonviable pregnancy: embryo greater than 7 mm with
no embryonic cardiac activity, irregular gestational sac
with mean sac diameter greater than 16 mm2, or a
gestational sac greater than 15 mm with no visible fetal
pole. Subjects with active vaginal bleeding, cramping,
dilatation of the internal os, or with a nonviable embryo
that measured greater than a 12-week size were excluded. However, women who were experiencing light
spotting, without cramping, and had a closed internal os
were eligible. Subjects experiencing a steady flow of
blood were excluded.
After obtaining informed consent, subjects were randomly allocated to treatment with misoprostol 800 mg
per vagina or to placebo. Randomization was accomplished by a computer-generated random number list
with subjects randomized into varying blocks of sizes 4 to
8. According to the randomization schedule, pharmacy
staff placed the misoprostol or placebo tablets into num-

VOL. 99, NO. 4, APRIL 2002

2002 by The American College of Obstetricians and Gynecologists. Published by Elsevier Science Inc.

0029-7844/02/$22.00
PII S0029-7844(01)01765-3

563

bered envelopes. The investigators were not aware of the

randomization schedule, and the envelopes were not
handled or opened until after randomization. As the
misoprostol and placebo tablets were not identical, additional precautions were taken to maintain allocation
concealment. After the clinical assessment, the study
nurse placed the pills in an opaque vaginal introducer,
which the physician then used to insert the tablets. The
subjects were provided with acetaminophen and combined acetaminophen/codeine tablets for analgesia.
They were instructed to use one or two of these tablets
every 4 hours as needed. All Rhogam-negative women
received Rhogam 300 g intramuscularly. Subjects were
also asked to complete a patient satisfaction questionnaire and a symptom log. An information sheet was
provided with instructions to return to the hospital if
heavy bleeding occurred. Heavy bleeding was defined as
saturating more than one heavy pad every hour for more
than 2 hours or more than one heavy pad per 30 minutes
for more than 1 hour.
A container was also provided for any products of
conception that the subjects were able to retrieve. Baseline hemoglobin and serum -human chorionic gonadotropin (hCG) levels were obtained. The serum hCG
was repeated at 48 hours and the hemoglobin at 1 week.
Follow-up was arranged at 24 hours, 48 hours, and at 1
week. Speculum and bimanual examinations were performed at each visit, and any tissue passed by the subjects was examined. If complete abortion was not suspected after 24 hours, the medication was repeated. At
48 hours, if there had been no response to the medication
or an incomplete abortion was suspected, the subjects
were offered D&C. Transvaginal ultrasound was used in
cases of suspected incomplete abortion as clinically appropriate. An ultrasound finding of a focal hyperechoic
intrauterine mass was considered sufficient for diagnosis
of incomplete abortion. All subjects with a clinically
suspected complete abortion were instructed to have
urine hCG test after 4 weeks. Pathology reports for all
tissue submitted for examinations were reviewed.
The subjects were also asked to complete a posttreatment questionnaire. Patient satisfaction was assessed by asking the subjects to rate their degree of
agreement with two statements: 1) I would recommend
the treatment with the vaginal tablets to a friend or
family member who had a missed abortion. 2) I would
try treatment with the vaginal tablets again if I had
another missed abortion. The subjects indicated their
degree of agreement with the statements on a five-point
scale: Strongly Disagree, Disagree, Neutral, Agree, or
Strongly Agree. The primary outcomes were rates of
complete abortion and D&C. Complete abortion was
defined as expulsion of the products of conception with-

564

Wood and Brain

Treatment of Missed Abortions With Misoprostol

Table 1. Demographics

Age (u, SD)

Gestational age (u, SD)
Diameter of gestational
sac (u, SD)
Nulliparous
Pretreatment hemoglobin
(u, SD)

Misoprostol
(n 25)

Placebo
(n 25)

32 (5.0)
11.4 (2.2) wk
3.8 (1.6) mm

33 (3.9)
11.7 (2.7) wk
3.6 (1.5) mm

56% (14)
135 (10.6) g/L

48% (12)
135 (9.3) g/L

u mean; SD standard deviation.

out D&C and a negative follow-up urine hCG test at 4

weeks or as the absence of products of conception in the
surgical specimen from D&C in subjects who had suspected incomplete abortion. The rates of complete abortion and D&C were compared and relative risks and
confidence intervals calculated. Statistical significance
was determined with a Fisher exact test, and analysis was
by intention to treat. Also, t tests were used to compare
continuous variables with log transformations where
appropriate. A sample size calculation had estimated that
25 subjects in each group would be necessary to achieve
80% power to detect an estimated reduction in the rate of
D&C from 50% in the placebo group to 10% in the
treatment group. The study protocol was approved by
the University of Calgary Ethics Review Board.
RESULTS
Between February 1999 and April 2000, 50 women were
enrolled in the study. One half of the subjects received
misoprostol and one half placebo. Their gestational age
ranged from 7 weeks to 17 weeks (median 12 weeks).
The diameter of the gestational sac on ultrasound ranged
from 1.4 cm to 7.5 cm. The demographic and clinical
characteristics were similar between the two groups (Table 1). All of the subjects completed the study protocol.
Within 24 hours of the first dose, all of subjects in the
misoprostol group (25 of 25) and 20% (five of 25) of the
subjects in the placebo group reported uterine cramping
and bleeding.
In the misoprostol group, 15 of 25 appeared to have
aborted completely after the first dose. On examination
at 48 hours after enrollment, 21 of 25 of the misoprostol
group appeared to have aborted completely, three of 25
had aborted incompletely, and one subject was unchanged. Typically, patients reported the bleeding and
cramping would reach a peak with the expulsion of a sac
or tissue from the uterus and then rapidly diminish. One
subject who appeared to have aborted completely passed
some necrotic products of conception on day 14 after
treatment. Two subjects had ongoing bleeding and had

OBSTETRICS & GYNECOLOGY

Table 2. Results

Complete abortion
Dilation and curettage
Hemoglobin day 17 (u, SD)
Hemoglobin day 17 10 g/L

Misoprostol
(n 25)

Placebo
(n 25)

80% (20)
28% (7)
3.2 (7.9) g/L
10% (5)

16% (4)
84% (21)
4.3 (10.1) g/L
8% (4)

.001
.001
.72
.71

Abbreviations as in Table 1.

an ultrasound, which suggested retained products of

conception. Both had D&Cs, but no products of conception were documented on histologic examination of the
surgical specimen. Only one subject who appeared to
have completely aborted had a positive pregnancy test 4
weeks after treatment. A D&C was performed, and a
small amount of trophoblastic tissue was removed. One
subject had heavy bleeding and had an emergency D&C.
Her hemoglobin dropped from 141 g/L on day 1 to
129 g/L on day 7.
In the placebo group, four subjects aborted completely, one by 48 hours and three after 1 week. Two
subjects had incomplete abortions, and the remainder
reported no change with treatment.
Overall, the rate of D&C was 28% (seven of 25) in the
misoprostol group and 84% (21 of 25) in the placebo
group, relative risk 0.33 (0.17, 0.64), P .001. The rate
of complete abortion was 80% (20 of 25) in the misoprostol group and 16% (four of 25) in the placebo group,
relative risk 0.20 (0.08, 0.50), P .001.
The laboratory data were also analyzed and compared between the two treatment groups (Table 2).
Baseline and post-treatment (day 7) hemoglobin levels
were obtained in 19 of 25 subjects in the placebo group
and 20 of 25 subjects in the misoprostol group. The
change in hemoglobin between day 1 and day 7 was not
significantly different between the two groups: misoprostol 3.2 g/L versus 4.3 g/L in the placebo group, P .72.
Nine subjects had a decrease in hemoglobin concentration of more than 10 g/L, five were in the misoprostol
group, and 4 were in the placebo group. No subject
required a blood transfusion. The mean serum HCG
levels, at presentation, were higher in the subjects who
had a complete abortion, 24,518 IU/L versus
15,674.5 IU/L. However, after logarithmic transformation of the data, the difference was not statistically significant (P .29). Likewise, the mean change in HCG
levels, from baseline to 48 hours after treatment, was
greater in the group that completely aborted,
18,652 IU/L versus 7768 IU/L, but the difference was
not statistically significant (P .39). The gestational sac
size was also similar between those who completely
aborted and those who did not, 3.16 mm versus 3.48 mm
(P .60).

VOL. 99, NO. 4, APRIL 2002

Vaginal misoprostol treatment appeared to be well

tolerated. Only one patient reported significant gastrointestinal side effects. All but two subjects required only
acetominophen with codeine for analgesia. One subject
had a D&C because of excessive pain, and one presented
to the emergency room and required an intramuscular
injection of narcotic. Twenty-one subjects completed
and returned the post-treatment questionnaire. Four subjects did not return the questionnaire; three of these
subjects failed misoprostol treatment and had a D&C.
Overall, patient satisfaction with the treatment appeared
to be high. For the statement I would try treatment with
misoprostol again if I had another missed abortion, 19
of 21 agreed or strongly agreed, one subject was neutral,
and one disagreed. For the statement I would recommend misoprostol treatment to friends or family with a
missed abortion, 18 of 21 agreed or strongly agreed,
and three subjects were neutral.
DISCUSSION
Obstetrician/gynecologists have recently been challenged to rethink their approach to miscarriage. The
doctrine of prompt surgical evacuation has been challenged by a small number of studies in women with
incomplete abortions. Furthermore, the high success
rates (greater than 90%) in the medical therapeutic abortion also suggest nonsurgical treatment should be considered.10 However, in North America, medical termination requires treatment with methotrexate injections,
which is not available in the average practitioners office
and may not be as acceptable to patients as misoprostol
alone. Furthermore, medical termination studies typically limited enrollment to women with less than 49 days
of amenorrhea because of concerns of excessive bleeding.
Our results suggest that two vaginal doses of 800 mg
of misoprostol alone are effective in producing complete
abortion in approximately 80% of subjects and significantly reduce the need for D&C. Although 28% of our
subjects had a D&C, this may be reduced with further
experience, as two of the subjects had no identifiable
products of conception at the time of surgery. Also, one
subject dilated to 2 cm but did not expel the pregnancy

Wood and Brain

Treatment of Missed Abortions With Misoprostol

565

sac after two doses of misoprostol. In a more flexible

setting, outside of a randomized clinical trial, further
doses could have been given and it is likely the sac would
have been expelled. There may be additional benefits
even if the treatment is not completely successful. All of
the subjects who had a D&C in the treatment group had
a dilated cervix at the time of surgery, which intuitively
should reduce the risk of perforation and cervical lacerations. The treatment also appeared to be well tolerated.
The vast majority of subjects required only codeine and
acetominophen for analgesia, and only one D&C was
performed because of excessive pain. The initial data
also suggest that medical management of missed abortion is safe. There was no occurrence of serious lifethreatening bleeding, and no subject required a transfusion. Only one D&C in the study group was performed
for significant bleeding. However, a sample of 25 subjects may be insufficient to detect rare serious side effects.
Ultimately, we hope to perform a large prospective
cohort study of women requesting medical management
of missed abortion. We anticipate that medical management with vaginal misoprostol will prove to be a viable
alternative to D&C for women with missed abortion.

4.
5.

6.

7.

8.

9.

10.
REFERENCES
1. Daya S. Habitual abortion. In: Copeland LJ, ed. Textbook
of gynecology. Philadelphia, PA: WB Saunders; 2000:
22771.
2. Aucott Ballagh S, Harris HA, Demasio K. Is curettage
needed for uncomplicated incomplete spontaneous abortion? Am J Obstet Gynecol 1998;179:1279 82.
3. Chipchase J, James D. Randomised trial of expectant ver-

566

Wood and Brain

Treatment of Missed Abortions With Misoprostol

sus surgical management of spontaneous miscarriage. Br J

Obstet Gynaecol 1997;104:840 1.
Nielsen S, Hahlin M. Expectant management of firsttrimester spontaneous abortion. Lancet 1997;345:84 6.
Chung T, Leung P, Cheung LP, Haines C, Chang AM. A
medical approach to management of spontaneous abortion
using misoprostol. Extending misoprostol treatment to a
maximum of 48 hours can further improve evacuation of
retained products of conception in spontaneous abortion.
Acta Obstet Gynecol Scand 1997;76:248 51.
Chung TKH, Cheung LP, Leung TY, Haines CJ, Chang
AMZ. Misoprostol in the management of spontaneous
abortion. Br J Obstet Gynaecol 1995;102:8325.
de Jong EM, Makin JD, Manefeldt E, De Wet GH, Pattinson RC. Randomised trial of medical evacuation and
surgical curettage for incomplete miscarriage. Br Med J
1995;311:662.
Henshaw RC, Cooper K, El-Refaey H, Smith NC,
Templeton AA. Medical management of miscarriage:
Nonsurgical uterine evacuation of incomplete and inevitable spontaneous abortion. Br Med J 1993;306:894 5.
Creinin M, Moyer R, Guido R. Misoprostol for medical
evacuation of early pregnancy failure. Obstet Gynecol
1997;89:768 72.
Grimes DA. Medical abortion in early pregnancy: A
review of the evidence. Obstet Gynecol 1997;89:790 6.

Address reprint requests to: S. L. Wood, MD, MSc, Foothills

Hospital, Department of Obstetrics and Gynecology, 1403
29th Street, NW, Calgary, AB T2N 2T9, Canada; E-mail:
stephen.wood@calgaryhealthregion.ca.
Received July 31, 2001. Received in revised form November 2, 2001.
Accepted November 19, 2001.

OBSTETRICS & GYNECOLOGY