Outpatient
Vaginal Misoprostol and Its Effect on Post Term
Pregnancy
.........................................................................................................................
Dr Nahid Mostaghel, Assistant Professor
of Obstetrics and Gynecology, Shahid Beheshti
university of medical science, Tehran, Iran
N.mosy33@yahoo.com,
Mobile: +989121209836
Dr Fatemeh Nakhaee, Resident, Obstetrics
and gynecology, Shahid Beheshti university of
medical science, Tehran, Iran
Fa_nakhaee@yahoo.com,
Mobile: +989123274714,
Fax: +98(21)44104062
Dr Zohreh Amiri, PhD of Biostatistics,
Assistant professor of biostatistics, Department
of Basic science, Faculty of Nutrition and Food
technology, Shahid Beheshti university of medical
science, Tehran, Iran, amiri_Z@sbmu.ac.ir
Tel: +98(21)22360656,
Fax: +98(21)22360657
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ABSTRACT
Background
and objectives: Misoprostol is a commonly
used prostaglandin to prevent post term
pregnancy; but a controversy about the
route of administration and the dose of
misoprostol remains unresolved. This study
was designed to determine whether outpatient
administration of vaginal misoprostol
safely decreases the incidence of post
term pregnancies.
Methods:
An open randomized controlled trial was
carried out in Mahdieh hospital, Tehran,
Iran (2008). Forty-four women were randomized
at 40 weeks gestation to receive 25 µg
vaginal misoprostol (22) or placebo (22)
on an outpatient basis. Women were then
allowed to go into spontaneous labor unless
an indication for induction developed.
Main outcome measures were incidence of
post term delivery, Misoprostol side-effects
and neonatal outcomes.
Results: Misoprostol
was associated with a significant decrease
in mean time to delivery (68.3 ±
6.263 versus 125.81 ± 72.744 hours;
P =0.013), earlier gestational age at
delivery (285.55 ± 2.417 versus
287.76 ± 2.644 days; P =0.008),
without any significant increase in uterine
hyper stimulation, fetal distress, low
Apgar score at delivery or other side-effects.
Conclusions:
Outpatient administration of 25 µg
vaginal misoprostol (single dose) in term
pregnancy can safely reduce the length
of gestation.
Keywords: misoprostol, post term
pregnancy, prostaglandin.
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Post-term pregnancy is a
common problem during pregnancies and is associated
with significant morbidity and mortality. Fetal
distress, macrosomia, and releasing of meconium
in amniotic fluid are some of these complications
(1). On the other hand induction of labor in
the presence of unfavorable cervix can increase
the risk of cesarean section(1).
Prostaglandins have proved
to have an effect on cervical ripening(2).
Misoprostol (prostaglandin E1 analog) is effective
for cervical ripening and induction of labor
in term pregnancies(3). Misoprostol
is an inexpensive drug that can be stable at
room temperature. There is a concern that misoprostol
may increase the rate of uterine hyper stimulation(4-9),
although in some studies misoprostol had no
adverse effect and were not associated with
uterine hyper stimulation(10).
There have been several meta-analyses
and systematic reviews of randomized controlled
trials evaluating the use of misoprostol for
cervical ripening and labor induction suggesting
that misoprostol is effective; despite this,
a controversy about the route of administration
and the dose of misoprostol remains unresolved.
Outpatient administration
of misoprostol has been studied only in few
investigations (10) but it may be efficient
and cheap to decrease post term pregnancies.
Misoprostol can decrease the rate of post term
pregnancy and its associated complications,
additionally outpatient administration of misoprostol
can haveconsiderable cost implications, and
with avoiding of hospital admission during administration
of misoprostol, it can be a practical method
with lower costs especially in developing countries.
The aim of this study was
to determine whether the administration of a
single low-dose vaginal misoprostol would prevent
post term pregnancy.
This study was an open randomized
controlled trial conducted from April 2007 to
December 2007 in Mahdieh hospital in Tehran,
Iran.
The approval for this research
proposal was granted by Research and Review
Committee of Shahid Beheshti University of medical
science in April 2007.
All women seen at the prenatal
care unit in Mahdieh hospital, who had uncomplicated
singleton pregnancies at 40 weeks gestation
and were candidates for vaginal delivery, were
invited to participate in this study. Inclusion
criteria were: singleton pregnancy, vertex presentation,
intact membrane, Bishop Score <6.
Women entered in this study were at their 40
weeks of gestational age and did not have any
indication for induction of labor and were not
in active phase of labor. Gestational age was
based on last menstrual period and ultrasonography
before 20 weeks.
Patients were excluded from the study if they
had non vertex presentation, cephalopelvic
disproportion, contraindication
of misoprostol administration (asthma, cardiovascular
diseases and allergy), previous cesarean section
or uterine incision, maternal systemic diseases,
fever, nausea, vomiting, diarrhea, fetal anomalies
or diseases, parity >5, unexplained
vaginal bleeding, fetal distress (Intra uterine
growth restriction, oligohydraminous, non-reactive
non-stress test), estimated fetal weight of
>4500 g. A non-stress test was carried out
and the women with non-reassurance pattern of
NST were excluded.
The main outcome measures
included the time from intervention up to delivery,
gestational age at delivery and post-term pregnancy
(defined in this study as gestational age of
41 weeks and 3 days or beyond). Other measures
were the proportion of cesarean section and
vaginal delivery, side-effects of misoprostol
(fever, nausea, vomiting and diarrhea), releasing
of meconium in amniotic fluid, neonatal outcomes
(1-minute and 5-minute Apgar score and admission
to NICU), uterine tachysystole (defined as >5
contractions in a 10-minute period) and hyper
tonus (defined as a single contraction that
lasted longer than 90 seconds).
Tablets (100 µg misoprstol
and placebo) were quartered by the pharmacist
with a pill cutter. The placebo tablets were
similar to the tablet of misoprostol in appearance
and texture. After signing an informed consent
form, eligible candidates randomly had a sealed
envelope containing either misorostol (25 µg)
or placebo. The tablet was placed in the posterior
fornix of vagina.
Women were monitored continuously for 2 hours
after intervention regarding the half life of
misoprostol that is about 20-40 minutes(11).
During this period, fetal
FHR and uterine contractions was monitored and
maternal signs and symptoms (nausea, vomiting,
fever and diarrhea) were recorded.
If the woman had regular contractions after
2 hours, she was sent to labor and delivery
unit for evaluation; otherwise she was discharged
home.
Women were examined every
3 days, and were admitted if they had rupture
of membranes, regular contractions, cervical
dilation > 3cm or gestational age = 41 weeks
and 3 days. Admission, delivery, and neonatal
outcome data were recorded when the women were
admitted.
Study participants, nurses,
residents and attending staff were unaware of
the randomization and group assignment until
completion of the trial.
A sample size and power calculation
determined that 34 women was sufficient (power
of 0·90, 
= 0·01, and 
= 0·10). Assuming a 25 percent reduction
in the number of cases during study, 44 cases
entered the study. These calculations were made
on the basis of other published studies (10).
The test was two-sided, and data were entered
into Excel and analyzed independently using
x2
or Fisher exact test and independent samples
t-test or Mann Whitney U test. A P-value of
<0·05 was considered significant.
Data were analyzed with SPSS 16.2. For discrete
data, relative risk (RR) with 95 percent confidence
intervals (CI) was used.
A total of 44 women were enrolled. 22 patients
were assigned randomly to the misoprostol group,
and 22 patients were assigned randomly to the
placebo group. Three women (2 of the misoprostol
group and 1 of the placebo group) were excluded,
because they ceased the study and didn't return
for latter visits. Complete outcome data was
collected on all 41 participants.
The groups were similar in maternal age, nulliparity,
Bishop's score and gestational age at the time
of intervention (Table 1).
|
Table
1 Demographic
characteristics of patients who received
vaginally either misoprostol or placebo |
| Characteristics |
Misoprostol
(n=20) |
Placebo
(n=21) |
P |
|
Maternal age (years)* |
27.25
± 5.476 |
25.95
± 5.861 |
0.469 |
| Gestational
age at the time of intervention (days)* |
282.80 ± 1.963 |
282.71 ± 1.678 |
0.881 |
|
Bishop’s score* |
3.00 ± 1.522 |
3.05 ± 1.431 |
0.918 |
|
Nulliparous |
60.00% |
61.90% |
0.016 |
*Data are given as mean ±
SD.
No statistical difference (P > 0.05) was
found between groups for each comparison.
Table 2 and 3 contain the delivery data. The
gestational age on delivery was significantly
less in the misoprostol group compared with
the placebo group (285.55 ± 2.417 days
versus 287.76 ± 2.644 days, P= 0.008).
|
Table
2 Delivery
data in misoprostol and control group |
| characteristics |
Misoprostol
(n=20) |
Placebo
(n=21) |
P |
| Gestational
age at the time of delivery (days) |
285.55
± 2.417 |
287.76
± 2.644 |
0.008 |
| The interval
between intervention and delivery (hours) |
68.30
± 68.263 |
125.81 ± 72.744 |
0.013 |
|
post term pregnancy |
2 (10%) |
7 (33.3%) |
0.130 |
|
cesarean section |
2 (10%) |
5 (23.8%) |
0.410 |
Data are given as mean ±
SD
|
Table
3 Delivery
data in nulliparous and parous groups |
| |
p |
n |
The interval
between intervention and delivery (hours) |
Gestational age
at the time of delivery (days) |
|
Misoprostol (n=20) |
Nulliparous |
12 |
53.50 (35.50 - 117.50) |
285.00 (284.00 - 287.00) |
|
Parous |
8 |
21.50 (12.25 - 35.75) |
285.00 (283.25 - 286.75) |
|
Placebo (n=21) |
Nulliparous |
13 |
154.00 (85.50 - 223.50) |
289.00 (286.00 - 291.00) |
|
Parous |
8 |
84.50 (43.75 - 121.50) |
286.50 (285.25 - 289.75) |
*Data are given as median(IQ 25-75)
The interval between intervention and delivery
was significantly shorter in the misoprostol
group compared with the placebo group (68.30
±68.263 hours versus 125.81 ±
72.744 hours, P= 0.013); misoprostol also shortened
the mean time from the intervention to vaginal
delivery in the nulliparous (84.33 ±
67.855 hours versus 151.77 ± 76.291 hours)
and parous (44.25 ± 65.661 hours versus
83.62 ± 43.084 hours) groups.
Two patients in the misoprostol group had post-term
pregnancy, compared with five in the control
group but it did not reach a significant level.
(P= 0.13)
There was no significant difference between
misoprostol and placebo groups in the cesarean
delivery rates. The indications for cesarean
delivery were fetal distress in labor (one in
the misoprostol group, two in the control group),
releasing of meconium in amniotic fluid (one
in the misoprostol group, two in the control
group) and secondary arrest of cervical dilatation
(one in the control group).
Newborn outcomes were comparable between treatment
groups (Table 4). Meconium was present in 10
percent of the misoprostol group compared with
19 percent in the control group (RR= 0.472;
95% CI= 0.076-2.921). Only one infant (in the
control group) was admitted to the neonatal
intensive care unit (because of meconium aspiration)
and 1 and 5-minute apgar scores were similar
in both groups.
|
Table 4
Neonatal outcomes in misoprostol and control
group |
| characteristics |
Misoprostol
(n=20) |
Placebo
(n=21) |
P |
|
NICU admission |
0 (0%) |
1 (4.8%) |
1.00 |
| 1-minute
apgar score |
8.85
± 0.366 |
8.9
± 0.301 |
0.603 |
| 5-minute
apgar score |
9.85 ± 0.366 |
9.9 ± 0.301 |
0.603 |
| meconium-stained
amniotic fluid |
2 (10%) |
4 (19%) |
0.663 |
Data are given as mean ± SD
There were no cases of fetal distress, tachysystole
(=5 contractions in a 10-minute period) and
hyper tonus (single contraction = 90 seconds)
in this study. During 2 hours after intervention,
nausea, vomiting, and diarrhea were not found
in the misoprostol and control groups; and increase
of body temperature during this period was similar
(one in the misoprostol group and two in the
control group).
In this randomized clinical
trial, the efficacy of a single dose of 25 µg
vaginal misoprostol on an outpatient basis was
investigated. This study is similar to a previous
cervical ripening investigation by Victor O.
Oboro who had used the same intervention (10).
Results in our study
showed that the single dose of misoprostol (25
µg) can be useful in decreasing the length
of pregnancy.
A single dose of 25 µg
misoprostol wasn't associated with nausea, vomiting,
and diarrhea; and fever wasn't significantly
different in two groups.
The relation between
misoprostol and uterine hyper stimulation has
been challenged in several studies (4-9). Uterine
hyper stimulation has been shown with the use
of higher doses of misoprostol and one single
dose of 25 µg was not associated with
hyper stimulation (10). There were no cases
of uterine hyper stimulation in our study either
when spontaneous labor occurred or when induction
was performed for pregnancies going beyond 41
weeks and 3 days of gestation.
In Victor O. Oboro's
study the neonatal outcome among patients who
received misoprostol was not significantly different
from the controls who did not receive misoprostol.
In our trial either the neonatal outcome (1-minute
Apgar score, 5-minute Apgar score and NICU admission)
was similar in misoprostol and control group.
In some studies it has
shown a trend towards a higher risk of meconium
staining with misoprostol (12), but we didn't
find a significant difference between misoprostol
and control group.
Cesarean delivery rates
in Jay M. Bolnick et al study (13) with the
use of 25 µg misoprostol every 4 hours
was 16.9 percent. In Victor O. Oboro's study
there was no significant difference between
groups (one single dose of 25 µg misoprostol
and placebo) in the cesarean delivery rates.
Although in our trial there was 10 percent cesarean
rate in the misoprostol group and 23.8 percent
in the control group, it did not reach a significant
level.
Findings in this study
show that misoprostol can have an important
role in cervical ripening and management of
uncomplicated postdate pregnancies, and the
use of misoprostol in low doses can limit its
side effects.
Outpatient administration
of misoprostol also has considerable cost implications,
and with avoiding of hospital admission during
administration of misoprostol, it can be a practical
way especially in developing countries.
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