Low Dose Vaginal Misoprostol Versus Prostaglandin E2 Suppository for Early Uterine Evacuation: A Randomized Clinical Trial
Misoprostol is a cheap product of prostaglandin E1 which has gained interest in pregnancy termination. The aim of this study was to compare the effect of vaginal misoprostol and prostaglandin E2 suppository in pregnancy termination before 20 weeks of gestational age. In this clinical trial, 111 participants under 20 weeks of gestational age who needed pregnancy termination were enrolled. They were divided into two groups misoprostol and prostaglandine E2 treatment. Fifty four people received vaginal misoprostol as 25 μg per 4 h up to 3 days and 57 participants received prostaglandine E2 vaginal suppositories. Data were analyzed using SPSS software. Mean age of participants was 27.5 years and its standard deviation was 6.1 years. Mean gestational age was 13.1 weeks based on sonographic measurement and it was 14.5 weeks by LMP estimation. Mean induction to evacuation time was 3.1 days and in misoprostol group was 2.4±0.88 days. Half of the patients in control group and 70% of them in misoprostol group succeeded pregnancy termination in 48 h. Vaginal misoprostol compared to prostaglandine E2 vaginal suppository has higher efficacy in shorter time.
Received: January 01, 2010;
Accepted: August 23, 2010;
Published: September 17, 2010
Induced abortion is considered as a necessity in obstetrics and gynecology
and developing more suitable methods to induce earlier termination of pregnancy
has always been a challenge to researchers in this field. It has been reported
that risk of legal abortion increases exponentially with gestational age and
that, although, death from legal abortion is very rare, 87% of the deaths that
are occur could be prevented if women terminating their pregnancies after 8
weeks of gestation had been able to access abortion services during the first
8 weeks of pregnancy instead (Bartlett et al., 2004).
Due to their inherent properties prostaglandins have always been thought of
possible indication in induces abortion. Prostaglandins are synthesized from
Arachidonic Acid (AA) first by cyclooxygenase (Cox) -1 or -2, which convert
AA into PGH2. This precursor PG is further processed by isoform-specific cytosolic
or microsomal prostaglandin synthases (c/mPGES) to become PGE2 or one of several
other effector prostaglandins. They are mediators and have a variety of strong
physiological effects, such as regulating the contraction and relaxation of
smooth muscle tissue. An increasing proportion of early abortions are induced
with the medications mifepristone and misoprostol rather than surgery. Risk
of abortion increases with gestational age and varies with type of procedure
(Bartlett et al., 2004).
The need for pregnancy termination in first or second trimester is a common
referral reason while using oxytocin and prostaglandin E2 have not proven to
be quick enough and completely satisfactory. This may lead to desperation of
patients and higher economic burden on them. Some reference books in obstetrics
have recommended to use misoprostol as an alternative to surgical procedures.
Although, this may need complementary evacuation or curettage but the low complication
rate with misoprostol makes it a preferable method (Brando
et al., 2002; Graziosi et al., 2004,
2005). There are some reviews about efficacy of misoprostol
in second and third trimesters. One review article on 16 papers has concluded
about the insufficiency of information regarding induction of labor using misoprostol.
A very recent review included 38 randomized controlled studies showing that
vaginal misoprostol was as effective as other agents in inducing labor and achieving
vaginal birth within 24 h, with a reduction in the occurrence of maternal side
effects (Dodd and Crowther, 2010). Regarding the safety
of the misoprostol after caesarean section it has been suggested to be safe
among those with one previous section however, evidence is limited in this regard
(Berghella et al., 2009). Misoprostol versus
prostaglandine E2 has been the focus of research but very little is known about
the compared efficacy of misoprostol under 20 weeks of gestational age especially
at lower doses. The aim of this study was to compare the efficacy of low dose
vaginal misoprostol and prostaglandin E2 suppository in pregnancy termination
before 20 weeks of gestational age.
MATERIALS AND METHODS
In this randomized clinical trial study a total of 111 pregnant women under 20 weeks of gestational age who needed pregnancy termination were enrolled. The patients were those referred to Alzahra University Hospital in 2008.
The participants were randomly assigned to receive either vaginal misoprostol tablets or prostaglandine E2. So, 54 women received 25 μg vaginal tablet quarters for every 4 h up to maximum 3 days. The tablets were applied by physician in posterior fornix of cervix. The control groups were 57 eligible women who received dynoproston suppositories every 4 h. In both groups either couretage or syntocinone were used to terminate the pregnancy.
The inclusion criteria were as: gestation under 20 weeks, fetal death diagnosed
by sonography or other induced aborthion indications and informed consent of
participation. The exclusion criteria were as: severe vaginal bleeding, contraindications
in using study drugs and ectopic pregnancy.
Statistical analysis: Data were analyzed using STATA statistical software package. Stata Statistical Software: Release 8. College Station, TX: StataCorp LP). The main outcome of interest was the time to termination and the main statistical method applied was survival analysis. Weibul and Cox parametric regression models were used to estimate survival and hazard ratios. Weibul method was used to compare the efficacy of drugs. Log-log graphical evaluation was used for model evaluation. Statistical significance was set at 0.05 point for an equivalence hypothesis testing. Study was approved by committee of ethics in Tabriz University of Medical Sciences.
Age of the participants ranged from 17 to 42 years with a mean of 27.5±6.1 (±SD) years. Mean gestational age was 13.1 days. Mean gravity and mean pariety were 2.1 and 0.8, respectively. The 23.2% of participants had at least one abortion in their history. Twenty three percent had at least one previous live child birth.
Study participants had spotting or vaginal bleeding in 22.3 and 57% of them were symptom free. The reason for termination of pregnancy was fetal anomaly in 17%, fetal death or missed abortion in 17%, preterm rupture of membranes in 12.5% and other causes as remander.
Mean time to Termination of Gestation (TTG) was 3.1±2 days in group receiving prostagandine E2 and 2.4±0.88 days in misoprostol group (Fig. 1a, b).
||Survival graphs for successful early pregnancy termination
compared between (a) misoprostol and (b) prostaglandine E2
|| Estimated success probability at daily intervals after receiving
each of the treatment modalities
||Compared efficacy of misoprostol and PgE2 48 h after treatment
The means were not different statistically using independent t-test. Mean TTG without considering the study group was 2.8 days. Minimum TTG was 1 day and maximum TTG 12 days but in majority of cases the gestation was terminated in 2 days. Half of the patients receiving PgE2 terminated gestation compared to 70% in misoprostol group. The relative risk of termination for misoprostol compared to PgE2 was 1.6 (Fig. 2).
Table 1 shows that although, cumulative expulsion probability is similar for the 1st day after receiving treatment in both groups but during 2-3 day period this probability increases 20% more for mispoprostol group.
Based on results from weibul regression, misoprostol terminates the pregnancy earlier than PgE2 with a Hazard ratio equal to 2.1 (95% CI: 1.4-3.1). Without considering the effect of treatment type, gestational age was the main predictor of time to termination of pregnancy (p<0.01).
One-third of participants receiving misoprostol had spontaneous pregnancy termination compared to five% in PgE2 group. The relative risk for spontaneous pregnancy termination was 2.1 for Misoprostol versus PgE2.
This study uses vaginal misoprostol. Although, the efficacy is shown to be
similar to sublingual misoprostol but the side effect profile puts a question
mark on its routine usage in maternal care (Souza et
The main side effects of misoprostol are reported to be tachi-systol and hyperstimulation.
Previous studies discuss higher incidence of specific side effects along with
higher efficacy for misoprostole (Crane et al., 2006;
Frohn et al., 2002; Jain
and Mishell, 1994; Makhlouf et al., 2003).
Uteral rupture has also been reported (Willmott et al.,
2008). This seems to be one of the first reported cases of uteral rupture
after induction with misoprostol in early pregnancy. Other cases are reported
to happen at term pregnancy or have risk factors of rupture of uterus. No specific
complication was observed using misoprostol in this study. However, a larger
study with 720 second trimester abortions in women with previous cesarean section
has also showed that complication rate is not different for women with a history
of cesarean section compared to those without it. This rate can be even smaller
when used in low doses and early through the pregnancy (Dickinson,
2005). In present study, even no non serious complication of the misoprostol
was observed which can be due to the very low dose of drug used which was quite
different from the previous studies.
Misoprostol was shown to be capable of terminating the pregnancy in shorter
period of time. Long hospital stays may impose a psychological pressure on the
patient affecting her health status. Economical factors must also be taken into
account. Mean termination time in our study was 2.4 days compared to findings
of Jansen et al. (2008) to be 18 h. They used
a primary 200 μg mifipriston followed by 200 μg vaginal misoprostol
given at 3 h intervals (Jansen et al., 2008).
Median termination time at second and third trimesters of pregnancy was 13 h
in another study and 88% of the pregnancies were terminated in first 24 h (De
Heus et al., 2004). Shorter time span in this study can be either
due to higher dose or termination time at third trimester. Another study on
misoprostol conducted in 13-30 weeks of gestational age showed a mean 12.7 h
of effect time (Langer et al., 2004).
In a review article drug induced abortion mean termination time was stated
to vary from 13.8 to 45 days (Tang and Ho, 2002).
Oral versus vaginal misoprostol is compared in a study on 214 pregnant women
showing the oral form to be more efficate, quicker and cosstbenefit (Hassan,
Consistent with present findings another study comparing misoprostol and prostaglandin
E2 has found quicker effect for misoprostol (Sifakis
et al., 2007). Crane et al. (2006) have
also consistent findings with others have observed quicker efficacy for misoprostol
but they also found that misoprostol didnt decrease the rate of cesarean
section and it causes tachsystols and hyperstimulation (Crane
et al., 2006). Nanda et al. (2007)
in their study comparing vaginal misoprostol and prostaglandin E2 found that
80% of misoprostol receivers compared to 62% in prostaglandin group terminated
pregnancy in 24 h (Nanda et al., 2007).
The findings of the present study is found to be in line with previous research
in quicker efficacy of misoprostol than prostaglandins, even though our study
used a very low dose of misoprostol which may explain longer mean termination
time. Regarding the acceptability of using misoprostol, studies have shown that
people prefer it to procedural termination of pregnancy and accept the possible
complications even knowing about higher efficacy of procedural methods (Graziosi
et al., 2005, 2006).
Using misoprostol even in very low doses is as efficient and more quicker than prostaglandin E2.
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