Labor Induction Clinical Trial
Official title:
A Randomized Trial of Two Regimens of Misoprostol for Second Trimester Intrauterine Fetal Death
Misoprostol (Cytotec®) is a synthetic prostaglandin E1 analog that has been marketed in the
United States since 1988 as a gastric cytoprotective agent. Despite a focused campaign by
the manufacturer to curtail its use in obstetric practice, misoprostol has, over the past
several years, gained widespread acceptance to effect the medical termination of pregnancy
in the second trimester, either alone or after pretreatment with mifepristone. The primary
reasons for this prompt incorporation into standard practice include its low cost and the
lack of stringent storage requirements.
Vaginal administration seems to be more efficacious than when given orally. The use of
sublingual misoprostol for first trimester abortions has been extensively investigated as
evidenced by the large number of publications comparing sublingual to other routes of
misoprostol for first trimester pregnancy termination, on the assumption that the sublingual
route would have a similar efficacy of the vaginal route. In addition, the sublingual route
would combine an easier administration with the added advantage of no restriction of
mobility after administration. There has been no previous report in the literature comparing
the use of misoprostol given sublingually to that given vaginally for the second trimester
termination following intrauterine fetal death. Our aim is to compare efficacy, safety and
patient satisfaction with misoprostol given vaginally (the current standard) to that given
sublingually.
Prostaglandins have been recognized as effective abortifacients for several decades.
Misoprostol, a synthetic analogue of prostaglandin E1, has several advantages over other
prostaglandins that include low cost, easy storage at room temperature, and favorable side
effect profile. In recent years, misoprostol has attracted attention as an effective and
cost-efficient agent for the medical interruption of the second-trimester pregnancy.
Nowadays, misoprostol has been accepted widely as a safe and effective agent for labor
induction during the second trimester. Various doses, routes, and protocols for medical
termination of pregnancy during the second trimester have been investigated. The optimal
dosage and route of administration, however, have yet to be defined. Previous studies have
demonstrated greater efficacy with vaginal misoprostol versus oral administration in
effecting mid-trimester termination. However, oral administration of any medication is
preferred by patients and health care providers alike. The higher efficacy after vaginal
administration may be explained by the pharmacokinetics of the drug. Zeiman et al showed
that the systemic bioavailability of vaginally administered misoprostol is 3 times higher
than that after oral administration. Plasma concentrations of its metabolite, misoprostol
acid, peak one to two hours after vaginal application as compared with the peak seen 30
minutes following oral administration, and although peak levels are lower with the vaginal
route, they are sustained longer and overall exposure to the drug is increased, perhaps
because of the presystemic gastrointestinal or hepatic metabolism that occurs with the oral
route. An additional explanation for the higher efficacy could be that there is a direct
effect on the cervix that initiates the physiologic events that lead to increased uterine
contractility. The sublingual route of administration has not been reported in the
literature prior to 2001. Since then and partly because of issues relating to patient
preference, investigators started studying the sublingual route of administration of
misoprostol. In theory, the sublingual route could mimic vaginal administration
pharmacokinetically, although there have been no such reported studies on this route of
administration.
Although many studies have been published on the use of sublingual misoprostol for medical
abortion in the first trimester, none were done to compare sublingual and vaginal routes in
the case of second trimester termination for intrauterine fetal death. The 400-µg dose was
chosen because it is the dose most commonly used orally and vaginally in various studies
reported in the literature.
To the best of our knowledge, no study comparing sublingual to vaginal misoprostol for
termination of pregnancy for intrauterine fetal death in the second trimester has been
previously published in the literature. Therefore, this study, when completed will provide
evidence on the relative effect and safety profile of different routes of administration of
misoprostol for indicated second trimester termination.
The aim of our study is to compare the efficacy of a 400-µg sublingual dose of misoprostol
Cytotec® (Searle Pharmaceuticals, Bucks, United Kingdom) administered at 4-hour intervals
with an equivalent dose regimen administered vaginally in women admitted for second
trimester termination for intrauterine fetal death. In addition, we want to assess patient
acceptability of the 2 modes of administration.
The study hypothesis is that the sublingual route of administration of misoprostol is as
effective as the vaginal route for induction of labor for mid trimester termination and is
more acceptable to patients as compared to vaginal misoprostol.
Randomization procedure:
The randomization to vaginal or sublingual misoprostol will be based on a computer-generated
table with the allocation concealed in sealed, sequentially numbered, brown envelopes, which
had been prepared by the principal investigator that will not be involved in the clinical
care of the patients. Because of the nature of the misoprostol administration, the patients
and staff will not blinded to the randomization allocation.
Routine studies and procedures:
- A pelvic exam will be done to make sure that the patient is eligible for inclusion in
the study (Bishop's score <8).
- Maternal pulse, blood pressure, and temperature will be recorded every 4 hours ( at the
time of the insertion of the Misoprostol).
- After delivery of the fetus, all patients will receive 20 units of oxytocin in 1000 mL
of intravenous crystalloid at an infusion rate of 125 mL per hour.
- Postpartum curettage will be performed at the discretion of the physician if the
placenta had not delivered spontaneously 2 hours after the delivery of the fetus.
- Patients will receive intravenous narcotics or epidural anesthesia as needed for pain
control.
- Antiemetics, antipyretics, and anxiolytics will be administered as indicated.
Interventions: The women will give a full informed consent, after which they will be
randomized to receive 400 µg of vaginal or sublingual misoprostol Cytotec® (Searle
Pharmaceuticals, Bucks, United Kingdom) after admission to the induction ward. This
dose and route of administration will be repeated every 4 hours, if required as long as
the patient is undelivered up to 48 hours following initiation of induction.
The induction will be categorized as having failed if the woman was undelivered after 48
hours and then she would receive extraamniotic PGF2 instillation or high-concentration
intravenous oxytocin, depending on their cervical status and amniotic membrane integrity.
Another option would be a further attempt at cervical ripening with vaginal Prostin tablets
(Upjohn Pharmaceuticals) after an interval of at least four hours following the last dose of
misoprostol.
- The women will complete a brief questionnaire using a visual analogue scale to ascertain
their perceptions of the process in terms of pain, control, and overall opinion of the
procedure every 12 hours. The women will perform the pain scale assessments with a visual
analogue ruler scaled from 0 to 10, with 0 representing no perception of pain and 10
representing the most intense pain ever experienced.
Statistical analysis Statistical analysis will be performed using the SPSS statistical
package. Categoric data like maternal characteristics will be compared using Chi square when
sample sizes support the approximation. Otherwise, categorical data will be analyzed with
two-tailed Fisher exact test if the expected cell frequencies were small. Continuous
variables will be compared by Student t test if assumptions of normality and homogeneity of
variances appeared to be reasonable. Unpaired variables and differences in distributions
will be compared using the Mann-Whitney test. A p-value <0.05 will be considered
statistically significant.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
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