Sublingual Versus Vaginal Misoprostol for Labor Induction at Term
Condition: Induction of Labor
Study type: Interventional
Phase: Phase 3

Summary: 
      Misoprostol (Cytotec®) is a synthetic prostaglandin E1 analog that has been marketed in the
      United States since 1988 as a gastric cytoprotective agent. In contradistinction to
      prostaglandin E2 preparations (dinoprostone, Prepidil, Cervidil), misoprostol is inexpensive
      and available in scored tablets that can be broken and inserted vaginally. Despite a focused
      campaign by the manufacturer to curtail its use in obstetric practice, misoprostol has, over
      the past several years, gained widespread acceptance as both a labor induction and a cervical
      ripening agent. Such off-label indication has been endorsed by the American College of
      Obstetricians and Gynecologists and other medical bodies. Recently, FDA approved a new label
      for the use of cytotec during pregnancy which removed pregnancy as a contraindication for its
      use. Vaginal administration seems to be more efficacious than when given orally, although
      there is the worry of uterine tachysystole and hyperstimulation with vaginal doses > 50-µg.
      The use of sublingual misoprostol for cervical ripening at term was recently investigated in
      two studies that compared it to the oral route, on the assumption that the sublingual route
      would have the higher efficacy of the vaginal route by avoiding the first pass effects of the
      gastrointestinal and hepatic systems, while having lower hyperstimulation rates by avoiding
      the direct effects on the cervix. 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 induction of labor at term. Our aim is to
      compare efficacy, safety and patient satisfaction with misoprostol given vaginally (the
      current standard) to that given sublingually.
    

Detailed description: 
      Misoprostol, a synthetic prostaglandin E1 analog, has been given both orally and vaginally
      for induction of labor in the third trimester.1 Vaginal misoprostol has been shown to be more
      efficacious than oral misoprostol in equivalent doses,2 although there is the worry of
      uterine tachysystole and hyperstimulation with vaginal doses of 50 µg or higher.2-4 The
      higher efficacy after vaginal administration may be explained by the pharmacokinetics of the
      drug. Zeiman et al5 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.6 However, there seems to be a trend toward patient
      preference for the oral route. 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.

      It is speculated that sublingual misoprostol could combine the higher efficacy of the vaginal
      route by avoiding gastrointestinal and hepatic metabolism, but it could have a more
      restrained effect on uterine contractility by avoiding direct effects on both the uterus and
      cervix. Therefore, in theory, the sublingual route may have lower hyperstimulation rates and
      would have the advantage of a less invasive administration and lack of restriction of
      mobility.

      Although many studies have been published on the use of sublingual misoprostol for medical
      abortion in the first and second trimesters, 7-11, only two studies (by the same group) have
      compared sublingual to oral misoprostol, in different doses.12,13 The 50-µg dose was chosen
      because it is the dose most commonly used orally and vaginally in various studies reported in
      the literature.3,14 To the best of our knowledge, no study comparing sublingual to vaginal
      misoprostol for labor induction at term 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 labor induction.

      The aim of our study is to compare the efficacy of a 50-µg sublingual dose of misoprostol
      administered at 4-hour intervals with an equivalent dose regimen administered vaginally in
      women admitted for induction of labor for a medical or obstetric indication at term. In
      addition, we want to assess the safety profile and 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 at term and is more acceptable to
      patients as compared to vaginal misoprostol.
    

Intervention name(s): Misoprostol (Cytotec®)
Intervention type(s): Drug
Intervention description(s): 50 micrograms of sublingual or vaginal misoprostol every 4 hours for a maximum of 5 doses
Other intervention name(s): Cytotec
Intervention MeSH terms: Misoprostol
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Vaginal, sublingual, misoprostol, cervical ripening