Drotaverine to Shorten the Length of Labor
Condition: Prolonged First Stage of Labor; Failure of Cervical Dilation as Antepartum Condition; Labor Pain; Mild Birth Asphyxia, APGAR 4-7
MeSH terms: Asphyxia Neonatorum; Labor Pain; Asphyxia
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Reducing the length of labor is a highly desirable goal of intrapartum care, both from a
      perspective of maternal and fetal well-being, and for the providers of the birth services.
      Avoiding along, protracted labor entails shorter exposure to pain, anxiety and stress and
      would thus translate into a major improvement in maternal satisfaction with the childbirth
      experience.

      Based on the premise that shortening the length of labor is beneficial, interventions aimed
      at accelerating the progression of labor have been introduced routinely as part of standard
      labor management and care throughout the 20th century. Certain labor accelerative procedures,
      such as amniotomy, became common practice and have been put to the acid test of randomized
      control trials to evaluate their efficacy. Use of anticholinergics/antispasmodics as a method
      of augmenting labor was ﬁrst described in 1937 by Hirsch, who reported a decrease in labor
      length by two to four hours following Intrapartum administration of an atropine-like drug
      (Syntropan®)mainly among older nulliparas.

      Drotaverine, an isoquinolone derivative is a superior smooth muscle relaxant which acts
      specifically on spastic sites and corrects the cAMP and calcium balance relieving smooth
      muscle spasm.

      This inhibitory action is detected only in lower uterine segment during labor since muscle
      fibers in upper uterine segment are strongly affected by contractile effect of oxytocin. Use
      of drotaverine during pregnancy is free of any teratogenic and embryotoxic effects.

      The Research question is: Does the use of antispasmodic Drotaverine shorten the duration of
      active first stage of labor in nulliparous women as compared to placebo?
    

Detailed description: 
      Research question:

      Does the use of antispasmodic Drotaverine shorten the duration of active first stage of labor
      in nulliparous women as compared to placebo?

      Research hypothesis: the population means of the Drotaverine and placebo groups are equal
      regarding the duration of the first stage of labor.

      Objectives:

      The purpose of this study was to determine the effectiveness of Drotaverine for reducing the
      duration of labor for the context of contemporary practice, among nulliparous women managed
      according to a standard intrapartum protocol.

      Study setting:

      Patients will be recruited from women admitted in labor at the delivery unit of Ain Shams
      Maternity Hospital.

      Study design:

      This study is a phase II to III, intervention study- Randomized Controlled double blind
      study.

      Procedure:

      Every patient will be subjected to:

        1. Complete history to exclude allergy to Drotaverine Hydrochloride and any
           contraindication for normal vaginal delivery.

        2. General examination of the patients including (pulse, blood pressure, temperature).

        3. Obstetric Abdominal examination including lie, presentation,station; fetal heart rate,
           uterine contraction, amount of liquor and to exclude multiple pregnancies.

        4. Vaginal examination under aseptic conditions to assess cervical dilation, effacement,
           state of fetal membranes, presenting part,position of fetal head, color of liquor and
           pelvic adequacy.

        5. Assessment of the frequency, duration of uterine contractions and monitoring of fetal
           wellbeing will be applied through CTG application on admission:

           - CTG will be applied half an hour to all participants before starting any intervention.

             1. If the contractions are not adequate:

                  -  Patients with intact membranes → AROM will be done, reassessment after one
                     hour. If still no adequate contraction, Oxytocin infusion will start (five
                     I.U. Oxytocin in 500 cc ringer I.V. drip) by titration method until complete
                     regulation of uterine contractions.

                  -  Those with ruptured of membranes, the amniotic fluid color will be checked for
                     any abnormalities and Oxytocin infusion will start (five I.U. Oxytocin in 500
                     cc ringer I.V. drip) by titration method until complete regulation of uterine
                     contractions.

             2. If the contractions are adequate: No interference will be done.

        6. Each participant will randomly take a prefilled syringe with two milliliters of the
           study medication solution (either Drotaverine Hydrochloride or saline). Each participant
           will take the selected syringe slowly intravenously over two minutes.

        7. Partographic representation of labor and duration of first stage to determine the
           primary end point of the study "duration of 1st stage".

        8. Cervical effacement and dilatation in addition to station and position of fetal head
           will be recorded every two hours by vaginal examination.

        9. Reassessment after four hours of the first dose:

      A) If poor progress: Initially, exclude C.P.D. & uterine inertia.

        -  If there is an obvious cause:

             -  C.P.D.: Urgent C-section will be done.

             -  Uterine inertia: adjust the dose of Oxytocin I.V drip via titration method until
                complete regulation of uterine contraction.

        -  If there is no obvious cause:

             -  Another dose of the colorless solution will be given then reassessment after four
                hours, If no progress → re evaluation for final decision of mode of delivery.

      B) If good progress: No interference will be done.

      Outcome:

        1. Primary outcomes:

             1. The duration of the active first stage of labor(Partographic representation for
                cervical effacement and dilatation will be plotted for each participant).

             2. Rate of cervical dilation (cm/h).

        2. Secondary outcomes:

             1. Effect on pain by using visual analogue scale once before and one hour after
                injection of solution. VAS will be done at 30, 60 and 120 minutes of the drug
                administration.

             2. Mode of delivery.

             3. APGAR score less than 7 at 1 and 5 minutes.

             4. Maternal drug side effect will be recorded.

                Randomization and Blinding:

                Randomization will be achieved using a computer-generated randomization sequence.
                Allocation will be in a 1:1 ratio. Records of group allocation will be maintained
                by a resident physician "other than the researcher" whose responsibility will be
                randomization and drawing up the injection after dark sealing of the syringes with
                black opaque stickers to make the yellowish colored Drotaverine Hydrochloride
                (Do-Spa®) in-differentiable from the translucent saline solution.

                This house officer has no direct involvement in the intrapartum decision making.
                Drotaverine Hydrochloride and saline injections will have an identical appearance.
                The midwives, the clinicians staffing labor and delivery and the patients could not
                distinguish the placebo from the active drug. The randomization list will be held
                in a secure box on the labor ward to ensure concealment of the allocation of
                intervention from those recruiting participants.

                Data Collection:

                Maternal characteristics and labor information will be prospectively collected in a
                computerized database that will be maintained with daily chart review by the
                researcher to ensure accuracy and to minimize missing data The primary end-point of
                this study will be the duration of the first stage of labor.The first stage
                encompasses the onset of active labor to complete cervical dilatation.

                However, as women will be randomized at different dilatation levels, to allow
                meaningful comparison the dilatation rates (from administration of study drug

                o full dilatation) will be calculated and will be used as the primary outcome
                measure.

                Analysis:

                Data analysis and reporting will strictly follow the recommendation of CONSORT 2010
                For each primary and secondary outcome, results for each group, and the estimated
                effect size and its precision (95% confidence interval).

                For binary outcomes, presentation of both absolute risk difference and relative
                (Risk Ratio) effect sizes will be reported.

                Ethical considerations

                IRB approval:

                The clinical research study will be conducted in accordance with the current
                IRB-approved clinical protocol; ICH GCP Guidelines; and relevant policies,
                requirements, and regulations of the Ain Shams University.

                Consent procedure:

                The investigator will make certain that an appropriate informed consent process is
                in place to ensure that potential research subjects, or their authorized
                representatives, are fully informed about the nature and objectives of the clinical
                study, the potential risks and benefits of study participation, and their rights as
                research subjects. The investigator will obtain written, signed informed consent of
                each subject, or the subject's authorized representative, prior to performing any
                study-specific procedures on the subject. The investigator will retain the original
                signed informed consent form.

                Subject confidentiality:

                All laboratory specimens, evaluation forms, reports, video recordings and other
                records that leave the site will not include unique personal data to maintain
                subject confidentiality.

                Funding: Internal funding by using the Hospital resources.
    

Intervention name(s): Drotaverine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 40 mg Drotaverine hydrochloride (Do-Spa) IV injection at the start of the study and repeated every 2 hours up to a maximum 3 injections.; Women who will receive 2ml of normal physiological saline (0.9% sodium chloride) I.V at the start of the active phase of labor.
Other intervention name(s): Do Spa; Normal physiological saline (0.9% sodium chloride)
Intervention MeSH terms: Drotaverin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment