Optimisation of the Management of Placental Delivery in Second Trimester Pregnancy Interruption
Condition: Placenta, Retained; Postpartum Hemorrhage
MeSH terms: Postpartum Hemorrhage; Placenta, Retained; Hemorrhage
Study type: Interventional

Summary: 
      Interruption of a pregnancy after 14 weeks gestation may be required when the fetus is dead,
      severely malformed or in cases of maternal illness. This process is usually conducted
      medically in Australia, using the prostaglandin E1 analogue misoprostol. This prostaglandin,
      although not specifically licensed for use in pregnancy termination, is now a common
      abortifacient with a lot of accumulated experience both within Australia and internationally.

      Since 1996, misoprostol, a synthetic prostaglandin, has been used at King Edward Memorial
      Hospital as the principal agent for second trimester pregnancy termination. This agent is
      administered vaginally, and in its current form and dosage regimen results in 75-80% of women
      delivering within 24 hours. As experience with this agent has grown, it has been observed
      that in approximately 40% of women the placenta is either completely retained or incompletely
      delivered, necessitating operative removal and an increased potential for maternal blood
      loss. In this study, it is planned, in a randomized controlled clinical trial, to evaluate
      three regimens for the management of placental delivery in women undergoing second trimester
      pregnancy interruption. The primary intention of this study is to develop a third stage
      management protocol to reduce the incidence of placental retention in second trimester
      medical pregnancy termination.

      The secondary aim of this study is to assess the ultrasound appearance of the uterus and its
      cavity within 24 hours of second trimester pregnancy termination. The ultrasound appearances
      of the uterus following second trimester pregnancy loss have not been previously investigated
      in detail. Previous ultrasound studies of the term postpartum uterus have demonstrated a high
      incidence of echogenic material within the uterine cavity soon after an uncomplicated vaginal
      delivery. These findings have been of concern as the ultrasound appearances may erroneously
      imply a need for operative intervention. The investigators wish to ascertain if this high
      incidence of echogenic tissue presence is also true in the second trimester. Ultrasound is
      frequently used by clinicians to define placental completeness and the potential requirement
      for surgical curettage. The data from this single sonographic examination of the uterus will
      provide baseline data for a planned longitudinal study of uterine appearances following
      second trimester pregnancy loss and their correlation with clinical symptoms.
    

Detailed description: 
      Methods:

      All women who are admitted to King Edward Memorial Hospital for Women for pregnancy
      interruption for severe fetal anomaly or maternal pregnancy complications between 14 and 24
      weeks gestation will be invited to participate in the study. No women with an intrauterine
      fetal demise will be recruited due to the potential confounding effects of the fetal death on
      the placental separation process.

      Once consent has been obtained, the women will be randomised to three placental management
      strategy groups:

      Group 1: Standard management protocol; Group 2: Oxytocin protocol; Group 3: Oral misoprostol
      protocol.

      Group 1:

      Women allocated to the standard management protocol will receive no routine oxytocic
      following the delivery of the fetus.

      If spontaneous placental expulsion has not occurred within 60 minutes of delivery, or if
      heavy vaginal bleeding ensues within that time period, manual removal of the placenta will be
      performed in the operating room under general or regional anaesthesia. No cord traction is
      used to facilitate placental expulsion, although maternal expulsive efforts or digital
      extraction if the placenta is visible at the vaginal introitus are permissible.

      Group 2:

      Women allocated to the oxytocin protocol will receive a single intramuscular injection (IMI)
      into the upper thigh of 10 IU oxytocin (Syntocinon®) as soon as the fetus is expelled.

      If placental expulsion has not occurred within 60 minutes of delivery, or if heavy vaginal
      bleeding ensues within that time period, manual removal of the placenta will be performed in
      the operating room under general or regional anaesthesia. No cord traction is used to
      facilitate placental expulsion, although maternal expulsive efforts or digital extraction if
      the placenta is visible at the vaginal introitus are permissible.

      Group 3:

      Women allocated to the oral misoprostol protocol will receive a single oral dose of 600 mcg
      misoprostol as soon as the fetus is expelled.

      If placental expulsion has not occurred within 60 minutes of delivery, or if heavy vaginal
      bleeding ensues within that time period, manual removal of the placenta will be performed in
      the operating room under general or regional anaesthesia. No cord traction is used to
      facilitate placental expulsion, although maternal expulsive efforts or digital extraction if
      the placenta is visible at the vaginal introitus are permissible.

      The midwife or nurse caring for the woman will inspect all placentas visually after
      non-surgical expulsion for completeness. This may not occur in the case of obvious incomplete
      expulsion of the placenta, as the woman will be transferred to the operating room for
      completion of evacuation on the basis of clinical need. Due to the placental fragmentation
      that may occur during manual removal of the placenta in the operating room it will not be
      possible for those women who require surgical removal of their placenta to have a visual
      placental inspection, however the surgeon will assess the completeness of the removal
      digitally in the operating room.

      A maternal full blood count will be performed prior to the commencement of the termination
      process and repeated 6 hours after the delivery of the placenta, as an index of blood loss.
      The pre-termination full blood count is a standard investigation in the current clinical
      pathway. The attending nurse or midwife will weigh all pads/sheets after fetal delivery until
      placental expulsion to estimate blood loss in the three groups.

      Maternal pulse, blood pressure and temperature will be recorded every 15 minutes from fetal
      expulsion until 1 hour post-placental delivery.

      Maternal symptoms of nausea, headache and abdominal pain will be recorded every 15 minutes on
      a visual analogue scale from fetal expulsion until placental delivery or transfer to the
      operating room. Maternal emesis will be recorded from fetal expulsion until 1-hour
      post-placental delivery.

      All women will undergo a transabdominal ultrasound assessment of the uterine cavity prior to
      hospital discharge (approximately 6-12 hours post-delivery) in the King Edward Memorial
      Hospital Diagnostic Imaging Department. The uterine size, myometrial thickness, myometrial
      vascularity, uterine cavity dimensions and appearance of the uterine cavity contents will be
      assessed sonographically. Myometrial vascularity will be correlated with the pre-delivery
      placental position. All images will be reviewed by the Chief Investigator, who will be blind
      to clinical outcomes, using the hospital PACS. The Chief Investigator (who has formal
      ultrasound qualifications) will assess the image quality, measurements and appearances of the
      uterine cavity. The ultrasound appearances of those women who have undergone an operative
      placental removal will be used as the baseline control group for uterine cavity appearances,
      as it is assumed there is no placental tissue present in this group. The ultrasound
      appearances of the uterus will not be reported to the clinicians caring for the woman, as the
      evidence from the term uterine cavity ultrasound studies is that echogenic material is
      frequent and does not impact adversely upon the postnatal course. The exception to this will
      be when the clinician caring for the woman requests an ultrasound evaluation of the uterine
      cavity for suspected retained placental tissue.

      It is estimated that 3-5 women per week will be eligible for recruitment into this study and
      that this additional workload can be conducted without adversely impacting on other duties of
      the Diagnostic Imaging Department. The Chief Investigator is the head of the KEMH Ultrasound
      Department and is responsible for workload distribution within the unit.

      All women will be telephoned at 4 weeks post-termination by the Chief Investigator to enquire
      about post-discharge bleeding complications (eg. antibiotic prescription, curettage, duration
      of vaginal bleeding).

      The primary objectives to be achieved from the conduct of this study are:

        1. The efficacy of routine ecbolic agents to facilitate spontaneous placental expulsion
           compared with a non-pharmacologic intervention. This will primarily be determined by
           ascertaining the percentage of women in each group who require operative removal of the
           placenta.

           The investigators' aim is to reduce the requirement for operative placental removal from
           the current 40% to 20%.

        2. Comparison of the frequency and severity of side-effects associated with routine ecbolic
           administration in the third stage.

        3. The sonographic appearances of the uterus and its cavity in the immediate post-delivery
           period. It is planned in future studies to assess the sonographic appearances of the
           second trimester uterus after delivery in a longitudinal manner over time, using these
           data as baseline information.

      Sample size:

      Up to 300 women will be recruited into the study (100 per group). This sample size will
      achieve 80% power to detect a reduction from 40% placental retention on the current regimen
      of non-pharmacological third stage management to 20% placental retention using either 5IU
      oxytocin IMI after delivery or 600 mcg misoprostol orally. Two pairwise comparisons between
      the current regimen and a new regimen will be conducted at 0.025 significance level each to
      attain an overall 0.05 significance level using a test of proportions. This sample size also
      allows for an interim analysis consisting of two pairwise tests, when 60 patients per group
      have been recruited (at the nominal significance level of 0.003 per test, critical
      Z-statistic=3.02) and a final analysis (at the nominal significance level of 0.024 per test,
      critical Z-statistic=2.25). Sequential sample size calculations were obtained using
      O'Brien-Fleming spending function for the test statistics boundaries (PASS 2002 for Windows,
      Kaysville Utah). At the time of interim analysis, the placental retention rate per study arm
      will be estimated and a possibility of stopping recruitment to one of the arms due to
      futility will be considered.

      Statistical Analysis:

      Descriptive statistics will utilise means and standard deviations (or medians and
      interquartile ranges) for continuous data and frequency distributions for categorical data.
      The primary endpoint will be evaluated using pairwise tests of proportions. Secondary
      analyses will implement logistic regression modelling to investigate other patient
      characteristics that are relevant for prediction of placental retention.
    

Intervention name(s): Misoprostol; Oxytocin
Intervention type(s): Drug; Drug
Intervention description(s): 600 mcg misoprostol swallowed after delivery of fetus; 10 units oxytocin administered intramuscularly after delivery fetus
Other intervention name(s): Cytotec; Syntocinon
Intervention MeSH terms: Misoprostol; Oxytocin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Abortion; Retained placenta; Hemorrhage; Postpartum ultrasound