The Use of Progesterone to Reduce Preterm Birth
Condition: Preterm Birth
MeSH terms: Premature Birth
Study type: Interventional

Summary: 
      Preterm birth is the most common and costly complication in obstetrics. It complicates up to
      11 % of all pregnancies and it is responsible for 70% of sick babies. Recently two studies
      have shown that giving progesterone (a normal hormone made by the ovaries) prolongs gestation
      in women who have had a preterm birth in an earlier pregnancy (and therefore are at risk for
      another early delivery). There are other studies that show that this technique of giving a
      weekly shot of progesterone does not prevent preterm birth. In addition, There are other
      groups of patients who are at very high risk for preterm birth which have not been studied.
      They include: 1.) Cervical cerclage (a stitch in the mouth of the womb); 2.) Multifetal
      gestation (twins, triplets, etc.); 3.) Women with preterm (<34 weeks) rupture of the
      membranes; 4.) Women with preterm labor during the current pregnancy with intact membranes
      who have been tocolyzed (have their labor stopped and are getting ready to go home). We
      purpose to give weekly shots of progesterone or a placebo in a randomized fashion to women in
      the first group who are at risk for preterm delivery due to an early birth in a previous
      pregnancy as well as the other four groups listed. If progesterone given weekly is successful
      at preventing early delivery as compared to the placebo group then great benefit for these
      women as well as future pregnancies would be accrued.
    

Detailed description: 
      A. Introduction Preterm birth occurs in 7-12% of all deliveries, but accounts for over 85% of
      all perinatal morbidity and mortality.1 Despite many strategies for reducing the incidence of
      preterm birth none have been totally effective. One treatment that showed promise in earlier
      small trials was the prophylactic administration of progestational compounds.2,3 However, the
      reports of efficacy were mixed with some showing benefits4,5 while others did not.6,7 More
      recently, two randomized clinical trials have shown great promise8,9, and revealed a
      significant decrease in preterm births among women who received 17 alpha-hydroxyprogesterone
      caproate (17P)8, or 100mg of progesterone delivered by vaginal suppository per week.9 Indeed
      support by the American College of Obstetricians and Gynecologists, and March of Dimes as
      well as others have made this treatment the standard of care in many areas of the country.

      The limitations of these studies are that they have small numbers as well as a higher than
      expected preterm delivery rate among placebo patients. Because of the previous controversy as
      to the effectiveness of progesterone noted in the 70's - 80's it is incumbent upon other
      centers to carry out new investigational trials in an effort to confirm their results.
      Secondly, the studies were limited to singleton pregnancies who were "at risk" for preterm
      delivery thus not surveying three groups with the highest preterm delivery rate: 1.)
      Multifetal gestations and cervical insufficiency; 2.) Those who have preterm labor in the
      current pregnancy that have been tocolyzed; 3.) Women with preterm premature rupture of the
      membranes.

      The purpose of the current study to confirm if possible, the findings of the most recent
      investigations8,9 using the same patient population and in addition, we will study the effect
      of progesterone vs placebo in preventing early delivery among multifetal gestations in women
      who have been diagnosed with preterm labor in the current pregnancy.

      B. Specific Aim The aim of this study is to compare progesterone (100mg progesterone weekly)
      to ascertain if there is a reduction in preterm birth and subsequent neonatal morbidity among
      patients receiving the active drug. If weekly treatment with this agent can be shown to
      reduce the incidence of preterm delivery and its surrogate adverse outcomes in the neonate,
      it will have major impact upon patients and the health care delivery system.

      C. Rationale Progesterone as indicated in the Introduction has been shown in some, but not
      all, studies to reduce incidence of preterm delivery and the adverse effects of prematurity.
      Progesterone has been shown to reduce the number of oxytocin receptors in the myometrium and
      be responsible in the near term pregnant women for blocking the onset of labor. Weekly use of
      this compound, if effective, would be much superior to the tocolytic agents currently
      available.

      D. Benefit to Risk Ratio There is no known harm to mother/fetus/infant of progesterone
      therapy. This compound has been used in early pregnancies at risk for abortion as well as
      later in pregnancy to reduce the incidence of prematurity as noted in the Introduction. On
      the beneficial side, if this treatment proves effective it could prolong pregnancy thus
      reduce significant neonatal morbidity as well as the emotional cost and expense of such
      pregnancies.

      E. Patient Population Patients will be recruited from the University of Mississippi Medical
      Center Perinatal Clinics, Antepartum Service and Labor and Delivery area. All patients who
      meet admission criteria will be offered participation in the study.

      F. Materials and Methods Patients seen in the University of Mississippi Perinatal Clinics,
      Antepartum ward or Labor and Delivery area with preterm labor or who are at risk for preterm
      labor and who meet other admission criteria (without having exclusion criteria) will be
      offered participation of this study.

      Study Protocol Patients meeting the inclusion criteria will have the study explained to them,
      including benefits risks and alternative therapy. Patients not desiring to participate in the
      study will receive our current regimen of preterm birth prevention (observation, risk factor
      assessment, steroids, progesterone, etc). If they accept inclusion into the study after the
      above explanation they will be randomized by the use of sequentially numbered, sealed opaque
      envelopes to either receive progesterone or a placebo injection on a weekly basis. Patients
      with risk factors for preterm birth (prior preterm birth) will be separately randomized from
      the multifetal gestations or cervical cerclage and the patients with preterm labor in the
      current pregnancy as well as preterm rupture of the membranes will also separately randomized
      (four groups total). Neither patients nor participants will know to which group (placebo vs.
      progesterone) they are assigned as the pharmacy will keep the randomization schedule and will
      dispense the two solutions in identical syringes for blinding purposes.

      Treatment will begin at different gestational ages dependent upon the four groups noted
      above. For example, multifetal gestation due to their incidence of labor at earlier
      gestational ages, will begin treatment at 20 weeks' gestation. Those in the preterm labor
      with the current pregnancy group or premature rupture of membranes will begin their therapy
      after admission to the hospital following stabilization. All patients will stop therapy at 34
      completed weeks of gestation.

      After inclusion into the study, prenatal care will be exactly the same as is our standard for
      such patients at risk for early delivery with the exception of the weekly administration of
      the study medicine or placebo. For example, weekly prenatal visits, cervical examinations,
      ultrasounds, steroids and/or tocolytic treatment (given when preterm labor is diagnosed) will
      be the same regardless of the group to which the patient is randomized. All groups will have
      one tube of blood drawn from the placental cord at the time of delivery. There will be no
      additional visits or costs due to the study itself.

      F. Data Analysis Data analysis will be by the standard statistical methodology.

      VI. Number of Patients Needed:

      A sample size estimation indicates that 320 patients (40 in each of four groups-treatment and
      placebo) will be necessary to have an 80% power of detecting a significance of < 0.05 in the
      number of preterm births. It is anticipated that a time period of approximately two years
      will be needed to enroll this number of participants.
    

Intervention name(s): Progesterone (OHP17); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 100mg of OHP17 or comparable amount of placebo administered by IM injection weekly until either 34 weeks' gestation or delivery has been achieved, whichever occurs first.; 2cc of placebo liquid formulated by pharmacy personnel at the University of Mississippi Medical Center injected IM weekly until 34 weeks' gestation has been reached or delivery, whichever occurs first.
Intervention MeSH terms: Progesterone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment