Prevention of Preterm Delivery in Twin Pregnancies by 17 Alpha-hydroxyprogesterone Caproate
Condition: Preterm Delivery
MeSH terms: Premature Birth
Study type: Interventional
Phase: Phase 2

Summary: 
      Preterm birth remains a major cause of perinatal morbidity and mortality in developing as
      well as in developed countries. Despite major clinical research efforts aimed at reducing the
      incidence of preterm births in the United States, the preterm birth rate reached its highest
      level in 2 decades, 11.9% in 2001, which translates to a 27% rise since 1981. Much of this
      increase may be accounted for by the increase in multiple gestations brought about by
      assisted reproductive technology. Twin gestations accounting for 20% to 25% of all
      pregnancies conceived following such procedures. Twin gestations are at a particularly
      increased risk of preterm labor and they deliver at a mean gestational age of 37 weeks
      compared to 40 weeks for singleton pregnancies. In a study by our group, we estimated that
      about 54.5% of twin gestations would deliver prior to 37 completed weeks of gestation; i.e.
      preterm.

      Evidence regarding efficacy of interventions designed to prevent preterm birth has been
      disappointing. Most well-designed clinical trials have failed to demonstrate any reduction in
      preterm births with such interventions as home uterine activity monitoring, reduced physical
      activity, administration of antibiotic or tocolytic therapy, and intensive and frequent
      antenatal follow ups. Recently, progesterone has shown some promise in the prevention of
      preterm birth among women with prior preterm births. Whether this intervention will prove
      effective in other populations, such as women with multiple gestations, remains to be seen.

      The objective of our study is to compare the effectiveness of weekly intramuscular injections
      of 17-alpha Hydroxyprogesterone Caproate, a natural metabolite of progesterone, in preventing
      delivery at less than 37 weeks of gestation in a population of 290 patients with twin
      gestations between 16 and 36 weeks of gestation compared to a placebo. The data generated
      will be invaluable in managing this group of patients that is considered at a very high risk
      for preterm labor and delivery.
    

Detailed description: 
      Preterm birth remains the leading public health problem in obstetrics. A recent analysis of
      neonatal mortality (death at age < 28 days) in the United States between 1989 and 2001
      revealed that preterm delivery (< 37 weeks) accounted for 70% of neonatal deaths.9 In
      addition to being at risk for neonatal death, preterm infants are at increased risk for
      long-term neurologic and developmental morbidity, with an estimated risk of significant
      handicaps in up to 15% of the survivors. These statistics have led many investigators to
      identify those women at greatest risk (e.g., those with prior preterm delivery, multiple
      gestations, maternal weight <50 kg, African-American race, bleeding, and concurrent sexually
      transmitted diseases). Despite identification of these risk factors, no reproducible and
      effective method of preventing preterm delivery has been demonstrated. On the contrary,
      preterm birth rates has risen 27% since 1981.1 A significant contributor to this tremendous
      rise is the increase in the rate of multiple gestations observed in over the past years. This
      is partly due to the advances in assisted reproductive technologies with twin gestations
      accounting for around a quarter of pregnancies conceived following these procedures.

      One modality that showed promise for prevention of preterm labor in small trials was
      treatment with progestational agents. Two separate meta-analyses assessing the effects of
      progesterone on preterm labor arrived at contradictory conclusions. Goldstein found no
      evidence of effectiveness of progestational compounds in the prevention of preterm delivery.
      Daya, on the other hand, showed a beneficial effect. A third meta-analysis, restricted to
      trials of 17-alpha Hydroxyprogesterone Caproate showed, in composite, a significant reduction
      in the rate of preterm delivery. A recently reported trial comparing 17-alpha
      Hydroxyprogesterone Caproate therapy with placebo to prevent preterm birth in a select,
      high-risk group of women (documented history of a previous spontaneous preterm birth <37
      weeks of gestation) was terminated prematurely when results showed a significant protection
      against recurrent preterm birth for women who received 17-alpha Hydroxyprogesterone Caproate.
      Other studies, using the same form of progesterone, did not demonstrate such a beneficial
      effect. A study in 1980 has failed to show any benefit of 17-alpha Hydroxyprogesterone
      Caproate in women with twin gestations. In that study, 77 women with twin gestations were
      treated during the last trimester with weekly injections of either 17-alpha
      Hydroxyprogesterone Caproate or a placebo. The study was limited by the small sample size. In
      addition, the progesterone therapy was started late in the third trimester of gestation which
      could partly explain the inability to detect a beneficial effect of progesterone in this
      group of patients using that particular regimen. Most reported trials on other progesterone
      compounds have failed to demonstrate a substantial effect in reducing the risk of preterm
      delivery. However, a recent small randomized placebo-controlled trial of supplemental vaginal
      progesterone in women at high risk for preterm birth revealed that the preterm birth rate at
      less than 34 weeks of gestation was significantly lower among women receiving progesterone
      than among those receiving placebo.8 The results of this study and that of the National
      Institute of Child Health and Human Development7 support the hypothesis that progesterone
      supplementation reduces preterm birth in a select very high-risk group of women. In fact, the
      American College of Obstetricians and Gynecologists Committee on Obstetric Practice believes
      that further studies are needed to evaluate the use of progesterone in patients with other
      high-risk obstetric factors, such as multiple gestations, short cervical length, or positive
      test results for cervicovaginal fetal fibronectin.

      The mechanisms of action of 17-alpha Hydroxyprogesterone Caproate in prolonging gestation are
      not entirely known. They include relaxation of myometrial smooth muscle, blocking of the
      action of oxytocin, and inhibition of the formation of gap junctions. There is also evidence
      that local changes in the progesterone level or the ratio of progesterone to estrogen in the
      placenta, decidua, or fetal membranes may be important in the initiation of labor in humans.
      As for its safety profile, aside from local injection-site reactions like soreness, swelling,
      itching and bruising, 17-alpha Hydroxyprogesterone Caproate appears to be safe during
      pregnancy with absence of teratogenic effects. The safety of 17-alpha Hydroxyprogesterone
      Caproate administration in pregnancy is well documented by animal and clinical studies.
      Reviews of this topic by knowledgeable authors have uniformly concluded that no evidence
      exists that administration of 17-alpha Hydroxyprogesterone Caproate in pregnancy represents a
      significant risk to mother, fetus or newborn.

      SPECIFIC AIM(S):

      To test the effectiveness of weekly injections of 250 mg of 17-alpha Hydroxyprogesterone
      Caproate as compared with placebo in the prevention of preterm delivery in patients with twin
      gestations, when given from 16-20 weeks of gestation until 36 weeks.

      We chose the 250 mg dose of 17-alpha Hydroxyprogesterone Caproate because this is the dose
      that was used in the studies that showed a beneficial effect of this medication in the
      prevention of preterm delivery.

      The study hypothesis is that placebo is equivalent in its efficacy to 17-alpha
      Hydroxyprogesterone Caproate in preventing preterm delivery in twin pregnancies.

      to participate in the trial.

      Randomization procedure:

        -  We will stratify patients by reduced/non-reduced and IVF/ no-IVF. Patients will be then
           randomized to the different treatment groups using permuted block randomization.

        -  Randomization envelopes will be prepared by means of random number tables. Randomization
           will occur between 16 weeks and 20 weeks of gestation whereby the next numbered opaque
           envelope will be opened to assign each consenting patient to receive identically
           appearing active 17-alpha Hydroxyprogesterone Caproate (Proluton® Depot, Schering AG,
           Germany) or placebo (castor oil) injections prepared by our pharmacy.

        -  The women, their obstetricians, and research personnel will be blinded to the study
           medication allocation.

        -  A 2:1 ratio will be used for the assignment of women to 17-alpha Hydroxyprogesterone
           Caproate or placebo, because the patients assigned to placebo would be receiving painful
           injections on a weekly basis with no possibility of direct benefit.

      Routine studies and procedures:

        -  An ultrasonographic examination, a routine procedure that is done on every pregnant
           patient, will be performed between 14 weeks and 20 weeks of gestation to confirm the
           gestational age and to identify any major fetal anomalies.

        -  Gestational age will be calculated based on the last menstrual period and/or first
           trimester ultrasonography for spontaneously conceived twins and the day of egg retrieval
           for twins conceived by assisted reproductive technology.

      Interventions:

        -  After consenting, the patients will be offered to come for weekly injections of 17-alpha
           Hydroxyprogesterone Caproate (250 mg) or placebo given by a study nurse. If they cannot
           come for weekly injections, they will be handled the medications at the time of their
           follow up visits to their obstetricians to be given by a private nurse, whichever is
           more convenient for them. In order to avoid the burden on the clinic staff, it was
           decided to use the OPD premises from 11:30 a.m. to 1:30 p.m., a time where OPD sessions
           are over. Flow sheets to document the date of the injection will be available with the
           RA, obviating the need for pulling out patients charts. The financial compensation of
           the staff-nurse will comply with AUMBC rules and regulations.

        -  For those patients who elect to receive their injections at home, they will be called on
           the day of the injection to remind them of the injection to ensure that they are
           receiving the medication in due time.

        -  The patient will be categorized as non-compliant if there is ≥ 10 day-gap between any
           two injections.

        -  The injections will be continued until 36 weeks of gestation or delivery, whichever
           occurs first.

        -  In addition to the weekly visits for the study injections, the women will receive
           routine prenatal care with her obstetrician. Twin gestations at our department are
           usually asked to come for routine checkup visits every 3-4 weeks in the first and second
           trimester and every 2 weeks from 28 weeks to 36 weeks and weekly thereafter.

        -  The possible side effects of the medication, written in the consent form, will be
           explained to the patient by the research assistants.

        -  If a patient goes into preterm delivery, she will be managed by her obstetrician
           according to standard protocols that might necessitate admission and even tocolysis. In
           these cases, the injections will continue on a weekly basis till 36 weeks of gestation
           or delivery, whichever occurs first.

      Statistical analysis Statistical analysis will be performed using the SPSS statistical
      package adjusting for the stratified design. The analyses will be done on the intent-to-treat
      basis. Categorical data like maternal characteristics and the rates of neonatal morbidity
      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 or the
      Wilcoxon rank-sum test. Unpaired variables and differences in distributions will be compared
      using the Mann-Whitney test. Neonatal outcomes will be analyzed on the assumption that if a
      neonatal outcome variable occurs in at least one of the fetuses, the pregnancy will be
      considered affected for that variable. A p-value <0.05 will be considered statistically
      significant.

      A Logistic regression model will include all the confounding variables to for check their
      contribution to the primary outcome. The variables that we are going to control for include:
      need for tocolysis, BMI, smoking, assisted reproductive technology, prior preterm delivery,
      prior term delivery, spontaneous or reduced twins, etc ….

      Prolongation of pregnancy will be assessed by life-table methods. The duration will be
      considered as the period between the time of randomization and the time a woman gives birth,
      is lost to follow-up, or reaches 40 weeks of gestation, whichever comes first.

      CLINICAL RELEVANCE AND LIMITATIONS

        -  Managing preterm neonates is a major burden on the health system medically and
           financially. The results of this study will therefore have major implications if such
           treatment proves effective in reducing preterm delivery in twins.

        -  Limitations: Since the study is limited to twin gestations, the results cannot be
           generalized to singletons without risk factors for preterm labor or to higher order
           gestations.
    

Intervention name(s): 17-alpha Hydroxyprogesterone Caproate; Castor oil
Intervention type(s): Drug; Drug
Intervention description(s): 250 mg IM weekly; weekly IM injections
Other intervention name(s): Proluton depot
Intervention MeSH terms: Castor Oil; 17 alpha-Hydroxyprogesterone Caproate; 11-hydroxyprogesterone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Keywords: Hydroxyprogesterone Caproate, twins, preterm delivery