Preterm Delivery Clinical Trial
Official title:
Prevention of Preterm Delivery in Twin Pregnancies by 17 Alpha-hydroxyprogesterone Caproate
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.
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.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
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