Status:Active, not recruiting
Preterm birth remains a major problem throughout the world. Treatment efficacy in women with a documented previous spontaneous preterm birth has recently been demonstrated in one randomized trial using a 17 α-hydroxyprogesterone caproate (17P) and a second using a vaginal progesterone. Presently, 17P as prophylaxis for preterm delivery has not been demonstrated to be effective in any other group of women and its indicated use remains limited to women with a prior preterm delivery. One risk factor for preterm delivery that has been consistently demonstrated is short cervical length, especially in nulliparous women.
Progesterone administration has been hypothesized in various studies to reduce preterm birth since at least the early 1960s. However, these studies were limited in scope since they had low power due to a small number of women enrolled. The MFMU progesterone trial, which enrolled women who were at high risk by virtue of a prior preterm birth in a two to one allocation of subjects to study drug and placebo, demonstrated that 17P substantially reduced the risk of preterm birth at < 37 weeks, < 35 weeks, and < 32 weeks.7 Other clinical trials and meta-analyses have been conducted with results indicating a decrease in preterm birth rates.8,16, 17,18 These studies are describe in more detail in Section 2.2.2 of the full protocol.
This randomized trial will address the primary research question: does treatment with 17 α-hydroxyprogesterone caproate (17P) initiated prior to 23 weeks of gestation prevent delivery prior to 37 weeks in nulliparous women with singleton pregnancies who have a short cervix?
This study is a randomized double-masked placebo-controlled multicenter clinical trial. Participants will be nulliparous women with a short cervix measured between 16 weeks 0 days and 22 weeks 3 days who will be randomized between 16 weeks 0 days and 22 weeks and 6 days to one of two treatments:
• 17 α-hydroxyprogesterone caproate (17P): weekly injections containing 250 mg of 17P until 37 weeks gestation or delivery
• Placebo: weekly injections until 37 weeks gestation or delivery
Principle Investigator: Michael Varner
Principle Department: Maternal-Fetal Medicine
• Nulliparity, defined as no prior pregnancy that has progressed beyond 19 weeks and 6 days;
• A cervical length measured by transvaginal ultrasound <30 mm between the gestational ages of 16 weeks 0 days to 22 weeks 3 days based on clinical information and evaluation of the first ultrasound. (See Section 3.4.2 for more details about gestational age determination.)
• Gestational age 16 weeks 0 days to 22 weeks 6 days at the time of randomization.
At this time, we do not anticipate enrolling non-English speaking participants. It is not a protocol-specific exclusion criteria. Since this study is conducted at 13 other sites, enrollment of Hispanics is adequately covered and exclusion in Utah does not jeopardize statistical significance or create undue burden on one specific population.
• Multifetal gestation including selective reduction from a multifetal gestation to a singleton pregnancy or any ultrasound evidence of an additional fetal pole/embryo of 12 weeks gestation or later;
• Progesterone treatment after 14 weeks 6 days by project gestational age during the current pregnancy due to potential contamination of the randomized trial;
• Vaginal bleeding, heavier than spotting, after 15 weeks 6 days of pregnancy by project gestational age due to an increased risk for preterm delivery;
• Amniotic membranes prolapsed beyond the external os or protruding into the vagina since this is likely to result in a cerclage placement, a secondary outcome;
• Preterm rupture of membranes;
• Fetal anomaly;
• Pregnancy without a viable fetus;
• Current or planned cervical cerclage, due to the interference with the natural course of delivery and a secondary outcome of the study;
• Congenital Mullerian abnormality of the uterus due to an increased risk of preterm delivery which is likely to be unaffected by progesterone;
• Contradiction to intra-muscular injections such as known idiopathic thrombocytopenia purpura (ITP), or known platelet count less than 100,000 per cubic millimeter or any planned or current heparin or low-molecular weight heparin therapy during the pregnancy; patients on low-dose aspirin do not need to be excluded;
• Maternal conditions such as:
o Hypertension requiring medication due to increased risk of adverse pregnancy outcome
o Diabetes managed with oral hypoglycemic agents or insulin due to an increased risk for adverse pregnancy outcome
o DES exposure due to an increased risk of preterm delivery
o Seizure disorder, currently on anti-seizure medication because of the potential for the alteration of seizure threshold
o Cervical surgery such as cold knife conization, laser vaporization or LEEP; cryotherapy is not an exclusion;
• Planned indicated preterm delivery for any reason;
• Participation in another interventional study that influences gestational age at delivery or neonatal morbidity or mortality;
• Participation in this trial in a previous pregnancy; patients screened but not randomized in a previous pregnancy do not need to be excluded;
• Prenatal care or delivery planned elsewhere (unless study visits can be made as scheduled and complete outcome information can be obtained).