Examining the Evidence
Q. Does progesterone reduce the risk of preterm birth among women with a short cervix?
<huc>A.</huc> Yes. In this randomized, placebo-controlled study of 250 gravidas with a cervical length of 15 mm or less, those who were randomized to a daily dose of 200 mg of intravaginal micronized progesterone starting at 24 weeks’ gestation had a lower rate of spontaneous delivery before 34 weeks (19.2%) than did women in the control group (34.4%) (relative risk, 0.56; 95% confidence interval, 0.36 to 0.65). However, progesterone did not reduce the rate of perinatal mortality or neonatal morbidity.
The trial included both singleton and twin gestations.
The study by Fonseca and colleagues is an important contribution to the ever-expanding body of literature on ways to reduce preterm birth. It immediately follows a paper in the same issue of the New England Journal of Medicine declaring the failure of intramuscular 17α-hydroxyprogesterone caproate (17P) to prevent preterm birth in twin gestations.1 In contrast, an earlier study from 2003 found 17P to be more effective than no treatment in preventing spontaneous preterm delivery in singleton pregnancies of women with a history of premature delivery.2
The trial by Fonseca and colleagues capitalizes on two unique aspects of the prematurity debate. The first is that history is probably not any more useful in screening for risk of prematurity than it is for screening for gestational diabetes. This is not to say that history is unimportant, but rather to emphasize that history alone may be insufficient to identify populations that may be at risk for preterm delivery and therefore might possibly benefit from intervention.
The second is the suggestion, based on earlier work by Iams and associates,3 that decreased cervical length may distinguish a group of women at high risk for preterm delivery.
What to make of equivocal findings?
Is an intervention worthwhile if it has no effect on key outcomes such as morbidity and mortality? And what are we to make of the fact that intramuscular 17P is effective in singleton but not twin gestations?
The current trial was insufficiently powered to affirm the null hypothesis with respect to perinatal mortality and neonatal morbidity—ie, there were not enough patients in the study to determine whether the lack of difference in these variables was real or due to insufficient sample size. However, intravaginal progesterone seems more attractive than intramuscular injection—at least intuitively. It may be that a local anti-inflammatory response is what reduced spontaneous preterm delivery—and that may be why intramuscular injection of synthetic progestin at a remote site was less effective, depending on whether the pregnancy was a singleton or twin gestation.
We must also be concerned about the yet-unexplained observation of higher—though statistically insignificant—rates of miscarriage and intrauterine fetal death among women receiving intramuscular 17P, compared with placebo.2
Preventing preterm birth: Lessons from the real world
In my own practice, I estimate that fewer than 20% of patients who might be eligible for progesterone accept the treatment after I review all the data with them. Two illustrative cases highlight the conundrum a clinician faces with respect to “measurable outcome differences.”
Patient #1 is a healthy 30-year-old gravida 3 para 1102 whose obstetric history includes:
- a full-term delivery in 2002 that was complicated by premature onset of contractions but never required tocolytic therapy
- a delivery at 29 weeks in 2005 that was complicated by preterm premature rupture of membranes and chorioamnionitis.
Her current pregnancy is managed with cervical-length assessment (all measurements exceed 35 mm) and 17α-hydroxyprogesterone caproate. She delivers a healthy 3,500-g infant at term without complication.
Patient #2 is a healthy 31-year-old gravida 3 para 0202 who delivered at 33 weeks in 2002 and at 35 weeks in 2003. Both deliveries were secondary to idiopathic preterm labor. Her current pregnancy is followed routinely, with no cervical-length assessment. After counseling, she decides against progesterone therapy and goes on to deliver a 3,300-g healthy infant at 39 weeks’ gestation.
These two cases are medically similar; both were eligible for progesterone treatment. One patient chose it and one did not—yet their obstetric outcomes were identical.—John T. Repke, MD
Too early to elevate either regimen to “standard of care”
In my opinion, it is still too early to elevate either intravaginal or intramuscular progesterone to the level of “standard of care.” What may be reasonable in this age of increasing use of first- and mid-trimester ultrasonographic screening is to make certain that information on cervical length is provided. Also important is a candid discussion with the patient about the range of options for management of a short cervix in pregnancy. In the meantime, more than a dozen trials on the prevention of prematurity are in progress. The hope is that more definitive answers to the prematurity riddle are “just around the corner”—which, I suspect, was also the hope in 1975.4
1. Rouse DJ, Caritis SN, Peaceman AM, et al. For the National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. A trial of 17 alpha-hydroxyprogesterone caproate to prevent prematurity in twins. N Engl J Med. 2007;357:454-461.
2. Meis PJ, Klebanoff M, Thom E, et al. For the National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348:2379-2385.
3. Iams JD, Goldenberg RL, Meis PL, et al. The length of the cervix and the risk of spontaneous premature delivery. N Engl J Med. 1996;334:567-572.
4. Johnson JW, Austin KL, Jones GS, Davis GH, King TM. Efficacy of 17alpha-hydroxyprogesterone caproate in the prevention of premature labor. N Engl J Med. 1975;293:675-680.