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Abstract & Commentary
By John C. Hobbins, MD, Professor, Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Denver, is Associate Editor for OB/GYN Clinical Alert.
Dr. Hobbins reports no financial relationship to this field of study.
Synopsis:Vaginal progesterone gel treatment reduces preterm birth by 50% in women found to have a short cervical length by transvaginal ultrasound.
Source:Hassan SS, et al. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: A multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol 2011;38:18-31.
In a commentary on preterm birth (PTB) in the april issue of OB/GYN Clinical Alert, I mentioned that data are on the horizon that would support the use of vaginal progesterone to reduce the risk of PTB in patients with short cervices. Well, the study has now been published, and the results may change how PTB is approached. Virtually all previous PTB studies have focused on patients with a history of PTB, but Hassan et al1 initiated a screening study in which all pregnant women were enrolled. At 21 centers around the world, 32,091 patients with singleton pregnancies were screened with transvaginal cervical length (CL) between 19 weeks 0 days and 23 weeks 6 days. Of the women screened, 733 patients (2.3%) had a CL between 1.0 cm and 2.0 cm. The authors further concentrated on this high-risk group. After appropriate exclusions were applied, the remaining 458 (458/733) patients were randomly assigned to placebo (n = 223) or to treatment (n = 235). Both groups were given packs of vaginal applicators containing either 90 mg of 8% progesterone gel or placebo. The product used in the study was Prochieve® 8%, also known as Crinone® 8%.
Progesterone gel performed superiorly. For example, 21 patients treated with progesterone gel (8.9%) delivered before 33 weeks compared to 36 placebo patients (16.1%) (relative risk [RR] of 0.52, 95% confidence interval [CI] 0.31-0.91). A difference also was found in those having PTB < 28 weeks (5.1% vs. 10.3%, RR 0.50; 95% CI 0.25-0.97). In addition, statistically significant differences were found in the rate of respiratory distress syndrome (3.0% vs 7.6%, RR 0.39), neonatal morbidity and mortality (7.7% vs 13.5%; RR 0. 57), and birth weight below 1500 g (6.4% vs 13.6%; RR 0.47).
The authors concluded that giving vaginal progesterone to those with CL of 1.0 cm to 2.0 cm decreased PTB before 33 weeks by 45% and improved neonatal outcome by 50%.
There are two very important up-shots from the study:
1. Daily vaginal progesterone can work as well as weekly IM 17-alpha hydroxyprogesterone caproate (17P) in preventing preterm birth, with the caveat that 17P mainly has been studied in those with a history of previous PTB.
2. Outcomes were improved in everyone with a short cervix, whether or not they had a history of prior PTB.
In a study published in 2007, Fonseca et al showed a very similar reduction in PTB with vaginal suppositories.2 Ever since the well-known Meis et al study surfaced demonstrating the efficacy of IM progesterone in those with a history of PTB,3 many practitioners have begun using 17P for prophylaxis of PTB. However, this new study adds another major facet to the mix — the concept of screening everyone between 19 and 24 weeks with transvaginal assessments of CL.
In a separate article in the same issue of Ultrasound in Obstetrics and Gynecology, Werner et al4 evaluated the cost-effectiveness of universal screening with CL, followed by treating those with progesterone who have short cervices. They estimated that for every 100,000 patients screened, $12 million could be saved and "423.9 quality-adjusted life years could be gained" However, if the cost of the ultrasound exam exceeded $187, or if there was less than a 20% reduction in PTB, then the economic efficacy of screening everyone diminished appreciably.
Interestingly, I could find no figures in the Werner study regarding the cost of vaginal progesterone. We have had trouble finding a product that is not expensive and has the same makeup as the product used in the above clinical trial. Crinone 8% costs about $15 per application or $450 per month. The contentious product history regarding 17P has been instructive. At first, compound pharmacies charged modest prices for 17P. However, one company garnered official approval from the FDA to make a branded 17P (Makena™), and the compound pharmacies were warned off. When it was announced that Makena was priced at $1500 per injection, this triggered an uproar from some official bodies, causing the company to reduce the price of Makena to $600 an injection. This still could represent a total outlay of up to $12,000 per pregnancy. Hopefully, this story will not repeat itself with vaginal progesterone.
The concept of screening each of the more than 4 million pregnant women in the United States is daunting. According to the Werner et al study, the charge of a CL exam must not exceed $187 if this is to remain cost effective. This should be attainable, but in this land of opportunity the motivation for profit is difficult to blunt. A way to accomplish this screening process with less cost would be to tack the CL exam on to the usual 18- to 20-week fetal anatomy survey that most patients receive as standard of care in pregnancy. It is clear that measuring the cervix transabdominally is not as precise as the transvaginal approach. However, although I have reservations about this as a screening compromise, the transabdominal approach may represent a less expensive and logistically easier way to go. It should be emphasized that the transvaginal exam should always be a first-line approach for those with a history of PTB, and should be used for confirmation in those who seem to have a short cervix on a transabdominal scan.