By John C. Hobbins, MD
Professor, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora
Dr. Hobbins reports no financial relationships relevant to this field of study.
A recent indirect comparison meta-analysis has shown that vaginal progesterone is as useful in decreasing preterm birth and its associated adverse outcomes as cervical cerclage in patients with a history of preterm birth and short cervices.
Conde-Agudelo A, et al. Vaginal progesterone is as effective as cervical cerclage to prevent preterm birth in women with a singleton gestation, previous spontaneous preterm birth, and a short cervix: Updated indirect comparison meta-analysis. Am J Obstet Gynecol 2018;219:10-25.
The 2003 sentinel study by Meis et al showing that 17 hydroxyprogesterone caproate (17P) decreased the rate of recurrent preterm birth (PTB)1 gave hope that progress was being made in combating a major cause of perinatal mortality and morbidity. A later study by Hassan et al suggested that vaginal progesterone could diminish PTB by about one-third in patients with singletons and short cervices.2 The authors of a 2011 meta-analysis of randomized, controlled trials (RCTs) suggested that a mechanical deterrent, cervical cerclage, could diminish the chances of PTB in patients with cervical length < 2.5 cm.3 Since then, only two small RCTs have emerged that have compared cerclage to vaginal progesterone (with no differences found).4,5 All other studies have compared progesterone to placebo or cerclage to no treatment. Conde-Agudelo et al recently fashioned an individual patient data meta-analysis from information mined from these studies to indirectly compare the ability of these two methods to prevent PTB.
The authors scanned the literature for RCTs published between October 2011 and March 2018, in which patients with singletons, a history of PTB, and a transvaginal cervical length (CL) of < 2.5 cm were enrolled in studies comparing cerclage to no cerclage or vaginal progesterone to placebo. If data were incomplete or unclear regarding the individual patients in these studies, the original authors were asked to submit the missing data for inclusion.
Thirty-nine studies were considered. Of these, the authors determined there was enough data to evaluate 10 (five cerclage and five progesterone). Individual patient data were collected, combined, and analyzed to assess outcome variables such as birth prior to 37 weeks, 32 weeks, and 28 weeks; respiratory distress syndrome; intraventricular hemorrhage (IVH); necrotizing enterocolitis; sepsis; and composite adverse neonatal outcome. Other endpoints included birth weight < 2,500 g, < 1,500 g, and admission to the newborn special care unit. The indirect analysis compared cerclage to control and vaginal progesterone to control.
The direct analysis for vaginal progesterone showed significant reductions for PTB < 35 weeks (relative risk [RR], 0.68; 95% confidence interval [CI], 0.50-0.93) and < 32 weeks (RR, 0.60; 95% CI, 0.39-0.92), composite neonatal morbidity (RR, 0.43; 95% CI, 0.20-0.94), and admission to newborn unit (RR, 0.46; 95% CI, 0.30-0.70). For cerclage, the direct analysis showed significant reductions in birth < 35 weeks (RR, 0.70; 95% CI, 0.55-0.89) and < 32 weeks (RR, 0.66; 95% CI, 0.48-0.91), composite neonatal adverse outcome (RR, 0.64; 95% CI, 0.45-0.91), and birth weight < 1,500 g (RR, 0.64; 95% CI, 0.45-0.90). Interestingly, the numbers needed to treat to attain one or more of the above triumphs was between five to 16 patients for progesterone vs. six to 14 patients for cerclage. All other comparisons showed no statistically significant difference.
The indirect analysis addressed the authors’ investigative query. For every outcome variable, no significant differences were noted between the two treatment regimens, although a few non-significant variables showed trends that were somewhat discrepant. For example, for composite neonatal adverse outcome, the RR favored progesterone (0.48), but for grade 3 to 4 IVH, the RR favored cerclage (1.79). However, most results mirrored the results for delivery < 35 weeks, where the RR for progesterone was 0.97 (95% CI, 0.66-1.44).
COMMENTARY
After sifting through the data, one should conclude that patients with short cervices (< 2.5 cm) and histories of previous PTB would benefit equally from either method. However, there are downsides to each method. Vaginal progesterone is messy and requires daily application. Occasionally, there is a complaint of vaginal irritation. Cerclage has been associated with rupture of membranes, chorioamnionitis, bleeding, and lacerations. It is invasive, requiring a procedure in a hospital setting. Not surprisingly, 80% of simulated cost analyses have shown it to be more expensive than vaginal progesterone. Its advantage is that it is a one-time only method, obviating the hassle of daily administration, and it gives the patient a sense of security that something has been done to mechanically strengthen her “weak” cervix.
Enthusiasm for vaginal progesterone wavered somewhat in 2016 when the OPPTIMUM study was published.6 The results of this randomized trial suggested no difference in outcomes when vaginal progesterone was compared with placebo. Interestingly, Conde-Agudelo et al included this negative study in their meta-analysis, which, as described above, was not enough to affect the favorable results with vaginal progesterone. The original study by Meis et al demonstrated the efficacy of 17P in patients with a history of PTB alone.1 When this initially was endorsed by the American College of Obstetricians and Gynecologists, its use in these patients seemed to have been cast in stone.7 However, unlike vaginal progesterone, the benefit of 17P has yet to be demonstrated in women with short cervices.8,9 Therefore, based on current data, there is now ample evidence to favor vaginal progesterone over 17P in patients with a history of PTB and, based on the direct and indirect meta-analysis above, to use it as an alternative to cerclage in patients with short cervices.
REFERENCES
- Meis PJ, et al. Prevention of preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379-2385.
- Hassan SS, et al; PREGNANT Trial. 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.
- Berghella V, et al. Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: A meta-analysis. Obstet Gynecol 2011;117:663-671.
- Ionescu AC, et al. Randomized trial of cerclage and progesterone to prevent spontaneous preterm birth in high risk women with short cervix. J Perinat Med 2011;39:(Suppl):Abstract 008.
- Chandiramani M, et al. Limited relationship between cervico-vaginal fluid cytokine profiles and cervical shortening in women at high risk of spontaneous preterm birth. PLoS One 2012;7:e52412.
- Norman JE, et al; for the OPPTIMUM study group. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): A multicenter, randomized, double-blind trial. Lancet 2016;387:2106-2116.
- Committee on Practice Bulletins — Obstetrics, the American College of Obstetricians and Gynecologists. Practice bulletin no. 130: Prediction and prevention of preterm birth. Obstet Gynecol 2012;120:964-973.
- Berghella V, et al. 17-alpha-hydroxyprogesterone caproate for the prevention of preterm birth in women with prior preterm birth and a short cervical length. Am J Obstet Gynecol 2010;202:351.e1-6.
- Grobman WA, et al. 17 alpha-hydroxyprogesterone caproate to prevent prematurity and nulliparas with cervical length less than 30 mm. Am J Obstet Gynecol 2012;201:390.e1-8.
