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We sought to provide evidence-based guidelines for using progestogens for the prevention of preterm birth (PTB).
Methods
Relevant documents, in particular randomized trials, were identified using PubMed (US National Library of Medicine, 1983 through February 2012) publications, written in English, which evaluate the effectiveness of progestogens for prevention of PTB. Progestogens evaluated were, in particular, vaginal progesterone and 17-alpha-hydroxy-progesterone caproate. Additionally, the Cochrane Library, organizational guidelines, and studies identified through review of the above were utilized to identify relevant articles. Data were evaluated according to population studied, with separate analyses for singleton vs multiple gestations, prior PTB, or short transvaginal ultrasound cervical length (CL), and combinations of these factors. Consistent with US Preventive Task Force suggestions, references were evaluated for quality based on the highest level of evidence, and recommendations were graded.
Results and Recommendations
Summary of randomized studies indicates that in women with singleton gestations, no prior PTB, and short CL ≤20 mm at ≤24 weeks, vaginal progesterone, either 90-mg gel or 200-mg suppository, is associated with reduction in PTB and perinatal morbidity and mortality, and can be offered in these cases. The issue of universal CL screening of singleton gestations without prior PTB for the prevention of PTB remains an object of debate. CL screening in singleton gestations without prior PTB cannot yet be universally mandated. Nonetheless, implementation of such a screening strategy can be viewed as reasonable, and can be considered by individual practitioners, following strict guidelines. In singleton gestations with prior PTB 20-36 6/7 weeks, 17-alpha-hydroxy-progesterone caproate 250 mg intramuscularly weekly, preferably starting at 16-20 weeks until 36 weeks, is recommended. In these women with prior PTB, if the transvaginal ultrasound CL shortens to <25 mm at <24 weeks, cervical cerclage may be offered. Progestogens have not been associated with prevention of PTB in women who have in the current pregnancy multiple gestations, preterm labor, or preterm premature rupture of membranes. There is insufficient evidence to recommend the use of progestogens in women with any of these risk factors, with or without a short CL.
From 2003 through 2011, several randomized trials evaluating the effect of either 17-alpha-hydroxy-progesterone caproate (17P) given intramuscularly (IM) or natural progesterone given vaginally or orally for prevention of preterm birth (PTB) have been published. The term “progestogens” includes both vaginal progesterone and 17P.
The quality of evidence for each article was evaluated according to the method outlined by the US Preventative Services Task Force:
I
Properly powered and conducted randomized controlled trial (RCT); well-conducted systematic review or metaanalysis of homogeneous RCTs.
II-1
Well-designed controlled trial without randomization.
II-2
Well-designed cohort or case-control analytic study.
II-3
Multiple time series with or without the intervention; dramatic results from uncontrolled experiment.
III
Opinions of respected authorities, based on clinical experience; descriptive studies or case reports; reports of expert committees.
Recommendations were graded in the following categories:
Level A
The recommendation is based on good and consistent scientific evidence.
Level B
The recommendation is based on limited or inconsistent scientific evidence.
Level C
The recommendation is based on expert opinion or consensus.
Given this large amount of new important information, the scope of this article is to review the level-1 evidence (randomized controlled trials [RCTs] and metaanalyses of RCTs) evaluating the role of progestogens in the prevention of PTB, and to provide clinicians with current recommendations for their use in possible clinical scenarios. Other publications have not addressed the totality of this new information.
they will be addressed separately. The effects of interventions for reduction of PTB often vary by the population studied, and in particular by major risk factor categories for PTB. Major differences exist when analyzing effects of other interventions by number of fetuses (ie, singleton vs multiple gestations), prior PTB (vs not), and short cervical length (CL) on transvaginal ultrasound (TVU) (vs not).
Therefore data will be analyzed according to these major categories of risk.
What are the mechanism of action and safety data of progestogens? (Levels II and III)
The mechanisms of action and safety of progestogens are not the purpose of this review, and are discussed only briefly. While the exact mechanism of action of progestogens in preventing PTB is unknown, several possibilities have been proposed (Table 1).
Effect of progesterone on cervical shortening in women at risk for preterm birth: secondary analysis from a multinational, randomized, double-blind, placebo-controlled trial.
In general, the evidence seems to favor 2 mechanisms: an antiinflammatory effect that counteracts the inflammatory process leading to PTB, and a local increase in progesterone in gestational tissues that counteracts the functional decrease in progesterone leading to PTB (Table 1).
Effect of progesterone on cervical shortening in women at risk for preterm birth: secondary analysis from a multinational, randomized, double-blind, placebo-controlled trial.
Effect of progesterone on cervical shortening in women at risk for preterm birth: secondary analysis from a multinational, randomized, double-blind, placebo-controlled trial.
Stimulate transcription of ZEB1 and ZEB2, which inhibit connexin 43 (gap-junction protein that helps synchronize contractile activity) and oxytocin-receptor gene
Decrease prostaglandin synthesis, infection-mediated cytokine production (antiinflammatory effects) by fetal membranes/placenta
Changes in PR-A and PR-B expression (decreased PR-A/PR-B ratio keeps uterus quiescent)
Membrane-bound PR in myometrium
PRs, when stimulated by progesterone, help selected gene promotion, or prevent binding of other factors
Interfere with cortisol-mediated regulation of placental gene expression
Nongenomic pathways
Reduce cervical stromal degradation in cervix
Alter barrier to ascending inflammation/infection in cervix
Reduce contraction frequency in myometrium
Attenuate response to hemorrhage/inflammation in decidua
Alter estrogen synthesis in fetal membranes/placenta
Alter fetal endocrine-mediated effects
PR, progesterone receptor; ZEB1, zinc finger E-box binding homeobox protein 1; ZEB2, zinc finger E-box binding homeobox protein 2.
SMFM. Progesterone and preterm birth prevention. Am J Obstet Gynecol 2012.
Regarding safety, several studies failed to detect any long-term effect from the intrauterine exposure of the fetus to pharmacologic progestogens, even when given in the first trimester.
Follow-up, at a mean of 4 years, of 278 children randomized in the largest RCT evaluating 17P for prevention of recurrent PTB revealed no differences in physical examination, health status, or performance (motor, problem solving, personal-social) compared to placebo.
National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network Follow-up of children exposed in utero to 17 a-hydroxyprogesterone caproate compared with placebo.
What is the evidence and recommendation for use of progestogens for prevention of PTB in singleton gestations with no prior PTB, with unknown CL? (Levels I and III)
17P
In 168 women in active military duty with only a 3% rate of prior PTB and unknown CL, 17P 1000 mg IM weekly starting at 16-20 weeks was not associated with any effect on the incidence of PTB or perinatal outcomes compared to placebo.
No RCT has evaluated the effect of vaginal progesterone in this population.
In summary, there is insufficient evidence to determine the impact on PTB of progestogens in singleton gestations with no history of PTB, and with unknown or normal CL.
What is the evidence and recommendation for use of progestogens for prevention of PTB in singleton gestations with no prior PTB, but short CL? (Levels I, II, and III)
17P
It is particularly important to assess the effectiveness of progesterone in women without prior PTB, as most PTBs occur in this population. In 657 nulliparous women with singleton gestations with TVU CL ≤30 mm at 16-22 3/7 weeks, 17P 250 mg IM weekly through 36 weeks was associated with similar incidences of PTB <35 weeks (13.5% vs 16.1%; P = .35) and <37 weeks (25.1% vs 24.2%; P = .80) compared to placebo.
Eunice Kennedy Shriver National Institute of Health and Human Development Randomized controlled trial of progesterone treatment for preterm birth prevention in nulliparous women with cervical length less than 30mm.
This RCT was stopped due to a planned interim analysis that revealed further enrollment was statistically very unlikely to demonstrate a significant difference between the groups.
In 79 women with singleton pregnancies (66% of whom had no prior PTB) with TVU CL <25 mm between 16-24 weeks, 17P was associated with similar rates of PTB and neonatal morbidity and mortality compared to cerclage.
This RCT was stopped before planned recruitment was completed as the authors stated that “it had become impractical, unethical, and unreasonable to withhold progesterone from one study group.”
In 250 women from the United Kingdom, Chile, Brazil, and Greece, with mostly (90%) singleton gestations and TVU CL ≤15 mm at 20-25 weeks, of whom about 85% had no prior PTB, vaginal progesterone 200 mg nightly started at 24 weeks until 34 weeks was associated with a 44% significant decrease in spontaneous PTB (SPTB) <34 weeks (19% vs 34%; relative risk [RR], 0.56; 95% confidence interval [CI], 0.36–0.86), but no significant effect on neonatal morbidities (composite neonatal adverse outcome: RR, 0.57; 95% CI, 0.23–1.31).
A subgroup analysis of only women without prior PTB confirmed significant benefit of progesterone in preventing PTB <34 weeks (RR, 0.54; 95% CI, 0.34–0.88).
The prevalence of TVU CL ≤15 mm in the population screened for the study was 1.7%. Based on the frequency of short TVU CL and effectiveness for prevention of SPTB <34 weeks from the work of Fonseca et al,
the number of women needed to be screened with CL to prevent 1 SPTB <34 weeks is approximately 387, if all women with a CL ≤15 mm receive vaginal progesterone. Once a TVU CL ≤15 mm is identified, the number needed to treat to prevent 1 PTB <34 weeks is about 7.
In 458 women with singleton gestations and TVU CL 10-20 mm at 19-23 6/7 weeks, of whom about 84% had no prior PTB, vaginal progesterone 90-mg gel daily started at 20-23 6/7 weeks until 36 6/7 weeks was associated with a 45% significant reduction in PTB <33 weeks (9% vs 16%; RR, 0.55; 95% CI, 0.33–0.92), and a 43% significant reduction in composite neonatal morbidity and mortality (8% vs 14%; RR, 0.57; 95% CI, 0.33–0.99).
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.
The incidences of PTB <28 and <35 weeks, and respiratory distress syndrome (RDS), were also significantly decreased. Analysis of only women without prior PTB confirmed significant benefit of progesterone in preventing PTB <33 weeks (8% vs 15%; RR, 0.50; 95% CI, 0.27–0.90).
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.
The prevalence of CL 10-20 mm was 2.3% in the population screened. The study enrolled patients in 44 centers in 10 countries (largest enrollment from United States, 46% of total), and the ethnic distribution of those included was about a third Caucasian, a third African American, and a third Asian. Protocol violations may have influenced the outcomes, and the study was both industry- and National Institutes of Health–sponsored. After evaluating data from this trial only, the Food and Drug Administration (FDA) concluded that the study did not meet the statistical significance generally expected to support the approval of the product in the US market from a single trial. The FDA raised the issue of robustness in efficacy in the US subgroup as compared to overall efficacy in the trial, and stated that additional clinical work would be required to support the approval.
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.
the number of women needed to be screened with CL to prevent 1 PTB <33 weeks is approximately 604, if all women with a CL 10-20 mm receive vaginal progesterone. Once a TVU CL 10-20 mm is identified, the number needed to treat to prevent 1 PTB <33 weeks is about 14. The study did not address the management of women with a CL <10 mm.
In a metaanalysis, including 554 singleton gestations, with no prior PTB, and TVU CL ≤25 mm mostly <25 weeks, vaginal progesterone was associated with a significant reduction in PTB <33 weeks (RR, 0.60; 95% CI, 0.39–0.92) and a nonsignificant reduction in composite neonatal morbidity and mortality (RR, 0.70; 95% CI, 0.42–1.16).
Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and meta-analysis of individual patient data.
Am J Obstet Gynecol.2012; 206 (Level I): 124.e1-124.e19
Two cost-effectiveness analyses evaluating universal CL screening in singleton gestations, to identify those with short CL eligible for vaginal progesterone, have been published so far.
Both reported that such a strategy would be cost-effective. In one study, compared to other managements, including no screening, universal sonographic screening of CL in singletons was predicted to result in a reduction of 95,920 PTBs <37 weeks annually in the United States, and was actually cost-saving (almost $13 billion saved).
Even varying the assumptions (eg, the cost of vaginal progesterone or of TVU screening), universal screening was the preferred strategy 99% of the time.
The other cost-effectiveness analysis targeted women with singleton gestation without prior PTB. A strategy of universal screening with a single TVU CL at 18-24 weeks and treatment with vaginal progesterone if the CL was ≤1.5 cm resulted in >$12 million saved, 424 quality-adjusted life-years gained, and 22 neonatal deaths or long-term neurologic deficits prevented for every 100,000 women screened compared with no screening. Even varying the assumptions over a wide range of possible values (eg, the cost of vaginal progesterone or of TVU screening), universal screening was cost-effective >99% of the time.
This cost-effectiveness analysis initially addressed only women with a TVU CL ≤1.5 mm. In an addendum, the authors mention that a reanalysis adding progesterone treatment for women with TVU CL between 1.6-2.5 mm did not change their conclusions, with the details of the reanalysis not provided.
In summary, in women with singleton gestations, no prior SPTB, and short TVU CL, vaginal progesterone is associated with reduction in PTB and composite perinatal morbidity and mortality. Based on these results,
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.
if a TVU CL ≤20 mm is identified at ≤24 weeks, vaginal progesterone can be offered for prevention of PTB. The 2 studies used different progesterone preparations and dosages. Vaginal progesterone 200-mg suppository was used in the trial for CL ≤15 mm,
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.
There is insufficient evidence that any of the vaginal preparations or doses are superior, as they have not been compared. CL, cost, availability, and other factors may influence preferred dosing.
A decision of whether to institute a policy of universal screening for short cervix with TVU in women with singleton gestations without prior PTB requires several careful considerations:
•
The available trials have addressed efficacy of progesterone for women identified with a TVU short cervix. There are no data regarding effectiveness of universal TVU screening for short cervix followed by vaginal progesterone for those with a short cervix, compared to no screening. The only evidence in favor of such an approach is based on cost-effectiveness analyses.
•
It is possible that a proportion of women with a short cervix may be identified without a specific universal TVU screening. This may result in a lower than estimated added benefit of universal screening over current practice of visualization of the lower uterine segment on all transabdominal ultrasound performed in the second trimester. Data are currently insufficient to suggest benefit, or harm, of transabdominal screening of CL for prevention of PTB using progesterone or any other intervention as therapy if a short CL is identified. Transabdominal ultrasound may not detect 57% of women with a short TVU CL.
Hernandez-Andrade E, Romero R, Ahn H, et al. Transabdominal evaluation of uterine cervical length during pregnancy fails to identify a substantial number of women with a short cervix. J Mat Fetal Neo Med 2012 Mar 16 [Epub ahead of print]. Level II-1.
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.
Universal screening approach may not produce the same results in practice as those in a controlled trial. This may be due to differences in population, logistical differences in screening methods, stretching of the eligibility and management criteria (scope creep), and unintended consequences of universal screening. Performing multiple follow-up scans, doing them outside of the studied gestational age (18-24 weeks), applying the treatment to women outside the studied CL range, or using other interventions for a short CL, such as bed rest or cerclage, may potentially result in adverse unintended consequences. The eligibility criteria were different between the 2 RCTs, and neither included all the women who had a CL below what is traditionally considered as short in the United States (<25 mm). The Fonseca 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.
trial did not include women with a CL <10 mm or between 20-25 mm. Neither trial included women with CL >20 mm, and therefore there is very limited evidence that vaginal progesterone is beneficial in these women.
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.
Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and meta-analysis of individual patient data.
Am J Obstet Gynecol.2012; 206 (Level I): 124.e1-124.e19
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.
The use of different progesterone formulations (90-mg gel and 200-mg suppository) between the 2 trials should also be taken into account. There is no evidence that the 2 preparations are interchangeable in that the one that was efficacious in the 10–20 mm range would also be efficacious in those with a CL <10 mm. In a metaanalysis, both of these 2 preparations had similar significant efficacy.
Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and meta-analysis of individual patient data.
Am J Obstet Gynecol.2012; 206 (Level I): 124.e1-124.e19
If an approach of universal screening is to be adopted, then TVU CL screening needs to be done with proper technique and with quality assurance to be effective.
•
There may be lack of availability of this screening test in some geographic areas.
All of the above need to be taken into consideration when deciding on whether to change prenatal care for million of women by instituting universal screening with a single TVU assessment of CL at around 18-24 weeks in women with a singleton gestation without prior SPTB. On the other hand, TVU CL screening of singleton gestations does fulfill many criteria for an effective screening test (Table 2).
Universal cervical-length screening and vaginal progesterone prevents early preterm births, reduces neonatal morbidity and is cost saving: doing nothing is no longer an option.
This is based mostly, in addition to what is listed on Table 2, on the following facts:
•
There is level-1 evidence of prevention of PTB and neonatal benefits based on treating with vaginal progesterone low-risk singleton gestations identified with TVU screening to have a short CL.
•
This strategy is not only beneficial in terms of improvement in health in a condition (PTB) of utmost importance to society, but also cost-effective, and in fact cost-saving.
•
TVU CL is a safe, acceptable, reproducible, and accurate screening test, with potentially widespread availability.
TABLE 2Cervical length as screening test in singleton gestations
TVU CL screening test criteria
Characteristic of screening test
Comments
TVU fulfills criteria
Disease
Disease is clinically important
PTB: no. 1 cause of perinatal mortality and morbidity in developed countries; associated with 1 million deaths annually worldwide
Yes
Disease is clearly defined
Birth <37 wk
Yes
Disease prevalence is well known
12% in United States, about 10% worldwide
Yes
Disease natural history is known/recognizable early asymptomatic phase
First cervical changes associated with later PTB occur at internal os, and can only be detected early by ultrasound
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.
Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and meta-analysis of individual patient data.
Am J Obstet Gynecol.2012; 206 (Level I): 124.e1-124.e19
Therefore, both proponents and opponents of universal screening raise valid issues. CL screening in singleton gestations without prior PTB cannot yet be mandated universally. Nonetheless, implementation of such a screening strategy should be viewed as reasonable, and can be considered by individual practitioners. Third-party payers should not deny reimbursements for this screening. Practitioners who decide to implement universal CL screening should follow strict guidelines:
•
TVU CL needs to be performed with proper technique to yield accurate results, with quality control and monitoring. To ensure quality, the Perinatal Quality Foundation is setting up a program on the proper training for clinical use of TVU CL measurement.
•
Randomized trials and cost-effectiveness studies were mostly based on performing a single TVU CL at 18-24 weeks on singleton gestations, and on using vaginal progesterone, either 90-mg gel or 200-mg suppository, as intervention when the TVU CL was ≤20 mm at <24 weeks. Clinicians should refrain from screening different populations, screening at different gestational ages, and stretching the definition of short CL to include measurements >20 mm. There is also no evidence that other preparations (eg, IM 17P) or doses would be efficacious, even within the specified CL range.
What is the evidence and recommendation for use of progestogens for prevention of PTB in singleton gestations with prior PTB, and unknown or normal CL? (Levels I, II, and III)
17P
In 43 women with mostly singleton gestation (>90%) and either prior PTB or >1 prior spontaneous abortion, 17P 250 mg IM weekly started as soon as prenatal care began was associated with significant reduction in PTB <37 weeks and perinatal mortality compared to placebo.
In 463 women with singleton gestation and prior SPTB at 20-36 6/7 weeks of a singleton gestation, compounded 17P 250 mg IM weekly started at 16-20 6/7 weeks was associated with reduction in the incidences of PTB <35 (RR, 0.66; 95% CI, 0.54–0.81), PTB <37 and <32 weeks, and supplemental oxygen and intraventricular hemorrhage (IVH) compared to placebo.
Prophylaxis with 17 alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery: does gestational age at initiation of treatment matter?.
Am J Obstet Gynecol.2007; 197 (Level II-2): 260.e1-260.e4
In 142 women with singleton gestations and mostly prior PTB (>90%), vaginal progesterone 100 mg nightly from 24-34 weeks was associated with significant reduction in the incidences of PTB <37 weeks (RR, 0.48; 95% CI, 0.25–0.96) and <34 weeks, as well as reduction in contraction frequency compared to placebo.
Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.
In 659 women with singleton gestation and prior SPTB 20-35 0/7 weeks, vaginal progesterone 90-mg gel every morning starting at 18-22 6/7 weeks and continued until 37 0/7 weeks was not associated with significantly different rates of PTB <37, 36, 33, or 29 weeks, or neonatal morbidity and mortality.
On the other hand, vaginal progesterone was associated with significant reduction in the incidence of short CL in women with singleton gestations and prior PTB.
Effect of progesterone on cervical shortening in women at risk for preterm birth: secondary analysis from a multinational, randomized, double-blind, placebo-controlled trial.
In 148 women with singleton gestation and prior SPTB 20-36 6/7 weeks, oral progesterone 100 mg twice a day was associated with significantly reduced rates of PTB <37 weeks and neonatal intensive care unit admission compared to placebo.
In 33 women with singleton gestation and prior PTB 20-36 6/7 weeks, oral progesterone 400 mg daily was associated with trend (but no significant differences) for reduced rates of PTB <37 weeks (26% vs 57%; P = .15) and ventilator use (0% vs 21%; P = .07) compared to placebo.
In summary, in singleton gestation with prior SPTB, in which CL is unknown, progestogen administration is beneficial in preventing PTB. Although we have limited data comparing the different preparations of progestogens, there is at present stronger evidence of effectiveness for 17P than for vaginal progesterone, based on the 2 largest trials.
Therefore, 17P 250 mg IM weekly starting at 16-20 weeks until 36 weeks should be recommended to women with singleton gestations and prior SPTB 20-36 6/7 weeks. In cases in which 17P is unavailable, other progesterone preparations may be considered.
Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.
What is the evidence and recommendation for use of progestogens for prevention of PTB in singleton gestations with prior PTB, and short CL? (Levels I, II, and III)
17P
There are no RCTs evaluating the effectiveness of 17P compared to placebo in women with singleton gestations, prior PTB, and short CL. In this population, 17P has only been evaluated as an adjunct or an alternative to cervical cerclage.
In singleton gestations with prior SPTB and a short TVU CL <25 mm at <23 weeks, 17P was associated with statistically significant decrease in PTB <24 weeks and perinatal death in women not receiving cerclage in a secondary analysis of a cerclage trial.
Vaginal Ultrasound Trial Consortium 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 (Level II-1): 351.e1-351.e6
Beneficial effects of 17P were noted primarily for women with CL 15-24.9 mm, while they were nonsignificant for women with CL <15 mm. Overall, women with a CL <25 mm had a 34% risk of PTB <32 weeks if they received neither 17P nor cerclage, 25% if they received cerclage, 21% if they received 17P, and 17% if they received both.
Vaginal Ultrasound Trial Consortium 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 (Level II-1): 351.e1-351.e6
While these results were not statistically significant, they suggest that further research is needed to evaluate the relationship and possible cumulative beneficial effect of progesterone and cerclage.
In a randomized trial that did not recruit the planned sample size, 17P had similar effects compared to cerclage in preventing PTB in women with a TVU CL <25 mm, but cerclage was more beneficial in women with CL <15 mm.
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.
Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and meta-analysis of individual patient data.
Am J Obstet Gynecol.2012; 206 (Level I): 124.e1-124.e19
evaluating just the 46 singleton gestations with prior SPTB <35 weeks and short TVU CL <28 mm at 18-22 6/7 weeks, vaginal progesterone 90-mg gel daily started at 18-23 6/7 weeks until 37 weeks was associated with significant decreases in the rates of both PTB <32 weeks and neonatal intensive care unit admission compared to placebo.
Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial.
In 71 singleton gestations with prior PTB, vaginal progesterone 100-mg suppositories daily between 24-34 weeks was associated with significant reduction in incidences of PTB <37 weeks (24% vs 50%; odds ratio [OR], 3.11; 95% CI, 1.13–8.53) and <34 weeks (5.4% vs 26.5%; OR, 6.30; 95% CI, 1.25–31.70) compared to placebo.
In a metaanalysis, including 169 singleton gestations with prior PTB and TVU CL ≤25 mm mostly <25 weeks, vaginal progesterone was associated with a significant reduction in PTB <33 weeks (RR, 0.54; 95% CI, 0.30–0.98) and in composite neonatal morbidity and mortality (RR, 0.41; 95% CI, 0.17–0.98).
Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and meta-analysis of individual patient data.
Am J Obstet Gynecol.2012; 206 (Level I): 124.e1-124.e19
Based on the pooled results of 5 clinical trials, in 504 singleton pregnancies with prior SPTB at <34 weeks and TVU CL <25 mm at <24 weeks' gestation, cerclage was associated with a significant 30% reduction in the risk of PTB <35 weeks (28% vs 41%; RR, 0.70; 95% CI, 0.55–0.89) and a 36% reduction in composite perinatal mortality and morbidity (16% vs 25%; RR, 0.64; 95% CI, 0.45–0.91).
Therefore screening women with singleton gestations with prior SPTB with TVU CL starting usually at 16 weeks and every 2 weeks until 23 weeks is suggested, so that cerclage can be offered for those who develop a TVU CL <25 mm. As the vast majority of women in this metaanalysis and its included randomized trials did not receive 17P, there is insufficient evidence to determine if the concurrent use of progesterone and cerclage offers an additive effect in reducing the risk of PTB in this group of women with prior PTB.
Vaginal Ultrasound Trial Consortium 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 (Level II-1): 351.e1-351.e6
Therefore, the optimal management of the patient with progressive cervical shortening despite progesterone therapy remains uncertain.
In summary, 17P should be recommended to women with prior SPTB starting at 16 weeks, as described above. If the cervix shortens <25 mm by TVU <24 weeks in such a woman with singleton gestation and prior SPTB, there is insufficient evidence to assess efficacy of a different progesterone therapy, and therefore it is reasonable to continue 17P until 36 weeks, and to offer cervical cerclage (Figure).
FIGUREAlgorithm for use of progestogens in prevention of PTB in clinical care
aIf TVU CL screening is performed; b17P 250 mg intramuscularly every week from 16-20 weeks to 36 weeks; ceg, daily 200-mg suppository or 90-mg gel from time of diagnosis of short CL to 36 weeks.
What is the evidence and recommendation for use of progestogens for prevention of PTB in multiple gestations, and unknown or normal CL? (Levels I and III)
17P
In 77 women with twin gestation, 17P 250 mg IM weekly from 28-33 weeks was not associated with any effect on PTB rates or perinatal morbidity and mortality compared to placebo.
In 655 women with dichorionic (DC) twin gestation, of whom <10% had prior PTB, 17P 250 mg IM weekly starting at 16-20 weeks and ending at 35 weeks was not associated with any effect on PTB rates or perinatal morbidity and mortality in a National Institute of Child Health and Human Development–sponsored RCT compared to placebo.
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.
In 30 women with twin gestation, of whom 27% had a prior PTB, 17P 250 mg IM weekly starting at 20-30 weeks and ending at 34 weeks was associated with similar incidences of PTB <35 weeks and <30 weeks, as well as similar rates of neonatal morbidity and mortality compared to placebo. CL was not reported.
In 240 women with DC twin gestation, 17P 250 mg IM weekly starting at 16-24 weeks until 34 weeks was associated with similar incidences of PTB and neonatal morbidity compared to placebo.
Two RCTs have evaluated the effect of 17P in triplet gestations. In a total of about 190 triplet gestations, 17P 250 mg IM weekly started at around 16-20/22 weeks' gestation until 34/35 weeks was not associated with effects on incidence of PTB or perinatal morbidity and mortality compared to placebo.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Maternal-Fetal Medicine Units Network (MFMU) Prevention of preterm birth in triplets using 17 alpha-hydroxyprogesterone caproate: a randomized controlled trial.
Obstetrix Collaborative Research Network Failure of 17-hydroxyprogesterone to reduce neonatal morbidity or prolong triplet pregnancy: a double-blind, randomized clinical trial.
Am J Obstet Gynecol.2010; 203 (Level I): 248.e1-248.e9
In 500 women with twin gestation, vaginal progesterone 90 mg daily starting at 24 weeks and continued for at least 10 weeks was not associated with significant effects in incidences of PTB or perinatal morbidity and mortality compared to placebo.
In 677 women with diamniotic twin gestation, vaginal progesterone 200-mg pessaries starting at 20-24 weeks until 34 weeks were not associated with significant effects on incidences of PTB or perinatal complications compared to placebo.
PREDICT Group Prevention of preterm delivery in twin gestations (PREDICT): a multicenter, randomized, placebo-controlled trial on the effect of vaginal micronized progesterone.
In 67 twin gestations, vaginal progesterone 100-mg suppositories daily between 24-34 weeks were associated with significant reduction in incidences of PTB <37 weeks (51% vs 79%; OR, 3.48; 95% CI, 1.16–10.46) but not <34 weeks (10% vs 25%; OR, 2.90; 95% CI, 0.76–11.20) compared to placebo.
Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial.
No RCT has yet been reported on the effect of vaginal progesterone on triplet gestations.
In summary, the evidence does not support the use of any type of progestogen for prevention of PTB in multiple gestations with unknown CL. In women with prior SPTB, and a current multiple gestation, some experts have suggested the use of 17P starting at 16 weeks based on the historic risk factor,
but there is insufficient evidence to make this a recommendation.
What is the evidence and recommendation for use of progestogens for prevention of PTB in multiple gestations, and short CL? (Levels I and III)
17P
In a secondary analysis of a trial involving women with DC twin gestation, 52 women, of whom 18.5% had prior PTB, were identified to have a TVU CL of ≤35 mm (25th percentile) between 16-20 weeks. 17P 250 mg IM weekly starting at 16-20 weeks and ending at 35 weeks was associated with similar incidences of PTB <35 weeks (64% vs 46%; P = .18) compared to placebo.
Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network Second-trimester cervical length and risk of preterm birth in women with twin gestations treated with 17-α hydroxyprogesterone caproate.
In a secondary analysis of a trial involving women with diamniotic twin gestation, 47 women, of whom 9% had prior PTB, were identified to have TVU CL ≤30 mm between 20-24 weeks. Vaginal progesterone 200-mg pessaries starting at 20-24 weeks until 34 weeks were not associated with an effect on PTB <34 weeks (29% vs 40%; RR, 0.63; 95% CI, 0.18–2.23) compared to placebo.
PREDICT Group Vaginal micronized progesterone and risk of preterm delivery in high-risk twin pregnancies: secondary analysis of a placebo-controlled randomized trial and meta-analysis.
In a metaanalysis, including 52 twin gestations found to have a TVU CL <25 mm at ≤24 weeks, vaginal progesterone was associated with similar incidence of PTB <33 weeks (30% vs 45%; RR, 0.70; 95% CI, 0.34–1.44) and <35 weeks (52% vs 62%; RR, 0.91; 95% CI, 0.57–1.46), but a significant reduction in composite neonatal morbidity and mortality (24% vs 40%; RR, 0.56; 95% CI, 0.30–0.97) compared to placebo.
Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and meta-analysis of individual patient data.
Am J Obstet Gynecol.2012; 206 (Level I): 124.e1-124.e19
In summary, there is insufficient evidence to assess the effect of progestogens in women with both multiple gestation and short CL.
What is the evidence and recommendation for use of progestogens for prevention of PTB in preterm labor? (Levels I, II, and III)
Primary tocolysis
In 57 women admitted between 13-36 weeks with contractions, progesterone 400 mg orally once was associated with a significant decrease in the frequency of contractions, but no PTB or neonatal outcomes were reported compared to placebo.
In 44 women with mostly singleton gestations (>90%) and threatened preterm labor (PTL) at <35 weeks treated with ritodrine, natural progesterone 400 mg orally every 6 hours × 24 hours (then 400 mg every 8 hours for next 24 hours, and then 300 mg every 8 hours onward) was associated with similar rates of PTB, but with lower total dose of ritodrine administered and shorter maternal hospital stay compared to placebo.
In 60 women with singleton gestation still pregnant after successful tocolysis for PTL, 17P 341 mg twice weekly started at 25-33 6/7 weeks until 36 weeks was associated with significant reduction in the incidence of PTB <37 weeks (but not 35 weeks) and of risk of cervical shortening compared to no such treatment.
In 188 women with singleton gestations still pregnant after successful tocolysis for PTL, 17P 500 mg IM twice weekly started at 24-31 6/7 weeks until 36 weeks was associated with similar incidences of PTB <37, <34, and <32 weeks, and of perinatal morbidity and mortality compared to no such treatment.
In 70 women with singleton gestation still pregnant after successful tocolysis for PTL, vaginal progesterone 400 mg daily until delivery was associated with longer latency until delivery, later gestational age at delivery (PTB was not reported), and RDS compared to no such treatment.
In summary, there is currently insufficient evidence to recommend progestogens for primary, adjunctive, or maintenance tocolysis.
What is the evidence and recommendation for use of progestogens for prevention of PTB in preterm premature rupture of membranes? (Levels I and III)
17P
In 69 women with singleton gestations and preterm premature rupture of membranes (PPROM) at 24-30 weeks, 17P 250 mg IM is associated with no effect on interval to delivery, gestational age at delivery, or neonatal mortality and morbidity compared to placebo.
No RCT has evaluated the effect of vaginal progesterone in this population.
In summary, there is insufficient evidence to assess effect of progesterone in women with PPROM. In a woman who has been receiving 17P for prior SPTB, in the absence of evidence to the contrary, it is reasonable to continue 17P once membranes have ruptured.
Conclusions
Assessment of efficacy of progestogens for prevention of PTB should be done separately for each type of progestogens, with vaginal and IM routes of administration the most studied types (Table 3). Efficacy probably varies also depending on each different risk factor. In addition, dose, gestational age at initiation and termination, compliance, and other issues are factors that influence efficacy of progestogens for prevention of PTB. Therefore, singleton vs multiple gestation, history (eg, prior PTB), short TVU CL (and degree of) or not, asymptomatic vs PTL and PPROM, etc, are all factors that should be considered, as progestogens have different effects in populations with any one (or combination of) risk factor. Several metaanalyses have been published,
but they either do not evaluate these studies according to the different populations just mentioned, or soon become out of date because of publications of new RCTs.
TABLE 3Current Society for Maternal-Fetal Medicine recommendations regarding use of progestogens for prevention of preterm birth
Population
Recommendation regarding use of progestogens
Asymptomatic
Singletons without prior SPTB and unknown or normal TVU CL
No evidence of effectiveness
Singletons with prior SPTB
17P 250 mg IM weekly from 16-20 wk until 36 wk
Singletons without prior SPTB but CL ≤20 mm at ≤24 wk
Vaginal progesterone 90-mg gel or 200-mg suppository daily from diagnosis of short CL until 36 wk
Level I and level III evidence, level A recommendation
1
There is insufficient evidence to recommend the use of progestogens in singleton gestations with no prior PTB, and unknown CL.
Level I evidence, level A recommendation
2
In women with singleton gestations, no prior SPTB, and short TVU CL ≤20 mm at ≤24 weeks, vaginal progesterone, either 90-mg gel or 200-mg suppository, is associated with reduction in PTB and perinatal morbidity and mortality, and can be offered in these cases.
Level I and level III evidence, level B recommendation
3
The issue of universal TVU CL screening of singleton gestations without prior PTB for the prevention of PTB remains an object of debate. CL screening in singleton gestations without prior PTB cannot yet be universally mandated. Nonetheless, implementation of such a screening strategy can be viewed as reasonable, and can be considered by individual practitioners. Given the impact on prenatal care and potential misuse of universal screening, stretching the criteria and management beyond those tested in RCTs should be prevented. Practitioners who decide to implement universal TVU CL screening should follow strict guidelines. Practitioners who choose to screen low-risk singleton gestations may consider offering vaginal progesterone, either 90-mg gel or 200-mg suppositories, for short TVU CL ≤20 mm at ≤24 weeks.
Level I and level III evidence, level A and B recommendations
4
In singleton gestations with prior SPTB 20-36 6/7 weeks, 17P 250 mg IM weekly preferably starting at 16-20 weeks until 36 weeks is recommended. In these women, if the TVU CL shortens to <25 mm at <24 weeks, cervical cerclage may be offered.
Level I, level II, and level III evidence, level B recommendation
5
Progestogens have not been associated with prevention of PTB in multiple gestations, PTL, or PPROM. There is insufficient evidence to recommend the use of progestogens in women with any of these risk factors, with or without a short CL. Some experts offer 17P to women with a prior SPTB and a current multiple gestation, but there are insufficient data to evaluate the risks and benefits of this intervention in this population.
This opinion was developed by the Publications Committee of the Society for Maternal–Fetal Medicine with the assistance of Vincenzo Berghella, MD, and was approved by the executive committee of the society on March 11, 2012. Dr Berghella and each member of the publications committee (Vincenzo Berghella, MD [chair], Sean Blackwell, MD [vice-chair], Brenna Anderson, MD, Suneet P. Chauhan, MD, Joshua Copel, MD, Cynthia Gyamfi, MD, Donna Johnson, MD, George Saade, MD, Hyagriv Simhan, MD, Lynn Simpson, MD, Joanne Stone, MD, Alan Tita, MD, Michael Varner, MD, Ms Deborah Gardner) have submitted a conflict of interest disclosure delineating personal, professional, and/or business interests that might be perceived as a real or potential conflict of interest in relation to this publication.
The practice of medicine continues to evolve, and individual circumstances will vary. This opinion reflects information available at the time of its submission for publication and is neither designed nor intended to establish an exclusive standard of perinatal care. This publication is not expected to reflect the opinions of all members of the Society for Maternal–Fetal Medicine.
References
Csapo A.
Goodall M.
Excitability, length tension relation and kinetics of uterine muscle contraction in relation to hormonal status.
Effect of progesterone on cervical shortening in women at risk for preterm birth: secondary analysis from a multinational, randomized, double-blind, placebo-controlled trial.
Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
Vaginal progesterone in women with an asymptomatic sonographic short cervix in the midtrimester decreases preterm delivery and neonatal morbidity: a systematic review and meta-analysis of individual patient data.
Am J Obstet Gynecol.2012; 206 (Level I): 124.e1-124.e19
Hernandez-Andrade E, Romero R, Ahn H, et al. Transabdominal evaluation of uterine cervical length during pregnancy fails to identify a substantial number of women with a short cervix. J Mat Fetal Neo Med 2012 Mar 16 [Epub ahead of print]. Level II-1.
Universal cervical-length screening and vaginal progesterone prevents early preterm births, reduces neonatal morbidity and is cost saving: doing nothing is no longer an option.
Prophylaxis with 17 alpha-hydroxyprogesterone caproate for prevention of recurrent preterm delivery: does gestational age at initiation of treatment matter?.
Am J Obstet Gynecol.2007; 197 (Level II-2): 260.e1-260.e4
Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study.
Vaginal progesterone is associated with a decrease in risk for early preterm birth and improved neonatal outcome in women with a short cervix: a secondary analysis from a randomized, double-blind, placebo-controlled trial.
Prevention of preterm delivery in twin gestations (PREDICT): a multicenter, randomized, placebo-controlled trial on the effect of vaginal micronized progesterone.
Vaginal micronized progesterone and risk of preterm delivery in high-risk twin pregnancies: secondary analysis of a placebo-controlled randomized trial and meta-analysis.
An incorrect word appeared in an SMFM Clinical Guideline (Society for Maternal-Fetal Medicine Publications Committee, Berghella V. Progesterone and preterm birth prevention: translating clinical trials data into clinical practice. Am J Obstet Gynecol 2012;206:376-86) published in the May 2012 issue of the Journal.
I read with great interest the recent Society for Maternal-Fetal Medicine Clinical Guideline concerning progesterone treatment to prevent preterm birth.1
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