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.

Vaginal progesterone

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.

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. 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. Cerclage was significantly more effective than 17P at reducing the incidences of PTB <35 weeks and <37 weeks in the subgroup with TVU CL ≤15 mm. 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.”

Vaginal progesterone

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). 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). 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. Based on the frequency of short CL and effectiveness for prevention of PTB <33 weeks from this study, 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).

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, 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, and 90-mg gel for the trial for CL 10-20 mm. 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. The randomized data on benefit from vaginal progesterone for women with short CL screened women utilizing TVU.

• •
  

  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 trial did not include women with a CL between 15-25 mm, and the Hassan et al 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. It should be noted that only 1.7-2.3% of women were identified to have short CL in the 2 large trials published, but that the incidence of CL ≤20 mm at 22-24 weeks in the largest blinded US study was 5%. 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.

• •
  

  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 ). A number of experts have recommended TVU CL universal screening. 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 2

Cervical 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	Yes
Screening
Screening technique well described	Described in several articles	Yes
Screening is safe and acceptable	TVU is safe even in women with PPROM ; 99% of women would have TVU again; <2% have severe pain	Yes
Screening has reasonable cutoff identified	20 mm is 5th percentile, 25 mm is 10th percentile in general US population	Yes
Results are reproducible (reliable)	<10% intraobserver and interobserver variability	Yes; extremely important to control quality of TVU CL
Results are accurate (valid)	Better than manual examination; predictive in all populations studied	Yes
Intervention, cost-effectiveness, and feasibility
“Early” intervention is effective	Two positive randomized trials both reported that using vaginal progesterone for short TVU CL is effective in preventing PTB	Yes
Screening and treating abnormals is cost-effective	Two cost-effectiveness articles published	Yes, in fact cost-saving
Facilities for screening are readily available	All pregnancies are offered ultrasound for fetal anatomy screening at around 18-24 wk	Yes, but must be properly organized
Facilities for treatment are readily available	Vaginal progesterone is easily administered as outpatient	Yes

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