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. Author manuscript; available in PMC: 2023 Dec 1.
Published in final edited form as: Am J Obstet Gynecol. 2022 Aug 2;227(6):923–926. doi: 10.1016/j.ajog.2022.07.054

Vaginal progesterone does not prevent recurrent preterm birth in women with a singleton gestation, a history of spontaneous preterm birth, and a midtrimester cervical length >25 mm

Agustin CONDE-AGUDELO 1,2, Roberto ROMERO 1,3,4,5,6
PMCID: PMC10358345  NIHMSID: NIHMS1909780  PMID: 35926647

Objective

We recently reported the results of a systematic review and meta-analysis that addressed the clinical question of whether vaginal progesterone is effective in preventing recurrent preterm birth and adverse perinatal outcomes in women with a singleton gestation and a history of spontaneous preterm birth.1 The results were conflicting. Although the administration of vaginal progesterone was associated with a reduction in the risk of preterm birth <37 and <34 weeks of gestation in small, poor-quality trials, vaginal progesterone had no effect in large, high-quality trials. Therefore, we concluded that no convincing evidence supports prescribing vaginal progesterone to prevent preterm birth in singleton gestations with a history of spontaneous preterm birth.

Vaginal progesterone is clearly effective in reducing the risk of preterm birth and improving perinatal outcomes in women with a singleton gestation and a sonographic short cervix (≤25 mm), both with and without a history of spontaneous preterm birth.2,3 Conversely, it is unclear if vaginal progesterone prevents preterm birth in patients with a singleton gestation, a history of spontaneous preterm birth, and a mid-trimester transvaginal sonographic cervical length >25 mm. Hence, we performed a post hoc subgroup analysis of the recently published meta-analysis1 to assess the efficacy of vaginal progesterone in preventing preterm birth in this subset of patients.

Study Design

A detailed description of the methods used in the conduct of our systematic review and meta-analysis can be found in the previous publication.1 Briefly, a protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (number CRD42021275154), and a literature search was performed in MEDLINE, Embase, the Latin American and Caribbean Health Sciences Literature (LILACS), CINAHL, the Cochrane Central Register of Controlled Trials, and clinical trial registries (all from their inception to February 28, 2022) using the keywords progesterone and preterm birth. Randomized controlled trials were eligible if they compared vaginal progesterone to placebo or no treatment for the prevention of preterm birth and/or adverse perinatal outcomes in women with a singleton gestation and a history of at least one spontaneous preterm birth in any of their previous pregnancies. The primary outcomes were preterm birth <37 and <34 weeks of gestation. The secondary outcomes were adverse maternal and perinatal outcomes. The risk of bias for each included study was assessed by using the Cochrane Risk of Bias 2 (RoB 2) tool, which classifies trials as at low risk of bias, some concerns of bias, or high risk of bias. Both authors independently retrieved and reviewed studies for eligibility, assessed their risk of bias, and extracted data. Relevant additional data of included trials supplied to previous meta-analyses were included in the meta-analysis.

The data synthesis was performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We calculated the pooled relative risk (RR) with a 95% confidence interval (CI) by using a random effects model. Heterogeneity of the results among studies was evaluated by visually inspecting forest plots and by estimating the I2 quantity. A significant level of heterogeneity was defined as I2 ≥30%. Heterogeneity was also addressed by performing several subgroup and sensitivity analyses and by calculating 95% prediction intervals. Standard and contour-enhanced funnel plots were constructed to investigate small-study effects and publication biases. Funnel plot asymmetry was assessed visually and with Egger’s and Harbord’s tests. Finally, we evaluated the quality of evidence for the primary and secondary outcomes by using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach, which categorizes the quality of evidence into four levels: high, moderate, low, and very low.

Results

Ten trials, comprising 2958 women, met the inclusion criteria for the original systematic review and meta-analysis.1 Six trials did not collect data on cervical length before randomization (5 trials) or did not report results for patients with a cervical length >25 mm (1 trial). We obtained data separately for women with a mid-trimester transvaginal sonographic cervical length >25 mm (N=1308) from the remaining four trials.4-7 The studies by O’Brien et al4 and Norman et al6 were double-blind, placebo-controlled, registered, multicenter trials (one conducted in high-income countries and one conducted in both high-income and low- and middle-income countries) and were judged to be at overall low risk of bias. The studies by Cetingoz et al5 and Abdou7 were conducted in single centers located in low- and middle-income countries and were unregistered; one compared vaginal progesterone to placebo and was deemed to be at overall low risk of bias,5 whereas the other evaluated vaginal progesterone vs no treatment and was considered to be at overall high risk of bias.7 The daily dose of vaginal progesterone used in the trials was 200 mg in two studies,6,7 100 mg in one study,5 and 90 mg in one study,4 and the treatment was administered between 18 to 24 and 34 to 37+0 weeks of gestation.

The frequency of preterm birth <37 weeks of gestation among women with a cervical length >25 mm allocated to receive vaginal progesterone was remarkably similar to that observed in women in the placebo or no treatment group (35.4% vs 35.4%; RR, 0.99; 95% CI, 0.84-1.16; P=.88; I2=8%; high-quality evidence) (Figure). As in the original meta-analysis,1 there was a tendency of small trials to report a beneficial effect of vaginal progesterone on the risk of both outcomes, whereas in large studies, this intervention had no effect. The effect of vaginal progesterone on the risk of preterm birth <37 weeks of gestation significantly differed between the subgroup of women with a singleton gestation, a history of spontaneous preterm birth, and a cervical length >25 mm (RR, 0.99; 95% CI, 0.84-1.16) and that of women with a singleton gestation, a history of spontaneous preterm birth, and a cervical length ≤25 mm (RR, 0.72; 95% CI, 0.58-0.90; high-quality evidence; P for interaction=.02).

Figure.

Figure.

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Effect of vaginal progesterone on preterm birth <137 weeks of gestation in women with a singleton gestation, a history of spontaneous preterm birth, and a midtrimester transvaginal sonographic cervical length >25 mm.

Similarly, among women with a cervical length >25 mm, there was no evidence that vaginal progesterone reduced the frequency of preterm birth <34 and <28 weeks of gestation compared to placebo or no treatment (for preterm birth <34 weeks: 13.6% [86/634] vs 15.0% [94/625]; RR, 0.86; 95% CI, 0.51-1.44; P=.57; I2=58%; low-quality evidence; for preterm birth <28 weeks: 3.9% [25/634] vs 2.4% [15/625]; RR, 1.65; 95% CI, 0.88-3.11; P=.12; I2=0%; moderate-quality evidence). The effect of vaginal progesterone on adverse perinatal outcomes is shown in the Table. No significant differences were observed between the vaginal progesterone and the placebo or no treatment groups in the risk of fetal death, neonatal death, perinatal death, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, neonatal sepsis, admission to the neonatal intensive care unit (NICU), use of mechanical ventilation, and birthweight <1500 g and <2500 g. The quality of evidence was considered low for seven of 11 perinatal outcomes evaluated and moderate for the remaining four.

TABLE.

Effect of vaginal progesterone on perinatal outcomes in women with a singleton gestation, a history of spontaneous preterm birth, and a midtrimester sonographic cervical length >25 mm

Outcome No. of
trials		 Vaginal
progesterone		 Placebo
or no treatment		 Relative risk
(95% CI)		 P value I2, %
 Fetal death 273,74 5/330 (1.5%) 3/313 (1.0%) 1.59 (0.38-6.58) 0.52 NA
 Neonatal death 378-80 16/641 (2.5%) 11/638 (1.7%) 1.40 (0.56-3.53) 0.47 19
 Perinatal death 273,74 12/330 (3.6%) 10/313 (3.2%) 1.12 (0.50-2.52) 0.79 0
  Respiratory distress syndrome 280,81 35/330 (10.6%) 33/313 (10.5%) 1.01 (0.64-1.58) 0.97 0
  Necrotizing enterocolitis 273,74 3/330 (0.9%) 4/313 (1.3%) 0.71 (0.16-3.16) 0.66 NA
  Intraventricular hemorrhage 273,75 6/330 (1.8%) 5/313 (1.6%) 1.14 (0.35-3.70) 0.82 NA
  Neonatal sepsis 273,76 4/306 (1.3%) 5/300 (1.7%) 0.79 (0.21-2.91) 0.72 NA
 Admission to NICU 273,74 55/330 (16.7%) 65/313 (20.8%) 0.51 (0.12-2.13) 0.35 75
  Use of mechanical ventilation 273,76 19/304 (6.3%) 29/300 (9.7%) 0.65 (0.37-1.13) 0.13 0
  Birthweight <1500 g 273,74 25/329 (7.6%) 17/309 (5.5%) 1.36 (0.76-2.46) 0.30 0
  Birthweight <2500 g 273,76 97/329 (29.5%) 103/309 (33.3%) 0.88 (0.70-1.11) 0.30 0
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Data are presented as number/total number.

CI, confidence interval; NA, not applicable; NICU, neonatal intensive care unit

Conclusion

According to the subgroup analysis reported herein, vaginal progesterone does not prevent preterm birth, nor does it improve perinatal outcomes in women with a singleton gestation, a history of spontaneous preterm birth, and a mid-trimester transvaginal sonographic cervical length >25 mm.

The limitations of subgroup analyses are well known and include the increased likelihood of statistically significant false-positive results due to multiple comparisons and false-negative results due to inadequate statistical power. In addition, most subgroup analyses that are not specified a priori in the protocol should be considered as hypothesis-generating rather than as hypothesis-testing. Although this subgroup analysis was post hoc, we think there are several reasons for considering its results as reliable: (1) according to the interaction P value of .02, differences in the treatment effect of vaginal progesterone on preterm birth <37 weeks of gestation between the subgroup of women with a cervical length >25 mm and those with a cervical length ≤25 mm would occur by chance only 2% of the time—when chance alone is unlikely to explain subgroup differences, a subgroup effect may be present; (2) the evidence was deemed to be high-quality for the outcome of preterm birth <37 weeks of gestation in both patients with a cervical length >25 mm and those with a cervical length ≤25 mm, which means that we are very confident that the true effect lies close to that of the estimate of the effect, and further research is unlikely to change our confidence in the estimate of the effect; (3) the subgroup effect was consistent across related outcomes; in fact, vaginal progesterone had no effect on preterm birth <34 and <28 weeks of gestation or on perinatal morbidity and mortality in patients with a cervical length >25 mm, whereas it reduced preterm birth <35 and <32 weeks of gestation, perinatal morbidity and mortality, and admission to the NICU in those with a cervical length ≤25 mm in a previous analysis3; (4) the sample size of the subgroup analysis was relatively large (1308 women); and (5) there is growing evidence that treatment with vaginal progesterone may prevent preterm birth in women with a sonographic short cervix by altering molecular pathways involved in premature cervical ripening and/or by its anti-inflammatory effects.8,9 Such evidence could explain the differential effect of vaginal progesterone on the risk of preterm birth in patients with a cervical length ≤25 mm and those with a cervical length >25 mm.

Ideally, the findings of the present subgroup analysis should be confirmed or refuted in subsequent trials. However, we were unable to identify ongoing or planned randomized controlled trials comparing vaginal progesterone to placebo or no treatment in women with a singleton gestation and a history of spontaneous preterm birth in major clinical trial registries. Therefore, until the results of such trials are available, the subgroup analysis reported herein is the best available evidence about the effect of vaginal progesterone in singleton gestations with a history of spontaneous preterm birth and a cervical length >25 mm.

In summary, our findings reaffirm that vaginal progesterone should be offered to patients with a singleton gestation and a history of spontaneous preterm birth only if they have a mid-trimester (18-24 weeks of gestation) transvaginal sonographic cervical length ≤25 mm.

Download video file (14.1MB, mp4)
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Text for the AJOG Video

SLIDE 1
  • Published today is a meta-analysis on the efficacy of vaginal progesterone to prevent recurrent preterm birth in asymptomatic women with a singleton gestation, a history of spontaneous preterm birth, and a midtrimester transvaginal sonographic cervical length >25 mm.
SLIDE 2
  • Recently, we published a systematic review and meta-analysis that assessed the efficacy of vaginal progesterone for preventing recurrent preterm birth in singleton gestations with a history of spontaneous preterm birth. The results were highly conflicting because vaginal progesterone was associated with a reduction in the risk of preterm birth in small, poor-quality trials, whereas it had no effect in large, high-quality trials. Click
  • We concluded that there is no convincing evidence to support prescribing vaginal progesterone to prevent preterm birth in singleton gestations with a history of spontaneous preterm birth.
SLIDE 3
  • We have previously reported that vaginal progesterone is clearly effective in reducing the risk of preterm birth and improving perinatal outcomes in women with a singleton gestation and a midtrimester transvaginal sonographic cervical length ≤25 mm, both with and without a history of spontaneous preterm birth.
SLIDE 4
  • Given that it is unclear if vaginal progesterone prevents preterm birth in patients with a singleton gestation, a history of spontaneous preterm birth, and a midtrimester transvaginal sonographic cervical length >25 mm, we performed a post-hoc subgroup analysis of the recently published meta-analysis aiming to assess the efficacy of vaginal progesterone to prevent preterm birth in this subset of patients.
SLIDE 5
  • Click For this subgroup analysis, we included randomized controlled trials that compared vaginal progesterone to placebo/no treatment in asymptomatic women with a singleton gestation and a history of spontaneous preterm birth and reported results separately for women with a midtrimester cervical length >25 mm.
  • Click The primary outcomes were preterm birth <37 and <34 weeks of gestation.
  • Click The systematic review was performed according to the methods recommended in the 2021 edition of the Cochrane Handbook for Systematic Reviews of Interventions.
SLIDE 6
  • Click Ten trials, comprising 2958 women, met the inclusion criteria for the original systematic review and meta-analysis.
  • Click Six trials were excluded: 5 because they did not collect data on cervical length before randomization and 1 because it did not report results for patients with a cervical length >25 mm.
  • Click The remaining 4 trials, including a total of 1308 women, provided data separately for women with a midtrimester cervical length >25 mm and were included in the post-hoc subgroup analysis.
SLIDE 7
  • This forest plot shows the results of the meta-analysis for the effect of vaginal progesterone on preterm birth <37 weeks of gestation among women with a singleton gestation, a history of spontaneous preterm birth, and a midtrimester transvaginal sonographic cervical length >25 mm. Click
  • The frequency of preterm birth <37 weeks of gestation among women allocated to receive vaginal progesterone was remarkably similar to that observed in women in the placebo or no treatment group. Click
  • The pooled relative risk was 0.99 with a 95% confidence interval from 0.84 to 1.16. Click
  • According to the GRADE methodology, the quality of the evidence for this outcome was judged to be high, which means that we are very confident that the true effect lies close to that of the estimate of the effect, and further research is unlikely to change our confidence in the estimate of the effect.
SLIDE 8
  • The effect of vaginal progesterone on the risk of preterm birth <37 weeks of gestation significantly differed between the subgroup of women with a singleton gestation, a history of spontaneous preterm birth, and a cervical length >25 mm and that of women with a singleton gestation, a history of spontaneous preterm birth, and a cervical length ≤25 mm, with an interaction P value of 0.02. Clearly, vaginal progesterone was beneficial only in women with a cervical length ≤25 mm but not in those with a cervical length >25 mm.
SLIDE 9
  • The frequencies of preterm birth <34 and <28 weeks of gestation did not significantly differ between the vaginal progesterone and the placebo or no treatment groups.
SLIDE 10
  • There were no significant differences between the vaginal progesterone and the placebo or no treatment groups in the risk of adverse perinatal outcomes.
SLIDE 11
  • Despite the well-known limitations of subgroup analyses, we think there are several reasons for considering the results of the present subgroup analysis as reliable: Click
  • First, according to the interaction P value of 0.02, differences in the treatment effect of vaginal progesterone on preterm birth <37 weeks of gestation between the subgroup of women with a cervical length >25 mm and those with a cervical length ≤25 mm would occur by chance only 2% of the time. Click
  • Second, the evidence was deemed to be high-quality for the outcome of preterm birth <37 weeks of gestation in both patients with a cervical length >25 mm and those with a cervical length ≤25 mm. Click
  • Third, the subgroup effect was consistent across related outcomes. In fact, vaginal progesterone had no effect on preterm birth <34 and <28 weeks of gestation or on perinatal morbidity and mortality in patients with a cervical length >25 mm, whereas it reduced preterm birth <35 and <32 weeks of gestation, perinatal morbidity and mortality, and admission to the neonatal intensive care unit in those with a cervical length ≤25 mm. Click
  • Fourth, the sample size of the subgroup analysis was relatively large; and finally… Click
  • There is growing evidence supporting that vaginal progesterone prevents preterm birth through its actions in women with a short cervix.
SLIDE 12
  • In conclusion, vaginal progesterone does not prevent preterm birth, nor does it improve perinatal outcomes in women with a singleton gestation, a history of spontaneous preterm birth, and a midtrimester transvaginal sonographic cervical length >25 mm.
SLIDE 13
  • Therefore, vaginal progesterone should be offered only to women if they have a cervical length ≤25 mm.

Acknowledgements

We are very grateful to Julian Conde, MA, from the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD and Detroit, MI, for creating the forest plot of the meta-analysis and preparing the video of the article. Mr Conde has no conflict of interest in relation to our systematic review and meta-analysis.

Funding Statement:

This work was supported, in part, by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services (NICHD/NIH/DHHS); and, in part, by federal funds from NICHD/NIH/DHHS (Contract No. HHSN275201300006C). Dr. Roberto Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government.

The funder had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript, or the decision to submit the manuscript for publication.

Footnotes

Disclosure: The authors declare no conflict of interest.

References

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