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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
    Affiliations
    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, United States Department of Health and Human Services, Bethesda, MD and Detroit, MI
    Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
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  • Roberto Romero
    Affiliations
    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, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI
    Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI
    Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI
    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI
    Hutzel Women’s Hospital, Detroit Medical Center, Detroit, MI
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Published:August 01, 2022DOI:https://doi.org/10.1016/j.ajog.2022.07.054

      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.
      • Conde-Agudelo A.
      • Romero R.
      Does vaginal progesterone prevent recurrent preterm birth in women with a singleton gestation and a history of spontaneous preterm birth? Evidence from a systematic review and meta-analysis.
      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.
      • Romero R.
      • Conde-Agudelo A.
      • Da Fonseca E.
      • et al.
      Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data.
      ,
      • Conde-Agudelo A.
      • Romero R.
      • Da Fonseca E.
      • 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.
      Conversely, 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. Hence, we performed a post hoc subgroup analysis of the recently published meta-analysis
      • Conde-Agudelo A.
      • Romero R.
      Does vaginal progesterone prevent recurrent preterm birth in women with a singleton gestation and a history of spontaneous preterm birth? Evidence from a systematic review and meta-analysis.
      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.
      • Conde-Agudelo A.
      • Romero R.
      Does vaginal progesterone prevent recurrent preterm birth in women with a singleton gestation and a history of spontaneous preterm birth? Evidence from a systematic review and meta-analysis.
      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 1 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 4 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.
      • Conde-Agudelo A.
      • Romero R.
      Does vaginal progesterone prevent recurrent preterm birth in women with a singleton gestation and a history of spontaneous preterm birth? Evidence from a systematic review and meta-analysis.
      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 midtrimester transvaginal sonographic cervical length >25 mm (N=1308) from the remaining 4 trials.
      • O’Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      • Norman J.E.
      • Marlow N.
      • Messow C.M.
      • et al.
      Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial.
      • Abdou A.M.
      Role of vaginal progesterone in prevention of preterm labor in women with previous history of one or more previous preterm births.
      The studies by O’Brien et al
      • O’Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      and Norman et al
      • Norman J.E.
      • Marlow N.
      • Messow C.M.
      • et al.
      Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial.
      were double-blind, placebo-controlled, registered, multicenter trials (1 conducted in high-income countries and 1 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 al
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      and Abdou
      • Abdou A.M.
      Role of vaginal progesterone in prevention of preterm labor in women with previous history of one or more previous preterm births.
      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,
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      whereas the other evaluated vaginal progesterone vs no treatment and was considered to be at overall high risk of bias.
      • Abdou A.M.
      Role of vaginal progesterone in prevention of preterm labor in women with previous history of one or more previous preterm births.
      The daily dose of vaginal progesterone used in the trials was 200 mg in 2 studies,
      • Norman J.E.
      • Marlow N.
      • Messow C.M.
      • et al.
      Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial.
      ,
      • Abdou A.M.
      Role of vaginal progesterone in prevention of preterm labor in women with previous history of one or more previous preterm births.
      100 mg in 1 study,
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      and 90 mg in 1 study,
      • O’Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      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,
      • Conde-Agudelo A.
      • Romero R.
      Does vaginal progesterone prevent recurrent preterm birth in women with a singleton gestation and a history of spontaneous preterm birth? Evidence from a systematic review and meta-analysis.
      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 thumbnail gr1
      FigureEffect of vaginal progesterone on preterm birth <37 weeks of gestation in women with a singleton gestation, a history of spontaneous preterm birth, and a midtrimester transvaginal sonographic cervical length >25 mm
      Conde-Agudelo. Vaginal progesterone to prevent preterm birth and adverse perinatal outcomes. Am J Obstet Gynecol 2022.
      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 7 of 11 perinatal outcomes evaluated and moderate for the remaining 4.
      TableEffect 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
      Number of trialsVaginal progesteronePlacebo or no treatmentRelative risk (95% CI)P valueI2, %
      Fetal death2
      • O’Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      ,
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      5/330(1.5%)3/313(1.0%)1.59 (0.38–6.58).52NA
      Neonatal death3
      • O’Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      • Norman J.E.
      • Marlow N.
      • Messow C.M.
      • et al.
      Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial.
      16/641(2.5%)11/638(1.7%)1.40 (0.56–3.53).4719
      Perinatal death2
      • O’Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      ,
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      12/330(3.6%)10/313(3.2%)1.12 (0.50–2.52).790
      Respiratory distress syndrome2
      • O’Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      ,
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      35/330(10.6%)33/313(10.5%)1.01 (0.64–1.58).970
      Necrotizing enterocolitis2
      • O’Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      ,
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      3/330(0.9%)4/313(1.3%)0.71 (0.16–3.16).66NA
      Intraventricular hemorrhage2
      • O’Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      ,
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      6/330(1.8%)5/313(1.6%)1.14 (0.35–3.70).82NA
      Neonatal sepsis2
      • O’Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      ,
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      4/306(1.3%)5/300(1.7%)0.79 (0.21–2.91).72NA
      Admission to NICU2
      • O’Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      ,
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      55/330(16.7%)65/313(20.8%)0.51 (0.12–2.13).3575
      Use of mechanical ventilation2
      • O’Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      ,
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      19/304(6.3%)29/300(9.7%)0.65 (0.37–1.13).130
      Birthweight <1500 g2
      • O’Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      ,
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      25/329(7.6%)17/309(5.5%)1.36 (0.76–2.46).300
      Birthweight <2500 g2
      • O’Brien J.M.
      • Adair C.D.
      • Lewis D.F.
      • et al.
      Progesterone vaginal gel for the reduction of recurrent preterm birth: primary results from a randomized, double-blind, placebo-controlled trial.
      ,
      • Cetingoz E.
      • Cam C.
      • Sakallı M.
      • Karateke A.
      • Celik C.
      • Sancak A.
      Progesterone effects on preterm birth in high-risk pregnancies: a randomized placebo-controlled trial.
      97/329(29.5%)103/309(33.3%)0.88 (0.70–1.11).300
      Data are presented as number/total number.
      CI, confidence interval; NA, not applicable; NICU, neonatal intensive care unit.
      Conde-Agudelo. Vaginal progesterone to prevent preterm birth and adverse perinatal outcomes. Am J Obstet Gynecol 2022.

      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 midtrimester 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 analysis
      • Conde-Agudelo A.
      • Romero R.
      • Da Fonseca E.
      • 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.
      ; (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 antiinflammatory effects.
      • Xu H.
      • Gonzalez J.M.
      • Ofori E.
      • Elovitz M.A.
      Preventing cervical ripening: the primary mechanism by which progestational agents prevent preterm birth?.
      ,
      • Furcron A.E.
      • Romero R.
      • Plazyo O.
      • et al.
      Vaginal progesterone, but not 17α-hydroxyprogesterone caproate, has antiinflammatory effects at the murine maternal-fetal interface.
      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 midtrimester (18–24 weeks of gestation) transvaginal sonographic cervical length ≤25 mm.

      Acknowledgments

      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.

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