Advertisement

Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: a randomized, double-blind trial

      Background

      In women with a singleton pregnancy and sonographic short cervix in midgestation, vaginal administration of progesterone reduces the risk of early preterm birth and improves neonatal outcomes without any demonstrable deleterious effects on childhood neurodevelopment. In women with twin pregnancies, the rate of spontaneous early preterm birth is 10 times higher than that in singletons, and in this respect, all twins are at an increased risk of preterm birth. However, 6 trials in unselected twin pregnancies reported that vaginal administration of progesterone from midgestation had no significant effect on the incidence of early preterm birth. Such apparent lack of effectiveness of progesterone in twins may be due to inadequate dosage or treatment that is started too late in pregnancy.

      Objective

      The early vaginal progesterone for the prevention of spontaneous preterm birth in twins, a randomized, placebo-controlled, double-blind trial, was designed to test the hypothesis that among women with twin pregnancies, vaginal progesterone at a dose of 600 mg per day from 11 to 14 until 34 weeks’ gestation, as compared with placebo, would result in a significant reduction in the incidence of spontaneous preterm birth between 24+0 and 33+6 weeks.

      Study Design

      The trial was conducted at 22 hospitals in England, Spain, Bulgaria, Italy, Belgium, and France. Women were randomly assigned in a 1:1 ratio to receive either progesterone or placebo, and in the random-sequence generation, there was stratification according to the participating center. The primary outcome was spontaneous birth between 24+0 and 33+6 weeks’ gestation. Statistical analyses were performed on an intention-to-treat basis. Logistic regression analysis was used to determine the significance of difference in the incidence of spontaneous birth between 24+0 and 33+6 weeks’ gestation between the progesterone and placebo groups, adjusting for the effect of participating center, chorionicity, parity, and method of conception. Prespecified tests of treatment interaction effects with chorionicity, parity, method of conception, compliance, and cervical length at recruitment were performed. A post hoc analysis using mixed-effects Cox regression was used for further exploration of the effect of progesterone on preterm birth.

      Results

      We recruited 1194 women between May 2017 and April 2019; 21 withdrew consent and 4 were lost to follow-up, which left 582 in the progesterone group and 587 in the placebo group. Adherence was good, with reported intake of ≥80% of the required number of capsules in 81.4% of the participants. After excluding births before 24 weeks and indicated deliveries before 34 weeks, spontaneous birth between 24+0 and 33+6 weeks occurred in 10.4% (56/541) of participants in the progesterone group and in 8.2% (44/538) in the placebo group (odds ratio in the progesterone group, adjusting for the effect of participating center, chorionicity, parity, and method of conception, 1.35; 95% confidence interval, 0.88–2.05; P=.17). There was no evidence of interaction between the effects of treatment and chorionicity (P=.28), parity (P=.35), method of conception (P=.56), and adherence (P=.34); however, there was weak evidence of an interaction with cervical length (P=.08) suggestive of harm to those with a cervical length of ≥30 mm (odds ratio, 1.61; 95% confidence interval, 1.01–2.59) and potential benefit for those with a cervical length of <30 mm (odds ratio, 0.56; 95% confidence interval, 0.20–1.60). There was no evidence of difference between the 2 treatment groups for stillbirth or neonatal death, neonatal complications, neonatal therapy, and poor fetal growth. In the progesterone group, 1.4% (8/582) of women and 1.9% (22/1164) of fetuses experienced at least 1 serious adverse event; the respective numbers for the placebo group were 1.2% (7/587) and 3.2% (37/1174) (P=.80 and P=.06, respectively). In the post hoc time-to-event analysis, miscarriage or spontaneous preterm birth between randomization and 31+6 weeks’ gestation was reduced in the progesterone group relative to the placebo group (hazard ratio, 0.23; 95% confidence interval, 0.08–0.69).

      Conclusion

      In women with twin pregnancies, universal treatment with vaginal progesterone did not reduce the incidence of spontaneous birth between 24+0 and 33+6 weeks’ gestation. Post hoc time-to-event analysis led to the suggestion that progesterone may reduce the risk of spontaneous birth before 32 weeks’ gestation in women with a cervical length of <30 mm, and it may increase the risk for those with a cervical length of ≥30 mm.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • UNICEF, World Health Organization, World Bank, UN-DESA Population Division
        Levels and trends in child mortality report 2019: estimates developed by the UN Inter-Agency Group for Child Mortality Estimation.
        United Nations Children’s Fund, New York2019
        • Martin J.A.
        • Osterman M.J.K.
        Describing the increase in preterm births in the United States, 2014-2016.
        NCHS Data Brief. 2018; 312: 1-8
        • To M.S.
        • Fonseca E.B.
        • Molina F.S.
        • Cacho A.M.
        • Nicolaides K.H.
        Maternal characteristics and cervical length in the prediction of spontaneous early preterm delivery in twins.
        Am J Obstet Gynecol. 2006; 194: 1360-1365
        • Fonseca E.B.
        • Celik E.
        • Parra M.
        • Singh M.
        • Nicolaides K.H.
        • Fetal Medicine Foundation Second Trimester Screening Group
        Progesterone and the risk of preterm birth among women with a short cervix.
        N Engl J Med. 2007; 357: 462-469
        • Hassan S.S.
        • Romero R.
        • Vidyadhari D.
        • et al.
        Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial.
        Ultrasound Obstet Gynecol. 2011; 38: 18-31
        • 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.
        Am J Obstet Gynecol. 2018; 218: 161-180
        • Likis F.E.
        • Edwards D.R.
        • Andrews J.C.
        • et al.
        Progestogens for preterm birth prevention: a systematic review and meta-analysis.
        Obstet Gynecol. 2012; 120: 897-907
        • Norman J.E.
        • Mackenzie F.
        • Owen P.
        • et al.
        Progesterone for the prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis.
        Lancet. 2009; 373: 2034-2040
        • Rode L.
        • Klein K.
        • Nicolaides K.H.
        • Krampl-Bettelheim E.
        • Tabor A.
        • PREDICT Group
        Prevention of preterm delivery in twin gestations (PREDICT): a multicenter, randomized, placebo-controlled trial on the effect of vaginal micronized progesterone.
        Ultrasound Obstet Gynecol. 2011; 38: 272-280
        • Wood S.
        • Ross S.
        • Tang S.
        • Miller L.
        • Sauve R.
        • Brant R.
        Vaginal progesterone to prevent preterm birth in multiple pregnancy: a randomized controlled trial.
        J Perinat Med. 2012; 40: 593-599
        • Serra V.
        • Perales A.
        • Meseguer J.
        • et al.
        Increased doses of vaginal progesterone for the prevention of preterm birth in twin pregnancies: a randomised controlled double-blind multicentre trial.
        BJOG. 2013; 120: 50-57
        • Brizot M.L.
        • Hernandez W.
        • Liao A.W.
        • et al.
        Vaginal progesterone for the prevention of preterm birth in twin gestations: a randomized placebo-controlled double-blind study.
        Am J Obstet Gynecol. 2015; 213: 82.e1-82.e9
        • Shabaan O.M.
        • Hassanin I.M.
        • Makhlouf A.M.
        • et al.
        Vaginal progesterone for prevention of preterm delivery in women with twin pregnancy: a randomized controlled trial.
        Facts Views Vis Obgyn. 2018; 10: 93-98
        • Schuit E.
        • Stock S.
        • Rode L.
        • et al.
        Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis.
        BJOG. 2015; 122: 27-37
        • Greco E.
        • Lange A.
        • Ushakov F.
        • Calvo J.R.
        • Nicolaides K.H.
        Prediction of spontaneous preterm delivery from endocervical length at 11 to 13 weeks.
        Prenat Diagn. 2011; 31: 84-89
        • Nicolaides K.H.
        • Wright D.
        • Syngelaki A.
        • Wright A.
        • Akolekar R.
        Fetal Medicine Foundation fetal and neonatal population weight charts.
        Ultrasound Obstet Gynecol. 2018; 52: 44-51
        • R Development Core Team
        R: a language and environment for statistical computing.
        R Foundation for Statistical Computing, Vienna, Austria2011 (Available at:) (Accessed January 6, 2020)
        • Bates D.
        • Maechler M.
        • Bolker B.
        • Walker S.
        Fitting linear mixed-effects models using lme4.
        J Stat Softw. 2015; 67: 1-48
        • Therneau T.M.
        A package for survival analysis in S. version 3.2-3.
        (Available at:)
        https://CRAN.R-project.org/package=survival
        Date: 2015
        Date accessed: January 6, 2020
        • Therneau T.M.
        Mixed effects Cox models. R package version 2.2-16.
        (Available at:)
        https://CRAN.R-project.org/package=coxme
        Date: 2019
        Date accessed: January 6, 2020
        • Revelle W.R.
        psych: procedures for psychological, psychometric, and personality research.
        (Available at:)
        https://CRAN.R-project.org/package=psych
        Date: 2017
        Date accessed: January 6, 2020
        • Romero R.
        • Stanczyk F.Z.
        Progesterone is not the same as 17α-hydroxyprogesterone caproate: implications for obstetrical practice.
        Am J Obstet Gynecol. 2013; 208: 421-426
        • Romero R.
        • Conde-Agudelo A.
        Is 17α-hydroxyprogesterone caproate contraindicated in twin gestations?.
        BJOG. 2015; 122: 6-7
        • Romero R.
        • Conde-Agudelo A.
        • El-Refaie W.
        • et al.
        Vaginal progesterone decreases preterm birth and neonatal morbidity and mortality in women with a twin gestation and a short cervix: an updated meta-analysis of individual patient data.
        Ultrasound Obstet Gynecol. 2017; 49: 303-314
        • Wright D.
        • Nicolaides K.H.
        Aspirin delays the development of preeclampsia.
        Am J Obstet Gynecol. 2019; 220: 580.e1-580.e6

      Linked Article

      • High dose progesterone for prevention of preterm birth in twins
        American Journal of Obstetrics & GynecologyVol. 224Issue 5
        • Preview
          We read with interest the recent randomized clinical trial comparing vaginal progesterone with placebo in women with twin pregnancies for the prevention of spontaneous preterm birth.1 We want to congratulate the authors on this large study that answers the question as to whether high dose vaginal progesterone reduces preterm birth in unselected women with a twin pregnancy: it does not. However, we have concerns regarding the study design, which downplays the potential of progesterone in women with short cervix.
        • Full-Text
        • PDF
      • High dose progesterone for prevention of preterm birth in twins
        American Journal of Obstetrics & GynecologyVol. 224Issue 5
        • Preview
          We thank McGannon et al1 for their letter. In the EVENTS trial, we found that in women with twin pregnancies universal administration of progesterone at a dose of 300 mg twice per day from 11 to 14 to 34 weeks’ gestation did not reduce the incidence of spontaneous birth between 24+0 and 33+6 weeks’ gestation.2 However, post hoc time-to-event analysis led to the suggestion that progesterone may reduce the risk of spontaneous birth at <32 weeks in women with first-trimester cervical length measurement of <30 mm.
        • Full-Text
        • PDF