Early vaginal progesterone versus placebo in twin pregnancies for the prevention of spontaneous preterm birth: a randomized, double-blind trial.
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2021
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American Journal of Obstetrics and Gynecology
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Abstract
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 in singletons and in this respect all twins are at increased risk of preterm birth. However, six trials in unselected twin pregnancies reported that vaginal progesterone from mid-gestation 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 which 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-blinded trial (EVENTS) was designed to test
the hypothesis that, among women with twin pregnancies, vaginal progesterone at a dose of 600
mg per day from 11-14 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.
Methods: 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 participating center.
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 incidence of spontaneous birth between 24+0 and 33+6
weeks’ gestation between the progesterone and placebo groups, adjusting for the effect of
participating centre, chrorionicity, parity and method of conception. Prespecified tests of
treatment interaction effects with chrorionicity, 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 1,194 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)
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, chrorionicity, parity and
method of conception, 1.35; 95% CI 0.88 - 2.05; p=0.17). There was no evidence of interaction
between the effects of treatment and chorionicity (p=0.28), parity (p=0.35) method of conception
(p=0.56) and adherence (p=0.34); however, there was weak evidence of an interaction with
cervical length (p=0.08) suggestive of harm to those with cervical length ≥30 mm (odds ratio
1.61, 95% CI 1.01-2.59) and potential benefit for those with cervical length <30 mm (odds ratio
0.56; 95% CI 0.20-1.60). There was no evidence of difference between the two treatment groups
for stillbirth or neonatal death; neonatal complications; neonatal therapy; and poor fetal growth. In
the progesterone group there were 1.4% (8/582) women and 1.9% (22/1,164) fetuses with at
least one serious adverse event; the respective numbers for the placebo group were 1.2%
(7/587) and 3.2% (37/1,174) (p=0.80 and p=0.06, 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% CI 0.08 - 0.69).
Conclusions: 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 <32 weeks in women with cervical length <30 mm and it may increase the risk
for those with cervical length ≥30 mm.
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Keywords
Cervical length, Preterm birth, Twin pregnancy, Progesterone, Randomized trial