Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in twin gestations: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy of vaginal progesterone for the prevention of preterm birth and adverse perinatal outcomes in twin gestations. DATA SOURCES: MEDLINE, Embase, LILACS, and CINAHL (from their inception to January 31, 2023), Cochrane databases, Google Scholar, bibliographies, and conference proceedings. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials that compared vaginal progesterone to placebo or no treatment in asymptomatic women with a twin gestation. METHODS: The systematic review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome was preterm birth <34 weeks of gestation. Secondary outcomes included adverse perinatal outcomes. Pooled relative risks with 95% confidence intervals were calculated. We assessed the risk of bias in each included study, heterogeneity, publication bias, and quality of evidence, and performed subgroup and sensitivity analyses. RESULTS: Eleven studies (3401 women and 6802 fetuses/infants) fulfilled the inclusion criteria. Among all twin gestations, there were no significant differences between the vaginal progesterone and placebo or no treatment groups in the risk of preterm birth <34 weeks (relative risk, 0.99; 95% confidence interval, 0.84-1.17; high-quality evidence), <37 weeks (relative risk, 0.99; 95% confidence interval, 0.92-1.06; high-quality evidence), and <28 weeks (relative risk, 1.00; 95% confidence interval, 0.64-1.55; moderate-quality evidence), and spontaneous preterm birth <34 weeks of gestation (relative risk, 0.97; 95% confidence interval, 0.80-1.18; high-quality evidence). Vaginal progesterone had no significant effect on any of the perinatal outcomes evaluated. Subgroup analyses showed that there was no evidence of a different effect of vaginal progesterone on preterm birth <34 weeks of gestation related to chorionicity, type of conception, history of spontaneous preterm birth, daily dose of vaginal progesterone, and gestational age at initiation of treatment. The frequencies of preterm birth <37, <34, <32, <30, and <28 weeks of gestation and adverse perinatal outcomes did not significantly differ between the vaginal progesterone and placebo or no treatment groups in unselected twin gestations (8 studies; 3274 women and 6548 fetuses/infants). Among twin gestations with a transvaginal sonographic cervical length <30 mm (6 studies; 306 women and 612 fetuses/infants), vaginal progesterone was associated with a significant decrease in the risk of preterm birth occurring at <28 to <32 gestational weeks (relative risks, 0.48-0.65; moderate- to high-quality evidence), neonatal death (relative risk, 0.32; 95% confidence interval, 0.11-0.92; moderate-quality evidence), and birthweight <1500 g (relative risk, 0.60; 95% confidence interval, 0.39-0.88; high-quality evidence). Vaginal progesterone significantly reduced the risk of preterm birth occurring at <28 to <34 gestational weeks (relative risks, 0.41-0.68), composite neonatal morbidity and mortality (relative risk, 0.59; 95% confidence interval, 0.33-0.98), and birthweight <1500 g (relative risk, 0.55; 95% confidence interval, 0.33-0.94) in twin gestations with a transvaginal sonographic cervical length ≤25 mm (6 studies; 95 women and 190 fetuses/infants). The quality of evidence was moderate for all these outcomes. CONCLUSION: Vaginal progesterone does not prevent preterm birth, nor does it improve perinatal outcomes in unselected twin gestations, but it appears to reduce the risk of preterm birth occurring at early gestational ages and of neonatal morbidity and mortality in twin gestations with a sonographic short cervix. However, more evidence is needed before recommending this intervention to this subset of patients.

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.

Aspirin for Evidence-Based Preeclampsia Prevention trial: influence of compliance on beneficial effect of aspirin in prevention of preterm preeclampsia.

BACKGROUND: The Aspirin for Evidence-Based Preeclampsia Prevention trial was a multicenter study in women with singleton pregnancies. Screening was carried out at 11-13 weeks' gestation with an algorithm that combines maternal factors and biomarkers (mean arterial pressure, uterine artery pulsatility index, and maternal serum pregnancy-associated plasma protein A and placental growth factor). Those with an estimated risk for preterm preeclampsia of >1 in 100 were invited to participate in a double-blind trial of aspirin (150 mg/d) vs placebo from 11-14 until 36 weeks' gestation. Preterm preeclampsia with delivery at <37 weeks' gestation, which was the primary outcome, occurred in 1.6% (13/798) participants in the aspirin group, as compared with 4.3% (35/822) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74). OBJECTIVE: We sought to examine the influence of compliance on the beneficial effect of aspirin in prevention of preterm preeclampsia in the Aspirin for Evidence-Based Preeclampsia Prevention trial. STUDY DESIGN: This was a secondary analysis of data from the trial. The proportion of prescribed tablets taken was used as an overall measure of compliance. Logistic regression analysis was used to estimate the effect of aspirin on the incidence of preterm preeclampsia according to compliance of <90% and ≥90%, after adjustment for the estimated risk of preterm preeclampsia at screening and the participating center. The choice of cut-off of 90% was based on an exploratory analysis of the treatment effect. Logistic regression analysis was used to investigate predictors of compliance ≥90% among maternal characteristics and medical history. RESULTS: Preterm preeclampsia occurred in 5/555 (0.9%) participants in the aspirin group with compliance ≥90%, in 8/243 (3.3%) of participants in the aspirin group with compliance <90%, in 22/588 (3.7%) of participants in the placebo group with compliance ≥90%, and in 13/234 (5.6%) of participants in the placebo group with compliance <90%. The odds ratio in the aspirin group for preterm preeclampsia was 0.24 (95% confidence interval, 0.09-0.65) for compliance ≥90% and 0.59 (95% confidence interval, 0.23-1.53) for compliance <90%. Compliance was positively associated with family history of preeclampsia and negatively associated with smoking, maternal age <25 years, Afro-Caribbean and South Asian racial origin, and history of preeclampsia in a previous pregnancy. CONCLUSION: The beneficial effect of aspirin in the prevention of preterm preeclampsia appears to depend on compliance.