Prenatal Administration of Progesterone for Preventing Preterm Birth

In women at increased risk of preterm birth, vaginal progesterone appears to reduce the risk of perinatal mortality, preterm birth less than 37 weeks' gestation, and infant birthweight less than 2500 grams compared to placebo. Level of evidence: "B"

A meta-analysis 2 included 5 hihg-quality trials with a total of 974 women (498 allocated to vaginal progesterone, 476 allocated to placebo) with a cervical length HASH(0x2fd8d10)25 mm. Vaginal progesterone was associated with a significant reduction in the risk of preterm birth <33 weeks of gestation (RR 0.62; 95% CI 0.47 to 0.81; P = .0006). Moreover, vaginal progesterone significantly decreased the risk of preterm birth <36, <35, <34, <32, <30, and <28 weeks of gestation; spontaneous preterm birth <33 and <34 weeks of gestation; respiratory distress syndrome; composite neonatal morbidity and mortality; birthweight <1500 and <2500 g; and admission to the neonatal intensive care unit (RR 0.47 to 0.82). There were 7 (1.4%) neonatal deaths in the vaginal progesterone group and 15 (3.2%) in the placebo group (RR, 0.44; 95% CI 0.18 to 1.07; P = .07). Maternal adverse events, congenital anomalies, and adverse neurodevelopmental and health outcomes at 2 years of age did not differ between groups.

Another meta-analysis 3 included 5 trials comparing vaginal progesterone vs placebo (265 women) and 5 comparing cerclage vs no cerclage (504 women). Vaginal progesterone, compared to placebo, significantly reduced the risk of preterm birth <35 and <32 weeks of gestation, composite perinatal morbidity/mortality, neonatal sepsis, composite neonatal morbidity, and admission to the neonatal intensive care unit (RRs from 0.29 to 0.68). Cerclage, compared to no cerclage, significantly decreased the risk of preterm birth <37, <35, <32, and <28 weeks of gestation, composite perinatal morbidity/mortality, and birthweight <1500 g (RRs from 0.64 to 0.70). Adjusted indirect comparison meta-analyses did not show statistically significant differences between vaginal progesterone and cerclage in the reduction of preterm birth or adverse perinatal outcomes.

A third meta-analysis 4 inclucded 36 trials (9425 women; 25 low risk of bias trials). Progesterone ranked first or second for most outcomes, reducing preterm birth (PTB) < 34 weeks [odds ratio (OR) 0.44; 95% credible interval (CrI) 0.22 to 0.79; NNT 9; low quality], <37 weeks (OR 0.58; 95% CrI 0.41 to 0.79; NNT 9; moderate quality), and neonatal death (OR 0.50; 95% CrI 0.28 to 0.85; NNT 35; high quality), compared with control, in women overall at risk. There was similar results in the subgroup with previous PTB, but only a reduction of PTB < 34 weeks in women with a short cervix. Pessary showed inconsistent benefit and cerclage did not reduce PTB < 37 or <34 weeks.

A Cochrane review [Abstract] 1 included 36 studies with a total of 8 523 women and 12 515 infants. Intramuscular progesterone was examined in 7 studies and vaginal progesterone in 4 studies. As the aetiology of preterm birth is multifactorial, results are presented according to the reason considered to be at risk for preterm birth. Progesterone was compared with placebo or no treatment.

Progesterone compared to placebo for women with a past history of spontaneous preterm birth was associated with a statistically significant reduction in the risk of perinatal mortality (RR 0.50, 95% CI 0.33 to 0.75; 6 trials, n=1453); preterm birth less than 34 weeks' gestation (RR 0.31, 95% CI 0.14 to 0.69); 5 trials, n=602); infant birthweight less than 2500 grams (RR 0.58, 95% CI 0.42 to 0.79; 4 trials, n=692 infants); preterm birth less than 37 weeks (RR 0.55, 95% CI 0.42 to 0.74; 10 trials; n=1750) and, a statistically significant increase in pregnancy prolongation in weeks (mean difference (MD) 4.47, 95% CI 2.15 to 6.79; 1 trial, n=148). No differential effects in terms of route of administration, time of commencing therapy and dose of progesterone were observed for the majority of outcomes examined. Progesterone for women with a short cervix identified on ultrasound was associated with a statistically significant reduction in the risk of preterm birth less than 34 weeks (RR 0.64, 95% CI 0.45 to 0.90; 2 trials, n=438); preterm birth at less than 28 weeks' gestation (RR 0.59, 95% CI 0.37 to 0.93; 2 trials, n=1115) and increased risk of urticaria in women when compared with placebo. Progesterone was associated with no statistically significant differences for the reported outcomes in multiple pregnancies. Progesterone given for women following presentation with threatened preterm labour or other' risk factors for preterm birth was associated with a reduction in the risk of preterm birth less than 37 weeks.

Comment: The quality of evidence is downgraded by risk of bias (unclear sequence generation or a allocation concealment, and no blinding of outcome assessment in many studies).

References

• Dodd JM, Jones L, Flenady V et al. Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Cochrane Database Syst Rev 2013;(7):CD004947. [PubMed]
• 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(2):161-180. [PubMed]
• 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. Am J Obstet Gynecol 2018;219(1):10-25.[PubMed]
• Jarde A, Lutsiv O, Park CK et al. Effectiveness of progesterone, cerclage and pessary for preventing preterm birth in singleton pregnancies: a systematic review and network meta-analysis. BJOG 2017;124(8):1176-1189. [PubMed]