PURPOSE:

• The EPPPIC group (Lancet, 2021) report on their systematic review of RCTs comparing vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate (17-OHPC), or oral progesterone for prevention of preterm birth

METHODS:

• Systematic review and meta-analysis
  • Funded by Patient-Centered Outcomes Research Institute (PCORI)
  • Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC)
• Study selection
  • Published and unpublished RCTs
  • Trials that assessed vaginal progesterone, IM 17-OHPC or oral progesterone with control, or with each other
  • Participants: Asymptomatic women at risk of preterm birth
  • Individual participant data were requested from investigators of eligible trials
  • Primary data collection before July 30, 2016, (12 months before data collection began), and July 30, 2019
  • Exclusion: Trials of progestogen to prevent early miscarriage or immediatelythreatened preterm birth
• Outcomes
  • Preterm birth | Early preterm birth | Mid-trimester birth
  • Adverse neonatal sequelae (composite of serious neonatal complications and individually)
  • Adverse maternal outcomes were investigated as a composite and individually

RESULTS:

• Individual participant data available for 31 trials | 11,644 women and 16,185 offspring

Singleton

• Risk factors and indications for treatment
  • Previous spontaneous preterm birth
  • Short cervix (≤25 mm)
• Preterm birth <34 weeks was reduced in women receiving progestogen
  • Vaginal progesterone: Relative risk (RR) 0.78 (95% CI, 0.68 to 0.90; 9 trials)
  • 17-OHPC: RR 0.83 (95% CI, 0.68 to 1.01; 5 trials)
  • Oral progesterone: RR 0.60 (95% CI, 0.40 to 0.90; 2 trials)  
• Other outcomes “were consistently favourable, but less certain”
• Subpopulation analysis suggests benefit was greatest for those with short cervix

Multifetal Pregnancies

• Generally, no additional risk factors
• Preterm birth <34 was was not reduced in women receiving progestogen
  • Vaginal progesterone (twins): RR 1.10 (95% CI, 0.84 to 1.20; 8 trials)
  • 17-OHPC (twins or triplets): RR 1.04 (95% CI, 0.92 to 1.18; 8 trials)
• PPROM <34 weeks was higher with 17-OHPC
  • RR 1.59 (95% CI, 1.15 to 2.22
• Evidence for other outcomes (risks or benefits) was not seen for vaginal progesterone or 17-OHPC

CONCLUSION:

• Preterm birth <34 weeks was reduced with vaginal progesterone and 17-OHPC in high risk pregnancies
• Absolute risk reduction is greater for women with a short cervix
• Evidence in this study did not support use of oral progesterone or treatment for unselected multifetal pregnancy
• An editorial suggests
  • This current meta-analysis supports “the use of either 17-OHPC or vaginal progesterone to prolonged pregnancy, even with the inclusion of the negative findings from PROLONG”
  • There are other trials currently underway and therefore this study should be considered a ‘living’ meta-analysis
• The EPPPIC authors conclude

Evidence of benefit in reducing preterm birth before 34 weeks was more certain for vaginal progesterone, but there was no clear evidence that either vaginal progesterone or 17-OHPC was superior

A consistent direction of benefit was noted for other birth and neonatal outcomes, including preterm birth before 28 weeks, preterm birth before 37 weeks, perinatal mortality, and composite serious neonatal complications 

Response from SMFM and ACOG:

SMFM

• EPPPIC reinforces current SMFM guidelines
• Singleton pregnancy and a short cervix (<25 mm) without a history of a prior spontaneous preterm birth
  • Offer vaginal progesterone
• Singleton gestation and a history of prior spontaneous preterm birth between 20 weeks and 36w6d
  • SMFM recommends “consideration of the use of 17-OHPC”

ACOG

• ACOG notes that while 17-OHPC didn’t quite reach significance, the authors did not see a clear difference between route of administration, nor indication for treatment
• ACOG states

Patients with a singleton pregnancy and a prior spontaneous preterm birth should be offered progesterone supplementation (either vaginal or intramuscular) in the context of a shared-decision making process with the patient incorporating the available evidence and the patient’s preferences

With regard to multiple gestations, the Evaluating Progestogens for Preventing Preterm Birth International Collaborative (EPPPIC) findings support the current recommendation that progesterone supplementation is not indicated for the indication of multiple gestation alone as there is no evidence of benefit

Response from FDA:

• The FDA has responded to EPPPIC and has not altered the recommendation to withdraw approval from Makena
• The FDA states

The EPPPIC meta-analysis grouped together HPC trials of patients with differences in their risk profiles, including combining women with a prior PTB and those without a prior PTB, and women with and without a short cervix

Because of this grouping, the meta-analysis does not provide relevant information regarding Makena’s effectiveness for its approved use. CDER continues to conclude the available data have not shown Makena is effective for reducing morbidity or mortality in newborns or for the prevention of recurrent PTB in women with a prior spontaneous PTB 

Learn More – Primary Sources:

Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials

Lancet Editorial: Role of progestogens in women at risk for spontaneous preterm birth: the final word?

SMFM Statement: Response to EPPPIC and considerations of the use of progestogens for the prevention of preterm birth

ACOG Clinical Guidance for the Integration of the Findings of the EPPPIC Meta-Analysis: Evaluating Progestogens for Preventing Preterm Birth International Collaborative

FDA: CDER perspective on recently published results of EPPPIC meta-analysis

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Progesterone, Cerclage or Pessary for Prevention of Preterm Birth: A Comparison

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Do Progestogens Prevent Preterm Birth in Symptomatic Pregnancies with a Short Cervix?

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