At what gestation should progesterone (17-alpha-hydroxyprogesterone caproate) therapy be initiated and what is the recommended dose and route in a patient with a history of previous preterm labor?

Progesterone Therapy for Prevention of Recurrent Preterm Birth

For patients with a history of previous preterm labor, 17-alpha-hydroxyprogesterone caproate (17OHP-C) should be administered at 250 mg intramuscularly weekly, starting at 16-20 weeks of gestation and continuing until 36 weeks of gestation or delivery. 1, 2

Recommended Regimen Based on Patient History

For Women with Prior Spontaneous Preterm Birth (20-36 6/7 weeks):

• Medication: 17OHP-C
• Dose: 250 mg
• Route: Intramuscular injection
• Frequency: Weekly
• Initiation: 16-20 weeks gestation
• Duration: Until 36 weeks gestation or delivery

Efficacy and Evidence

The Society for Maternal-Fetal Medicine (SMFM) strongly recommends 17OHP-C based on evidence from multiple randomized controlled trials 1. The landmark trial by Meis et al. demonstrated a 34% reduction in recurrent preterm birth with 17OHP-C treatment (from 54.9% to 36.3%) and significant reductions in infant complications 1.

Secondary analysis by gestational age shows that 17OHP-C is particularly effective for women with previous spontaneous preterm birth at <34 weeks. Women with earliest previous delivery at 20-27.9 weeks and 28-33.9 weeks delivered at significantly more advanced gestational ages when treated with 17OHP-C compared to placebo 3.

Alternative Approach

While vaginal progesterone has been suggested as an alternative by some recent studies 4, the SMFM guidelines explicitly state that "vaginal progesterone should not be considered a substitute for 17OHP-C" in women with a history of prior spontaneous preterm birth 1. This recommendation is based on multiple RCTs showing no significant benefit of vaginal progesterone in this specific population.

Special Considerations

Cervical Length Monitoring

• Approximately 69% of women with prior spontaneous preterm birth maintain cervical length >25mm throughout pregnancy 1
• If cervical shortening (≤25 mm) develops while on 17OHP-C:
  • Continue 17OHP-C therapy rather than switching to vaginal progesterone 1, 2
  • Consider cervical cerclage if cervical length ≤15 mm 2

Important Caveats

1. Timing matters: Starting progesterone therapy at 16-20 weeks is critical for efficacy. Starting too late may reduce effectiveness.
2. Patient selection: The evidence supports 17OHP-C specifically for singleton pregnancies with prior spontaneous preterm birth between 20-36 6/7 weeks.
3. Not recommended for:
   • Multiple gestations (twins, triplets)
   • Preterm labor (for tocolysis)
   • Preterm premature rupture of membranes
   • Singleton pregnancies without prior spontaneous preterm birth or short cervix 2

Side Effects

Intramuscular 17OHP-C may cause local injection site pain and requires weekly office visits, while vaginal progesterone has fewer systemic side effects and allows for self-administration 2. However, efficacy should be prioritized over convenience in this high-risk population.

Conclusion

The evidence strongly supports using 17OHP-C 250 mg intramuscularly weekly from 16-20 weeks until 36 weeks for women with singleton pregnancies and prior spontaneous preterm birth. This approach has been shown to significantly reduce the risk of recurrent preterm birth and associated neonatal complications.