What is the role of progesterone supplementation during early pregnancy?

Role of Progesterone Supplementation in Early Pregnancy

Progesterone supplementation in early pregnancy should be targeted to specific high-risk populations, as it is not beneficial for all pregnant women but can significantly reduce preterm birth in women with singleton pregnancies and prior spontaneous preterm birth or short cervical length. 1

Indications for Progesterone Supplementation

Recommended Uses:

• Women with singleton pregnancies and prior spontaneous preterm birth (SPTB): 17-alpha-hydroxyprogesterone caproate (17P) 250 mg IM weekly from 16-20 weeks until 36 weeks gestation 1
• Women with singleton pregnancies without prior SPTB but with short cervical length (≤20 mm): Vaginal progesterone 90-mg gel or 200-mg suppository daily from diagnosis until 36 weeks gestation 1, 2
• Women with history of recurrent miscarriage and current early pregnancy bleeding: Vaginal micronized progesterone has been shown to increase live birth rates compared to placebo (RR 1.08,95% CI 1.02 to 1.15) 3, 4

Not Recommended (No Evidence of Effectiveness):

• Women with singleton pregnancies without prior SPTB and normal cervical length 1
• Women with multiple gestations (twins, triplets) 1
• Women with preterm labor 1
• Women with preterm premature rupture of membranes (PPROM) 1

Progesterone Formulations and Dosing

For Preterm Birth Prevention:

• 17P: 250 mg IM weekly from 16-20 weeks until 36 weeks gestation for women with prior SPTB 1
• Vaginal Progesterone: 90-mg gel or 200-mg suppository daily from diagnosis of short cervical length until 36 weeks 1
• Oral Progesterone: 400 mg daily has shown some benefit but with less robust evidence than vaginal or IM formulations 5

For Threatened Miscarriage:

• Vaginal Micronized Progesterone: 400 mg twice daily until 16 completed weeks of pregnancy for women with previous miscarriage and current bleeding 6, 3
• Dydrogesterone: Has been studied but shows less consistent evidence compared to vaginal progesterone 4

Clinical Considerations and Monitoring

• Check progesterone levels at 16-20 weeks gestation for women with prior SPTB before initiating 17P therapy 2
• For women undergoing cervical length screening, check progesterone levels at 18-24 weeks gestation before starting vaginal progesterone therapy 2
• In women with prior SPTB who develop cervical shortening (<25 mm) despite 17P therapy, it is reasonable to continue 17P rather than switching to a different progesterone formulation 1

Important Caveats and Pitfalls

• Recent evidence suggests that progesterone supplementation for threatened miscarriage may only need to continue until 12 weeks rather than 16 weeks, as the beneficial effects appear complete by 12 weeks when placental progesterone production takes over 6
• For women with singleton pregnancies and no history of preterm birth, routine progesterone supplementation is not recommended 1
• Despite multiple studies, progesterone has not shown benefit for multiple gestations, even those with short cervical length 1
• Progesterone testing should be performed with proper technique to ensure accurate results 2
• In women with recurrent miscarriage but no current bleeding, vaginal micronized progesterone likely makes little or no difference to live birth rates (RR 1.04,95% CI 0.95 to 1.15) 4

Algorithm for Progesterone Use in Early Pregnancy

1. Assess risk factors:

   • History of spontaneous preterm birth?
   • Current cervical length measurement?
   • History of recurrent miscarriage?
   • Current early pregnancy bleeding?

2. For women with singleton pregnancy:

   • If prior SPTB → 17P 250 mg IM weekly (16-20 weeks until 36 weeks) 1
   • If no prior SPTB but CL ≤20 mm → Vaginal progesterone daily until 36 weeks 1
   • If prior miscarriage(s) and current bleeding → Vaginal progesterone until 12-16 weeks 6, 3

3. For women with multiple gestations:

   • Progesterone not recommended regardless of prior SPTB or cervical length 1