What is the role of progesterone supplementation in a woman with a history of miscarriages during early pregnancy?

Progesterone Supplementation for Preventing Miscarriage

For women with a history of recurrent miscarriages, 17-alpha hydroxyprogesterone caproate (17OHP-C) at 250 mg intramuscularly weekly, starting at 16-20 weeks of gestation until 36 weeks of gestation, is recommended for singleton pregnancies with prior spontaneous preterm birth, while vaginal micronized progesterone (400 mg twice daily) is recommended for women with both previous miscarriage(s) and current pregnancy bleeding. 1, 2

Treatment Recommendations Based on Clinical Scenario

For Women with History of Preterm Birth (20-36 6/7 weeks):

• First-line therapy: 17OHP-C at 250 mg intramuscularly weekly 1
• When to start: 16-20 weeks of gestation
• When to stop: 36 weeks of gestation or delivery
• Important note: Vaginal progesterone should not be considered a substitute for 17OHP-C in these patients 1

For Women with Current Bleeding AND Previous Miscarriage(s):

• First-line therapy: Vaginal micronized progesterone 400 mg twice daily 2, 3
• When to start: At first presentation with bleeding
• When to stop: Until 16 weeks of gestation (though evidence suggests benefit may be complete by 12 weeks) 4
• Efficacy: Increases live birth rate by 5% overall (75% vs 70%) 3
• Greater benefit: In women with 3+ previous miscarriages and current bleeding (15% increase in live birth rate: 72% vs 57%) 3

For Women with Short Cervix (≤20 mm) Without Prior Preterm Birth:

• Recommended therapy: Vaginal progesterone 1
• Dosage options: 90 mg gel or 200 mg suppository daily 5

Evidence Quality and Treatment Efficacy

For Recurrent Miscarriage:

• High-quality evidence from the PROMISE trial (836 women) showed vaginal micronized progesterone made little difference to live birth rates in women with unexplained recurrent miscarriage without current bleeding (RR 1.04,95% CI 0.95 to 1.15) 6

For Threatened Miscarriage (Current Bleeding):

• The PRISM trial (4153 women) demonstrated significant benefit in the subgroup of women with both previous miscarriage(s) and current bleeding 3
• Stronger effect observed with increasing number of previous miscarriages:
  • 1+ previous miscarriages: 5% increase in live births (RR 1.09,95% CI 1.03-1.15) 2
  • 3+ previous miscarriages: 15% increase in live births (RR 1.28,95% CI 1.08-1.51) 2

For Preterm Birth Prevention:

• The Society for Maternal-Fetal Medicine (SMFM) strongly recommends 17OHP-C for women with prior spontaneous preterm birth 1
• Multiple RCTs have failed to show benefit of vaginal progesterone in preventing recurrent preterm birth in women with history of prior spontaneous preterm birth 1

Safety Considerations

• No significant short-term safety concerns identified in the PROMISE and PRISM trials 2
• No increased rates of:
  • Congenital abnormalities (RR 0.70,95% CI 0.10 to 4.82) 7
  • Pregnancy-induced hypertension (RR 1.00,95% CI 0.54 to 1.88) 7
  • Antepartum hemorrhage (RR 0.76,95% CI 0.30 to 1.94) 7

Common Pitfalls and Caveats

1. Duration of treatment: While NICE guidelines recommend continuing vaginal progesterone until 16 weeks, evidence suggests the full effect may be present by 12 weeks when placental production of progesterone is established 4

2. Not substituting treatments: Vaginal progesterone should not be substituted for 17OHP-C in women with prior spontaneous preterm birth 1

3. Continuing 17OHP-C despite cervical shortening: For women on 17OHP-C who develop cervical shortening, continue 17OHP-C rather than switching to vaginal progesterone 1

4. Timing matters: Progesterone supplementation appears most effective when started early in pregnancy for women with bleeding and previous miscarriage(s) 3

5. No benefit in certain populations: Women with no previous miscarriages who develop early pregnancy bleeding show little to no benefit from progesterone supplementation (RR 0.99,95% CI 0.95 to 1.04) 6

By following these evidence-based recommendations, clinicians can appropriately prescribe progesterone supplementation to reduce the risk of miscarriage in women with specific risk factors, particularly those with both previous miscarriage(s) and current pregnancy bleeding.