Oral Progesterone in Pregnancy: Indication and Dosing
Primary Recommendation
Oral progesterone 400 mg daily is recommended for preventing preterm birth in singleton pregnancies, though vaginal progesterone (90-mg gel or 200-mg suppository) is the preferred route based on stronger evidence for preterm birth prevention. 1, 2
Specific Clinical Indications
1. Preterm Birth Prevention (Primary Indication)
For singleton pregnancies with short cervical length (≤20 mm) at 18-24 weeks:
- Oral progesterone 400 mg daily can be used, though vaginal administration has more robust evidence 2
- Treatment continues from diagnosis until 34-37 weeks of gestation 2
- Important caveat: Women with prior spontaneous preterm birth should receive 17-alpha-hydroxyprogesterone caproate (17P) 250 mg IM weekly instead, as this is the recommended first-line therapy for this population 1, 3
2. Threatened Miscarriage with Risk Factors
For women with early pregnancy bleeding AND history of previous miscarriage(s):
- Micronized progesterone 400 mg twice daily (800 mg total daily dose) is recommended 4
- Greatest benefit seen in women with ≥3 prior miscarriages and current bleeding (live birth rate increased from 57% to 72%) 4
- Treatment should begin in first trimester when bleeding occurs 4
3. Recurrent Pregnancy Loss
For women with unexplained recurrent miscarriages:
- Progesterone 400 mg daily or twice daily can be considered 4, 5
- Evidence shows increasing benefit with higher number of previous losses 4
- Treatment typically initiated in first trimester 4
Key Clinical Distinctions by Population
Singleton Pregnancy WITHOUT Prior Preterm Birth:
- If short cervix detected: Vaginal progesterone preferred (90-mg gel or 200-mg suppository daily) 1, 6
- Oral progesterone 400 mg daily is an alternative with less robust evidence 2
- Do NOT use 17P in this population - it has not shown benefit 1
Singleton Pregnancy WITH Prior Spontaneous Preterm Birth:
- 17P 250 mg IM weekly is the recommended therapy (NOT oral progesterone) 1, 3
- Start at 16-20 weeks, continue until 36 weeks 1, 3
- If cervical length shortens to ≤25 mm, consider adding cerclage 1
Multiple Gestations:
- Progestogens (including oral) are NOT recommended - no evidence of benefit 1
- This applies regardless of cervical length or prior preterm birth history 1
Populations Where Oral Progesterone Should NOT Be Used
Avoid oral progesterone in:
- Active preterm labor (insufficient evidence for tocolysis) 1
- Preterm premature rupture of membranes (no evidence of benefit) 1
- Twin or triplet pregnancies (multiple RCTs showed no benefit) 1
- Women with prior preterm birth as primary prevention (use 17P instead) 1
Common Clinical Pitfalls
Pitfall #1: Using oral progesterone instead of 17P for women with prior spontaneous preterm birth
- Solution: Always use 17P 250 mg IM weekly for this specific population 1
Pitfall #2: Prescribing progesterone for multiple gestations
- Solution: Recognize that all progestogen formulations have failed to show benefit in twins/triplets 1
Pitfall #3: Using progesterone as primary tocolysis
- Solution: Insufficient evidence supports this use; standard tocolytics remain first-line 1
Pitfall #4: Incorrect dosing for threatened miscarriage
- Solution: Use 400 mg twice daily (800 mg total) for women with bleeding and prior losses, not the lower 400 mg daily dose 4
Route Comparison for Preterm Birth Prevention
Vaginal progesterone has superior evidence over oral:
- Multiple RCTs demonstrate reduction in preterm birth <33 weeks and perinatal morbidity/mortality with vaginal administration 1
- Oral progesterone has "less robust evidence" per ACOG 2
- When both are available, vaginal route should be preferred 1, 6