What is the role of progesterone (a hormone) in managing early pregnancy loss?

Progesterone for Early Pregnancy Loss

Progesterone supplementation is NOT routinely recommended for early pregnancy loss prevention based solely on symptoms or hormone levels, but it IS indicated for specific high-risk populations: women with prior spontaneous preterm birth and women with sonographically short cervix. 1

Critical Distinction: Early Pregnancy Loss vs. Preterm Birth Prevention

The evidence base for progesterone primarily addresses preterm birth prevention, not first-trimester miscarriage prevention. 2 The guidelines from ACOG and SMFM do not recommend routine progesterone supplementation based on low serum progesterone levels or for general miscarriage prevention. 1

Evidence-Based Indications for Progesterone

For Preterm Birth Prevention (NOT Early Miscarriage)

Singleton pregnancy with prior spontaneous preterm birth (20-36 6/7 weeks):

• 17-alpha-hydroxyprogesterone caproate (17P) 250 mg IM weekly from 16-20 weeks until 36 weeks 2, 3
• This is the preferred formulation based on stronger evidence than vaginal progesterone 2

Singleton pregnancy WITHOUT prior preterm birth but with short cervical length ≤20 mm at 18-24 weeks:

• Vaginal progesterone 90-mg gel or 200-mg suppository daily from diagnosis until 36 weeks 2, 3

For Threatened Miscarriage (First Trimester Bleeding)

The evidence here is more nuanced and shows important subgroup effects:

Women with early pregnancy bleeding AND one or more prior miscarriages:

• Vaginal micronized progesterone 400 mg twice daily may increase live birth rates (RR 1.09,95% CI 1.03 to 1.15) 4, 5
• The PRISM trial showed a significant benefit in this subgroup (75% vs 70% live birth rate) 5

Women with early pregnancy bleeding but NO prior miscarriages:

• Vaginal progesterone probably makes little or no difference (RR 0.99,95% CI 0.95 to 1.04) 4, 5

Women with three or more prior miscarriages (recurrent miscarriage) and current bleeding:

• Vaginal progesterone shows the strongest effect (72% vs 57% live birth rate; RR 1.28,95% CI 1.08 to 1.51) 5

What Does NOT Work

Multiple gestations (twins, triplets):

• No evidence of effectiveness for progesterone supplementation 2, 3

Active preterm labor:

• No evidence of effectiveness 2

Preterm premature rupture of membranes (PPROM):

• No evidence of effectiveness 2, 3

Recurrent miscarriage without current bleeding:

• Vaginal micronized progesterone probably makes little or no difference (RR 1.04,95% CI 0.95 to 1.15) 4

Safety Profile

Congenital abnormalities:

• Vaginal micronized progesterone shows no increased risk for threatened miscarriage (RR 1.00,95% CI 0.68 to 1.46) 4
• Evidence for recurrent miscarriage is low-certainty but suggests no increased risk (RR 0.75,95% CI 0.31 to 1.85) 4

Adverse drug events:

• No significant difference compared to placebo for threatened miscarriage (RR 1.07,95% CI 0.81 to 1.39) 4

Clinical Algorithm

Step 1: Identify the clinical scenario

• Prior spontaneous preterm birth? → Use 17P starting at 16-20 weeks 2
• Short cervix (≤20 mm) at 18-24 weeks without prior PTB? → Use vaginal progesterone 2
• First trimester bleeding with prior miscarriage(s)? → Consider vaginal progesterone 400 mg twice daily 4, 5
• First trimester bleeding without prior miscarriage? → Progesterone unlikely to help 4, 5

Step 2: Do NOT base decisions on:

• Serum progesterone levels (not recommended for testing or treatment decisions) 1, 6
• Routine supplementation without specific risk factors 1

Critical Pitfalls to Avoid

Do not confuse preterm birth prevention with early miscarriage prevention - these are different clinical entities with different evidence bases. 2, 1

Do not use progesterone in multiple gestations - multiple large trials show no benefit and this wastes resources. 2

Do not check serum progesterone levels - current guidelines do not support this practice for treatment decisions. 1, 6

Recognize the subgroup effect in threatened miscarriage - benefit is primarily in women with prior miscarriage history, not first-time bleeders. 4, 5