Can early progesterone supplementation help maintain pregnancy in women with a history of recurrent miscarriages?

Progesterone Supplementation for Recurrent Miscarriage

Vaginal micronized progesterone (400 mg twice daily) is recommended for women with a history of one or more previous miscarriages who present with bleeding in early pregnancy, as this treatment increases live birth rates in this specific population. 1

Effectiveness Based on Clinical Scenario

For Women with Recurrent Miscarriage:

• For women with a history of recurrent miscarriage (three or more previous miscarriages) who present with bleeding in early pregnancy, vaginal micronized progesterone significantly increases live birth rates (72% vs 57%, a 15% absolute increase) compared to placebo 1
• For women with a history of one or more previous miscarriages and current pregnancy bleeding, vaginal micronized progesterone increases live birth rates (75% vs 70%, a 5% absolute increase) compared to placebo 1
• For women with unexplained recurrent miscarriage without current bleeding, progesterone therapy does not significantly improve live birth rates (65.8% vs 63.3%) compared to placebo 2, 3

For Women with Threatened Miscarriage:

• For women with threatened miscarriage (early pregnancy bleeding) but no history of previous miscarriage, progesterone supplementation likely makes little or no difference to live birth rates 4
• The benefit of progesterone increases with the number of previous miscarriages in women who present with bleeding in early pregnancy 1

Treatment Protocol

Recommended Regimen:

• Medication: Vaginal micronized progesterone 1
• Dosage: 400 mg twice daily 1
• Timing: Start as early as possible after positive pregnancy test and continue through at least 12 weeks of gestation 1, 2
• Target Population: Women with history of miscarriage(s) who present with bleeding in early pregnancy 1

Not Recommended:

• Progesterone is not recommended for women with threatened miscarriage who have no history of previous miscarriage 4
• Progesterone is not recommended as a routine preventive treatment for women with unexplained recurrent miscarriage who are not experiencing bleeding 2, 3

Clinical Considerations and Caveats

• The benefit of progesterone appears to be greatest in women with both risk factors: history of previous miscarriage AND current pregnancy bleeding 1
• The magnitude of benefit increases with the number of previous miscarriages, with the greatest benefit seen in women with three or more previous miscarriages 1
• No short-term safety concerns have been identified with vaginal micronized progesterone use in early pregnancy 1
• Different progesterone formulations may have different efficacy profiles; the evidence specifically supports vaginal micronized progesterone rather than other progestogens 4
• Treatment should be initiated as early as possible after pregnancy confirmation for maximum effectiveness 1, 2

Evidence Quality and Limitations

• The recommendations are based on high-quality evidence from large multicenter randomized controlled trials, particularly the PRISM trial which included over 4,000 women 1
• The subgroup analysis showing benefit in women with previous miscarriage and current bleeding fulfilled all criteria for credible subgroup analysis 1
• There is limited evidence on the comparative effectiveness of different progesterone formulations (vaginal vs. oral vs. injectable) 4
• Most studies have focused on first-trimester use; the optimal duration of therapy beyond 12 weeks is less well-established 1, 2