What is the role of progesterone in pregnancy disorders?

Role of Progesterone in Pregnancy Disorders

Progesterone supplementation is recommended for specific high-risk populations, including women with prior spontaneous preterm birth (using 17-alpha-hydroxyprogesterone caproate) and women with short cervical length (using vaginal progesterone), but is not beneficial for multiple gestations, preterm labor, or preterm premature rupture of membranes. 1

Physiological Role of Progesterone in Pregnancy

Progesterone is essential for pregnancy establishment and maintenance through several mechanisms:

• Maintains myometrial quiescence by counteracting prostaglandin stimulatory activity and oxytocin 2
• Provides immunomodulation that prevents rejection of the allogeneic fetus 3
• Supports proper decidualization and endometrial development 2
• Promotes trophoblast invasion by inhibiting apoptosis of extravillous trophoblasts 2
• Increases ventilation by 20-40% above baseline by term, producing mild respiratory alkalosis 4

Evidence-Based Indications for Progesterone Supplementation

For Preterm Birth Prevention

Women with Prior Spontaneous Preterm Birth

• 17-alpha-hydroxyprogesterone caproate (17P) 250 mg IM weekly from 16-20 weeks until 36 weeks is the preferred treatment 4, 1
• In a landmark study of 463 women with singleton gestation and prior spontaneous preterm birth, 17P reduced preterm birth <37 weeks (RR 0.66), preterm birth <32 weeks, and neonatal complications 4

Women with Short Cervical Length

• Vaginal progesterone 90 mg gel or 200 mg suppository daily is recommended for women with cervical length ≤20 mm on transvaginal ultrasound 4, 1
• Significant reduction in preterm birth and perinatal morbidity/mortality has been demonstrated in women with singleton gestations and short cervical length 4

For Threatened and Recurrent Miscarriage

• Vaginal micronized progesterone shows benefit primarily in women with previous miscarriage(s) and current pregnancy bleeding 1, 5
• Most significant benefit observed in women with ≥3 previous miscarriages and current bleeding (72% vs 57% live birth rate) 1, 5
• For women with recurrent miscarriage without bleeding, evidence suggests progesterone makes little difference to live birth rates 6

Populations That Do Not Benefit from Progesterone

Progesterone supplementation is not recommended for:

• Multiple gestations (twins, triplets) without other risk factors 4, 1
• Preterm labor (for tocolysis) 4, 1
• Preterm premature rupture of membranes (PPROM) 4, 1
• Singleton pregnancies without prior spontaneous preterm birth or short cervix 4, 1
• Threatened miscarriage in women without history of previous miscarriage 1

Clinical Algorithm for Progesterone Use in Pregnancy

1. For women with singleton gestation and prior spontaneous preterm birth (20-36 6/7 weeks):

   • Start 17P 250 mg IM weekly at 16-20 weeks until 36 weeks
   • If cervical length shortens to ≤25 mm at 24 weeks, consider adding cervical cerclage

2. For women with singleton gestation, no prior preterm birth, but short cervical length ≤20 mm:

   • Start vaginal progesterone 90 mg gel or 200 mg suppository daily until 36 weeks

3. For women with history of miscarriage(s) and current pregnancy bleeding:

   • Consider vaginal micronized progesterone 400 mg twice daily

Common Pitfalls and Considerations

• Inappropriate use: Avoid progesterone in multiple gestations, as it shows no benefit in preventing preterm birth in twins or triplets 4, 1
• Timing matters: For preterm birth prevention, start 17P at 16-20 weeks, not earlier or later 4
• Route of administration: Different routes (IM, vaginal, oral) have different efficacy profiles; don't substitute one for another without evidence 1
• Monitoring: No need to routinely monitor serum progesterone levels during supplementation 1
• Duration: After 8-10 weeks of pregnancy, the placenta produces sufficient progesterone to maintain pregnancy 1
• Side effects: Progesterone may cause fluid retention, requiring careful observation in women with cardiac or renal dysfunction 7
• Individual variability: Plasma concentrations vary substantially between individuals receiving identical doses 1

By following this evidence-based approach to progesterone supplementation, clinicians can appropriately target high-risk populations who will benefit most while avoiding unnecessary treatment in those unlikely to benefit.